Robert L. Barbieri, MD

All obstetrician-gynecologists know that pregnant patients who are Rh negative and exposed to a sufficient quantity of fetal red blood cells expressing Rh D antigen may become sensitized, producing Rh D antibodies that adversely impact future pregnancies with an Rh D-positive fetus, potentially causing hemolytic disease of the fetus and newborn. In countries where Rh D immune globulin is available, there is a consensus recommendation to administer Rh D immune globulin to Rh-negative pregnant patients at approximately 28 weeks’ gestation and at birth in order to decrease the risk of alloimmunization and hemolytic disease of the fetus and newborn in future pregnancies.¹ In contrast to this global consensus, there is no worldwide agreement about how to manage Rh testing and Rh D immune globulin administration in cases of early pregnancy loss or abortion care before 12 weeks’ gestation. This editorial examines the evolving guidelines of major professional societies.

Guidelines consistent with the routine use of Rh D immune globulin in all cases of early pregnancy loss and abortion care

As of the publication date of this editorial, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on prevention of Rh D alloimmunization provides the following guidance based on consensus and expert opinion²:

• “Although the risk of alloimmunization is low, the consequences can be significant, and administration of Rh D immune globulin should be considered in cases of spontaneous first trimester miscarriage, especially those that are later in the first trimester.”
• “Because of the higher risk of alloimmunization, Rh D-negative women who have instrumentation for their miscarriage should receive Rh D immune globulin prophylaxis.”
• “Rh D immune globulin should be given to Rh D-negative women who have pregnancy termination either medical or surgical.”

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends that, “After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, non-sensitized D-negative women should be given a minimum anti-D of 120 µg.”³

The liberal use of Rh D immune globulin in all cases of early pregnancy loss and abortion care is based, in part, on the following considerations:

1. the recognized safety of Rh D immune globulin administration^2,3
2. the report that fetal megaloblasts may express Rh antigen as early as 38 days of gestation⁴
3. the observation that 0.1 mL of Rh D-positive red cells may provoke an immune response in some Rh D-negative patients^5-7
4. the estimate that in some patients with threatened miscarriage a significant quantity of fetal blood may enter the maternal circulation.⁸

Guidelines that suggest restricted use of Rh D immune globulin before 7 to 8 weeks’ gestation

The Reproductive Care Program of Nova Scotia guideline from 2022 notes that “the benefits of administering Rh immune globulin before 8 weeks gestation have not been demonstrated.” Given the burden of Rh testing and Rh D immune globulin administration they suggest that clinicians may withhold Rh testing and Rh D immune globulin administration in cases less than 8 weeks’ gestation (less than 56 days) for spontaneous, threatened, or medication abortions if there is reliable pregnancy dating.⁹

The Dutch Association of Abortion Specialists guidelines from 2018 suggest to not provide Rh D immune globulin treatment in the following clinical situations: patients under 10 weeks’ gestation with spontaneous miscarriage or patients under 7 weeks’ gestation having an induced abortion.¹⁰

Continue to: Guidelines that suggest restricted use of Rh D immune globulin before 10 to 12 weeks’ gestation...

There are a growing number of guidelines that recommend restricting the use of Rh testing and Rh D immune globulin treatment in the management of early miscarriage and induced abortion. In 2019, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended that for patients having a spontaneous miscarriage, Rh testing and Rh D immune globulin are not necessary before 10 weeks 0 days of gestation.¹¹ In addition, NICE recommends, “Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks’ gestation.…Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks’ gestation.”¹¹

In 2019, the National Abortion Federation (NAF) Clinical Policies Committee recommended that “…it is reasonable to forgo Rh testing and anti-D immunoglobulin for women having any type of induced abortion before 8 weeks from the last menstrual period. Prior to 8 weeks, the likelihood of fetal-maternal hemorrhage adequate to cause sensitization is negligible. Given that medication abortion is more similar to spontaneous abortion with less risk of fetal-maternal hemorrhage, forgoing Rh testing and anti-D immunoglobulin for medication abortion under 10 weeks may be considered.”¹² In 2022, NAF noted, “Emerging epidemiologic and clinical evidence indicates that the risk of maternal-fetal hemorrhage caused by early abortion is negligible and Rh testing and provision of Rh immune globulin may not be necessary. It is reasonable to forego Rh testing and anti-D immunoglobulin for people having any type of abortion before 56 days and medication abortion before 70 days since the last menstrual period. The pregnancy dating at which people need Rh testing and anti-D immunoglobulin is not well established. Foregoing Rh testing and anti-D immunoglobulinfor those using medication abortion through 11 to 12 weeks may be considered.”¹³

In 2020 the International Federation of Gynaecology and Obstetrics (FIGO) Committee for Safe Motherhood and Newborn Health recommended, “The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK’s National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 and 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.”¹⁴

In 2022 the Royal College of Obstetricians and Gynaecologists recommended that for induced abortion, medication or surgical, “a determination of Rhesus blood status may be considered if the duration of pregnancy is over 12 weeks and anti-D is available.”¹⁵ “If available, anti-D should be offered to non-sensitised RhD-negative individuals from 12 weeks of pregnancy and provided within 72 hours of the abortion.”¹⁵

In 2022, the Society of Family Planning recommended that “Rh testing and administration are not recommended prior to 12 weeks gestation for patients undergoing spontaneous, medication or uterine aspiration abortion.” “For patients under 12 weeks gestation, although not recommended, Rh testing and Rh D immune globulin administration may be considered at patient request as part of a shared decision making process.”¹⁶

In 2022, the World Health Organization (WHO) reported “There are few studies examining Rh isoimmunization in unsensitized Rh-negative individuals seeking abortion before 12 weeks of gestation.” “The evidence on the effectiveness of the intervention may favor the intervention, because fewer women in the intervention group (anti-D administration) had antibody formation after the initial pregnancy compared to women in the comparison group (no anti-D) and no harms (undesirable effects) of the intervention were noted.”¹⁷ The evidence referenced for these statements are two low-quality studies from 1972.^18,19 The WHO continues, “…after consideration of the resources required, cost-effectiveness and feasibility of administering anti-D, as well as the very low certainty of evidence on effectiveness, the expert panel concluded that overall, the evidence does not favor the intervention and decided to recommend against it for gestational ages < 12 weeks, rather than < 9 weeks, as mentioned in the 2012 guidance.”¹⁷ In conclusion, the WHO recommended that “for both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration.”¹⁷

Guidelines that recommend restricted use of Rh D immune globulin during the first trimester, are based, in part, on the following considerations:

• there are no high-quality clinical trials demonstrating the benefit of Rh D immune globulin treatment in first trimester miscarriage and abortion care
• the Kleihauer-Betke technique cannot distinguish between maternal red blood cells expressing fetal hemoglobin (maternal F cells) and fetal cells, which has resulted in the over-estimation of the number of fetal cells in the maternal circulation²⁰
• using a dual-label flow cytometry method that distinguishes maternal F cells and fetal red blood cells, maternal F cells usually far outnumber fetal red blood cells in the maternal circulation in the first trimester²⁰
• among women in the first trimester undergoing uterine aspiration, the number of fetal cells in the maternal circulation is very low both before and after the procedure²⁰
• Rh testing and Rh immune globulin administration is burdensome and expensive.¹⁶

Implications for your practice

The fundamental reason for the proliferation of divergent guidelines is that there is no evidence from high-quality randomized clinical trials demonstrating that Rh testing and Rh D immune globulin treatment in early pregnancy miscarriage or induced abortion care reduces the risk of hemolytic disease of the fetus and newborn. The Cochrane review on Rh D immune globulin administration for preventing alloimmunization among patients with spontaneous miscarriage concluded, “There are insufficient data available to evaluate the practice of anti-D administration in an unsensitized Rh-negative mother after spontaneous miscarriage.”²¹

Given divergent guidelines, obstetrician-gynecologists must decide on which guideline to use in their practice. Clinicians may conclude that absent high-quality evidence from clinical trials, they will continue to use the ACOG/SOGC guidelines^2,3 in their practice, providing universal Rh testing and Rh D immune globulin treatment for all miscarriages and abortions, regardless of the gestational age. Other clinicians may conclude that Rh testing and Rh D immune globulin is not warranted before 8 to 12 weeks’ gestation, because the number of fetal red blood cells in the maternal circulation in cases of miscarriage and induced abortion is too low in early pregnancy to induce a maternal immune response.²² Based on recent studies demonstrating a low number of fetal red blood cells in the maternal circulation in the first trimester, family planning specialists are reducing the use of Rh testing and Rh immune globulin administration in both early pregnancy medication abortion and uterine aspiration abortion.¹⁶ With regard to Rh testing and Rh D immune globulin treatment, the future will definitely be different than the past. It is likely that many clinicians will reduce the use of Rh testing and Rh D immune globulin treatment in patients with miscarriage or induced abortion in early pregnancy. ●

All obstetrician-gynecologists know that pregnant patients who are Rh negative and exposed to a sufficient quantity of fetal red blood cells expressing Rh D antigen may become sensitized, producing Rh D antibodies that adversely impact future pregnancies with an Rh D-positive fetus, potentially causing hemolytic disease of the fetus and newborn. In countries where Rh D immune globulin is available, there is a consensus recommendation to administer Rh D immune globulin to Rh-negative pregnant patients at approximately 28 weeks’ gestation and at birth in order to decrease the risk of alloimmunization and hemolytic disease of the fetus and newborn in future pregnancies.¹ In contrast to this global consensus, there is no worldwide agreement about how to manage Rh testing and Rh D immune globulin administration in cases of early pregnancy loss or abortion care before 12 weeks’ gestation. This editorial examines the evolving guidelines of major professional societies.

Guidelines consistent with the routine use of Rh D immune globulin in all cases of early pregnancy loss and abortion care

As of the publication date of this editorial, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on prevention of Rh D alloimmunization provides the following guidance based on consensus and expert opinion²:

• “Although the risk of alloimmunization is low, the consequences can be significant, and administration of Rh D immune globulin should be considered in cases of spontaneous first trimester miscarriage, especially those that are later in the first trimester.”
• “Because of the higher risk of alloimmunization, Rh D-negative women who have instrumentation for their miscarriage should receive Rh D immune globulin prophylaxis.”
• “Rh D immune globulin should be given to Rh D-negative women who have pregnancy termination either medical or surgical.”

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends that, “After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, non-sensitized D-negative women should be given a minimum anti-D of 120 µg.”³

The liberal use of Rh D immune globulin in all cases of early pregnancy loss and abortion care is based, in part, on the following considerations:

1. the recognized safety of Rh D immune globulin administration^2,3
2. the report that fetal megaloblasts may express Rh antigen as early as 38 days of gestation⁴
3. the observation that 0.1 mL of Rh D-positive red cells may provoke an immune response in some Rh D-negative patients^5-7
4. the estimate that in some patients with threatened miscarriage a significant quantity of fetal blood may enter the maternal circulation.⁸

Guidelines that suggest restricted use of Rh D immune globulin before 7 to 8 weeks’ gestation

The Reproductive Care Program of Nova Scotia guideline from 2022 notes that “the benefits of administering Rh immune globulin before 8 weeks gestation have not been demonstrated.” Given the burden of Rh testing and Rh D immune globulin administration they suggest that clinicians may withhold Rh testing and Rh D immune globulin administration in cases less than 8 weeks’ gestation (less than 56 days) for spontaneous, threatened, or medication abortions if there is reliable pregnancy dating.⁹

The Dutch Association of Abortion Specialists guidelines from 2018 suggest to not provide Rh D immune globulin treatment in the following clinical situations: patients under 10 weeks’ gestation with spontaneous miscarriage or patients under 7 weeks’ gestation having an induced abortion.¹⁰

Continue to: Guidelines that suggest restricted use of Rh D immune globulin before 10 to 12 weeks’ gestation...

There are a growing number of guidelines that recommend restricting the use of Rh testing and Rh D immune globulin treatment in the management of early miscarriage and induced abortion. In 2019, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended that for patients having a spontaneous miscarriage, Rh testing and Rh D immune globulin are not necessary before 10 weeks 0 days of gestation.¹¹ In addition, NICE recommends, “Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks’ gestation.…Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks’ gestation.”¹¹

In 2019, the National Abortion Federation (NAF) Clinical Policies Committee recommended that “…it is reasonable to forgo Rh testing and anti-D immunoglobulin for women having any type of induced abortion before 8 weeks from the last menstrual period. Prior to 8 weeks, the likelihood of fetal-maternal hemorrhage adequate to cause sensitization is negligible. Given that medication abortion is more similar to spontaneous abortion with less risk of fetal-maternal hemorrhage, forgoing Rh testing and anti-D immunoglobulin for medication abortion under 10 weeks may be considered.”¹² In 2022, NAF noted, “Emerging epidemiologic and clinical evidence indicates that the risk of maternal-fetal hemorrhage caused by early abortion is negligible and Rh testing and provision of Rh immune globulin may not be necessary. It is reasonable to forego Rh testing and anti-D immunoglobulin for people having any type of abortion before 56 days and medication abortion before 70 days since the last menstrual period. The pregnancy dating at which people need Rh testing and anti-D immunoglobulin is not well established. Foregoing Rh testing and anti-D immunoglobulinfor those using medication abortion through 11 to 12 weeks may be considered.”¹³

In 2020 the International Federation of Gynaecology and Obstetrics (FIGO) Committee for Safe Motherhood and Newborn Health recommended, “The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK’s National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 and 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.”¹⁴

In 2022 the Royal College of Obstetricians and Gynaecologists recommended that for induced abortion, medication or surgical, “a determination of Rhesus blood status may be considered if the duration of pregnancy is over 12 weeks and anti-D is available.”¹⁵ “If available, anti-D should be offered to non-sensitised RhD-negative individuals from 12 weeks of pregnancy and provided within 72 hours of the abortion.”¹⁵

In 2022, the Society of Family Planning recommended that “Rh testing and administration are not recommended prior to 12 weeks gestation for patients undergoing spontaneous, medication or uterine aspiration abortion.” “For patients under 12 weeks gestation, although not recommended, Rh testing and Rh D immune globulin administration may be considered at patient request as part of a shared decision making process.”¹⁶

In 2022, the World Health Organization (WHO) reported “There are few studies examining Rh isoimmunization in unsensitized Rh-negative individuals seeking abortion before 12 weeks of gestation.” “The evidence on the effectiveness of the intervention may favor the intervention, because fewer women in the intervention group (anti-D administration) had antibody formation after the initial pregnancy compared to women in the comparison group (no anti-D) and no harms (undesirable effects) of the intervention were noted.”¹⁷ The evidence referenced for these statements are two low-quality studies from 1972.^18,19 The WHO continues, “…after consideration of the resources required, cost-effectiveness and feasibility of administering anti-D, as well as the very low certainty of evidence on effectiveness, the expert panel concluded that overall, the evidence does not favor the intervention and decided to recommend against it for gestational ages < 12 weeks, rather than < 9 weeks, as mentioned in the 2012 guidance.”¹⁷ In conclusion, the WHO recommended that “for both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration.”¹⁷

Guidelines that recommend restricted use of Rh D immune globulin during the first trimester, are based, in part, on the following considerations:

• there are no high-quality clinical trials demonstrating the benefit of Rh D immune globulin treatment in first trimester miscarriage and abortion care
• the Kleihauer-Betke technique cannot distinguish between maternal red blood cells expressing fetal hemoglobin (maternal F cells) and fetal cells, which has resulted in the over-estimation of the number of fetal cells in the maternal circulation²⁰
• using a dual-label flow cytometry method that distinguishes maternal F cells and fetal red blood cells, maternal F cells usually far outnumber fetal red blood cells in the maternal circulation in the first trimester²⁰
• among women in the first trimester undergoing uterine aspiration, the number of fetal cells in the maternal circulation is very low both before and after the procedure²⁰
• Rh testing and Rh immune globulin administration is burdensome and expensive.¹⁶

Implications for your practice

The fundamental reason for the proliferation of divergent guidelines is that there is no evidence from high-quality randomized clinical trials demonstrating that Rh testing and Rh D immune globulin treatment in early pregnancy miscarriage or induced abortion care reduces the risk of hemolytic disease of the fetus and newborn. The Cochrane review on Rh D immune globulin administration for preventing alloimmunization among patients with spontaneous miscarriage concluded, “There are insufficient data available to evaluate the practice of anti-D administration in an unsensitized Rh-negative mother after spontaneous miscarriage.”²¹

Given divergent guidelines, obstetrician-gynecologists must decide on which guideline to use in their practice. Clinicians may conclude that absent high-quality evidence from clinical trials, they will continue to use the ACOG/SOGC guidelines^2,3 in their practice, providing universal Rh testing and Rh D immune globulin treatment for all miscarriages and abortions, regardless of the gestational age. Other clinicians may conclude that Rh testing and Rh D immune globulin is not warranted before 8 to 12 weeks’ gestation, because the number of fetal red blood cells in the maternal circulation in cases of miscarriage and induced abortion is too low in early pregnancy to induce a maternal immune response.²² Based on recent studies demonstrating a low number of fetal red blood cells in the maternal circulation in the first trimester, family planning specialists are reducing the use of Rh testing and Rh immune globulin administration in both early pregnancy medication abortion and uterine aspiration abortion.¹⁶ With regard to Rh testing and Rh D immune globulin treatment, the future will definitely be different than the past. It is likely that many clinicians will reduce the use of Rh testing and Rh D immune globulin treatment in patients with miscarriage or induced abortion in early pregnancy. ●

All obstetrician-gynecologists know that pregnant patients who are Rh negative and exposed to a sufficient quantity of fetal red blood cells expressing Rh D antigen may become sensitized, producing Rh D antibodies that adversely impact future pregnancies with an Rh D-positive fetus, potentially causing hemolytic disease of the fetus and newborn. In countries where Rh D immune globulin is available, there is a consensus recommendation to administer Rh D immune globulin to Rh-negative pregnant patients at approximately 28 weeks’ gestation and at birth in order to decrease the risk of alloimmunization and hemolytic disease of the fetus and newborn in future pregnancies.¹ In contrast to this global consensus, there is no worldwide agreement about how to manage Rh testing and Rh D immune globulin administration in cases of early pregnancy loss or abortion care before 12 weeks’ gestation. This editorial examines the evolving guidelines of major professional societies.

Guidelines consistent with the routine use of Rh D immune globulin in all cases of early pregnancy loss and abortion care

As of the publication date of this editorial, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on prevention of Rh D alloimmunization provides the following guidance based on consensus and expert opinion²:

• “Although the risk of alloimmunization is low, the consequences can be significant, and administration of Rh D immune globulin should be considered in cases of spontaneous first trimester miscarriage, especially those that are later in the first trimester.”
• “Because of the higher risk of alloimmunization, Rh D-negative women who have instrumentation for their miscarriage should receive Rh D immune globulin prophylaxis.”
• “Rh D immune globulin should be given to Rh D-negative women who have pregnancy termination either medical or surgical.”

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends that, “After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, non-sensitized D-negative women should be given a minimum anti-D of 120 µg.”³

The liberal use of Rh D immune globulin in all cases of early pregnancy loss and abortion care is based, in part, on the following considerations:

1. the recognized safety of Rh D immune globulin administration^2,3
2. the report that fetal megaloblasts may express Rh antigen as early as 38 days of gestation⁴
3. the observation that 0.1 mL of Rh D-positive red cells may provoke an immune response in some Rh D-negative patients^5-7
4. the estimate that in some patients with threatened miscarriage a significant quantity of fetal blood may enter the maternal circulation.⁸

Guidelines that suggest restricted use of Rh D immune globulin before 7 to 8 weeks’ gestation

The Reproductive Care Program of Nova Scotia guideline from 2022 notes that “the benefits of administering Rh immune globulin before 8 weeks gestation have not been demonstrated.” Given the burden of Rh testing and Rh D immune globulin administration they suggest that clinicians may withhold Rh testing and Rh D immune globulin administration in cases less than 8 weeks’ gestation (less than 56 days) for spontaneous, threatened, or medication abortions if there is reliable pregnancy dating.⁹

The Dutch Association of Abortion Specialists guidelines from 2018 suggest to not provide Rh D immune globulin treatment in the following clinical situations: patients under 10 weeks’ gestation with spontaneous miscarriage or patients under 7 weeks’ gestation having an induced abortion.¹⁰

Continue to: Guidelines that suggest restricted use of Rh D immune globulin before 10 to 12 weeks’ gestation...

There are a growing number of guidelines that recommend restricting the use of Rh testing and Rh D immune globulin treatment in the management of early miscarriage and induced abortion. In 2019, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended that for patients having a spontaneous miscarriage, Rh testing and Rh D immune globulin are not necessary before 10 weeks 0 days of gestation.¹¹ In addition, NICE recommends, “Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks’ gestation.…Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks’ gestation.”¹¹

In 2019, the National Abortion Federation (NAF) Clinical Policies Committee recommended that “…it is reasonable to forgo Rh testing and anti-D immunoglobulin for women having any type of induced abortion before 8 weeks from the last menstrual period. Prior to 8 weeks, the likelihood of fetal-maternal hemorrhage adequate to cause sensitization is negligible. Given that medication abortion is more similar to spontaneous abortion with less risk of fetal-maternal hemorrhage, forgoing Rh testing and anti-D immunoglobulin for medication abortion under 10 weeks may be considered.”¹² In 2022, NAF noted, “Emerging epidemiologic and clinical evidence indicates that the risk of maternal-fetal hemorrhage caused by early abortion is negligible and Rh testing and provision of Rh immune globulin may not be necessary. It is reasonable to forego Rh testing and anti-D immunoglobulin for people having any type of abortion before 56 days and medication abortion before 70 days since the last menstrual period. The pregnancy dating at which people need Rh testing and anti-D immunoglobulin is not well established. Foregoing Rh testing and anti-D immunoglobulinfor those using medication abortion through 11 to 12 weeks may be considered.”¹³

In 2020 the International Federation of Gynaecology and Obstetrics (FIGO) Committee for Safe Motherhood and Newborn Health recommended, “The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK’s National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 and 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.”¹⁴

In 2022 the Royal College of Obstetricians and Gynaecologists recommended that for induced abortion, medication or surgical, “a determination of Rhesus blood status may be considered if the duration of pregnancy is over 12 weeks and anti-D is available.”¹⁵ “If available, anti-D should be offered to non-sensitised RhD-negative individuals from 12 weeks of pregnancy and provided within 72 hours of the abortion.”¹⁵

In 2022, the Society of Family Planning recommended that “Rh testing and administration are not recommended prior to 12 weeks gestation for patients undergoing spontaneous, medication or uterine aspiration abortion.” “For patients under 12 weeks gestation, although not recommended, Rh testing and Rh D immune globulin administration may be considered at patient request as part of a shared decision making process.”¹⁶

In 2022, the World Health Organization (WHO) reported “There are few studies examining Rh isoimmunization in unsensitized Rh-negative individuals seeking abortion before 12 weeks of gestation.” “The evidence on the effectiveness of the intervention may favor the intervention, because fewer women in the intervention group (anti-D administration) had antibody formation after the initial pregnancy compared to women in the comparison group (no anti-D) and no harms (undesirable effects) of the intervention were noted.”¹⁷ The evidence referenced for these statements are two low-quality studies from 1972.^18,19 The WHO continues, “…after consideration of the resources required, cost-effectiveness and feasibility of administering anti-D, as well as the very low certainty of evidence on effectiveness, the expert panel concluded that overall, the evidence does not favor the intervention and decided to recommend against it for gestational ages < 12 weeks, rather than < 9 weeks, as mentioned in the 2012 guidance.”¹⁷ In conclusion, the WHO recommended that “for both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration.”¹⁷

Guidelines that recommend restricted use of Rh D immune globulin during the first trimester, are based, in part, on the following considerations:

• there are no high-quality clinical trials demonstrating the benefit of Rh D immune globulin treatment in first trimester miscarriage and abortion care
• the Kleihauer-Betke technique cannot distinguish between maternal red blood cells expressing fetal hemoglobin (maternal F cells) and fetal cells, which has resulted in the over-estimation of the number of fetal cells in the maternal circulation²⁰
• using a dual-label flow cytometry method that distinguishes maternal F cells and fetal red blood cells, maternal F cells usually far outnumber fetal red blood cells in the maternal circulation in the first trimester²⁰
• among women in the first trimester undergoing uterine aspiration, the number of fetal cells in the maternal circulation is very low both before and after the procedure²⁰
• Rh testing and Rh immune globulin administration is burdensome and expensive.¹⁶

Implications for your practice

The fundamental reason for the proliferation of divergent guidelines is that there is no evidence from high-quality randomized clinical trials demonstrating that Rh testing and Rh D immune globulin treatment in early pregnancy miscarriage or induced abortion care reduces the risk of hemolytic disease of the fetus and newborn. The Cochrane review on Rh D immune globulin administration for preventing alloimmunization among patients with spontaneous miscarriage concluded, “There are insufficient data available to evaluate the practice of anti-D administration in an unsensitized Rh-negative mother after spontaneous miscarriage.”²¹

Given divergent guidelines, obstetrician-gynecologists must decide on which guideline to use in their practice. Clinicians may conclude that absent high-quality evidence from clinical trials, they will continue to use the ACOG/SOGC guidelines^2,3 in their practice, providing universal Rh testing and Rh D immune globulin treatment for all miscarriages and abortions, regardless of the gestational age. Other clinicians may conclude that Rh testing and Rh D immune globulin is not warranted before 8 to 12 weeks’ gestation, because the number of fetal red blood cells in the maternal circulation in cases of miscarriage and induced abortion is too low in early pregnancy to induce a maternal immune response.²² Based on recent studies demonstrating a low number of fetal red blood cells in the maternal circulation in the first trimester, family planning specialists are reducing the use of Rh testing and Rh immune globulin administration in both early pregnancy medication abortion and uterine aspiration abortion.¹⁶ With regard to Rh testing and Rh D immune globulin treatment, the future will definitely be different than the past. It is likely that many clinicians will reduce the use of Rh testing and Rh D immune globulin treatment in patients with miscarriage or induced abortion in early pregnancy. ●

The mission of OBG Management is to enhance the quality of reproductive health care and the professional development of obstetrician-gynecologists and all reproductive health care clinicians. As we celebrate the beginning of our 35th anniversary year, we recommit to our mission, providing the highest quality reproductive health information in both print and electronic portals. Guiding all our actions is our deep commitment to being worthy of the trust of our readers.

OBG Management is one of the most widely-read publications dedicated to obstetrician-gynecologists. We recognize that it is difficult for clinicians to keep up with the vast and growing corpus of information that is relevant to clinical practice. A priority goal of OBG Management is to ensure our readers are aware of practice-changing information. The OBG Management Board of Editors guide all aspects of the editorial work at OBG Management, alerting us to upcoming practice-changing discoveries, including new research findings, new medications, and important guidelines. As we begin our 35th anniversary year, we would like to highlight our distinguished Board of Editors. Of note, this year, Dr. Cheryl B. Iglesia was named as Deputy Editor, with an expanded responsibility to curate the gynecology content for OBG Management.

We wish all our readers a wonderful New Year and the best health possible for our patients.

Arnold P. Advincula, MD

I serve on the executive board that oversees the Fellowships in Minimally Invasive Gynecologic Surgery (FMIGS), and in January 2023 will transition into the role of President. I bring to this leadership role nearly 25 years of surgical experience, both as a clinician educator and inventor. My goal during the next 2 years will be to move toward subspecialty recognition of Complex Gynecology. 

Linda D. Bradley, MD

My passion is diagnostic and operative hysteroscopy, simple procedures that can both evaluate and treat intrauterine pathology. Recently, I was thrilled to coauthor an article on office hysteroscopy for Obstetrics & Gynecology (September 2022). I will have a chapter on operative hysteroscopy in the 2023 edition of TeLinde’s Textbook of Gynecology, and I am an author for the topic Office and Operative Hysteroscopy in UpToDate. Locally, I am known as the “foodie gynecologist”—I travel, take cooking classes, and I have more cookbooks than gynecology textbooks. Since Covid, I have embraced biking and just completed a riverboat biking cruise from Salamanca, Spain, to Lisbon, Portugal.

Amy L. Garcia, MD

I am fellowship trained as a minimally invasive gynecologic surgeon (MIGS) and have had a private surgical practice since 2005. I am involved with The American College of Obstetricians and Gynecologists (ACOG), AAGL, and international surgical education for office hysteroscopy and related practice management. I am passionate about working with start-up companies in the gynecologic medical device arena and innovation in gynecologic surgery.

Steven R. Goldstein, MD, NCMP, CCD

I just completed my term as President of the International Menopause Society. This culminated in the society’s 18th World Congress in Lisbon, attended by over 1,700 health care providers from 76 countries. I delivered the Pieter van Keep Memorial Lecture, named for one of the society’s founders who died prematurely of pancreatic cancer. I was further honored by receiving the society’s Distinguished Service Award. I am very proud to have previously received the NAMS Thomas B. Clarkson award for Outstanding Clinical and Basic Science Research in Menopause. I also have one foot in the gynecologic ultrasound world and was given the Joseph H. Holmes Pioneer Award and was the 2023 recipient of the William J. Fry Memorial Lecture Award, both from the American Institute of Ultrasound in Medicine, having written the second book ever on vaginal ultrasonography.

On a personal level, I love to play golf (in spite of my foot drop and 14 orthopedic surgeries). My season tickets show some diversity—the New York City Ballet and St. John’s basketball.

Cheryl B. Iglesia, MD

I am the 49th president of the Society of Gynecologic Surgeons, the 5th woman to hold this position, and the first of Filipino-American descent. I recognize that it is only through extraordinary mentorship and support from other giants in gynecology, like Drs. Andrew Kaunitz (fellow OBG Management Board member), Linda Brubaker, and Dee Fenner and the love, support, and encouragement of my parents, husband, and daughters that I have been able to reach this milestone. A feather in my cap is the recent appointment to Deputy Editor of Gynecology for this journal, under the tutelage of Dr. Robert Barbieri. Over the past 31 years, I have had the privilege of learning from the best experts and gynecologic surgeons and the honor of working with skilled partners as we pass on our collective knowledge to our fellows, residents, and medical students. The passion in this next generation of ObGyns is so invigorating!

PS—In the spirit of continually learning, I want to add the Argentine tango to my dancing repertoire and go on an African safari; both are on my bucket list as the pandemic eases.

Andrew M. Kaunitz, MD, NCMP

Since starting with the University of Florida College of Medicine-Jacksonville in 1984, I have enjoyed caring for patients, training residents and medical students, and being involved with publications and research. My areas of focus are menopause, contraception, gyn ultrasound and evaluation/management of women with abnormal uterine bleeding. In 2020, I received the North American Menopause Society/Leon Speroff Outstanding Educator Award. In 2021, I received the ACOG Distinguished Service Award. I enjoy spending time with my family, neighborhood bicycling, and searching for sharks’ teeth at the beach. 

Barbara Levy, MD

I have been privileged to serve on the OBG Management Editorial Board for several decades. I am passionate about delivering the best possible care for the patients we serve, and helping women’s health care professionals provide that care. Through positions at AAGL, ACOG, and the American Medical Association, I have worked hard to champion best practices and to support fair, equitable, and accessible care for our patients and reimbursement for our services. My true north is to base patient care on reliable, valid, and properly interpreted data.

Continue to: David G. Mutch, MD...

David G. Mutch, MD

I am ending my 6-year term as Chair of the National Cancer Institute’s (NCI) gynecologic cancer steering committee. That is the committee that vets all NCI-sponsored clinical trials in gynecologic oncology. I am on the International Federation of Gynecology and Obstetrics (FIGO) Cancer committee, Co-Chair of the American Joint Committee on Cancer gyn staging committee and on the Reproductive Scientist Development Program selection committee. I also am completing my term as Chair of the Foundation for Women’s Cancer; this is the C3, charitable arm, of the Society of Gynecologic Oncology. We have distributed more than $3.5 million to young investigators to help start their research careers in gynecologic oncology.

Errol R. Norwitz, MD, PhD, MBA

I am a physician-scientist with subspecialty training in high-risk obstetrics (maternal-fetal medicine). I was born and raised in Cape Town, South Africa, and I have trained/practiced in 5 countries on 3 continents. My research interests include the pathophysiology, prediction, prevention, and management of pregnancy complications, primarily preterm birth and preeclampsia. I am a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development. I am currently President & CEO of Newton-Wellesley Hospital, a comprehensive community-based academic medical center and a member of the Mass General Brigham health care system in Boston, Massachusetts.

Jaimey Pauli, MD

I am the Division Chief and Professor of Maternal-Fetal Medicine (MFM) at the Penn State College of Medicine and Penn State Health Milton S. Hershey Medical Center. I had exceptional mentoring throughout my medical career, particularly by a former member of the Editorial Board, Dr. John T. Repke. One of the biggest perks of my job is that our division provides full-scope MFM care. While I often serve as the more traditional MFM consultant and academic educator, I also provide longitudinal prenatal care and deliver many of my own patients, often through subsequent pregnancies. Serving as a member of the Editorial Board combines my passion for clinical obstetrical care with my talents (as a former English major) of reading, writing, and editing. I believe that the work we do provides accessible, evidence-based, and practical guidance for our colleagues so they can provide excellence in obstetrical care.

JoAnn Pinkerton, MD, NCMP

I am a Professor of Obstetrics and Gynecology and Division Chief of Midlife Health at the University of Virginia (UVA) Health. Passionate about menopause, I am an executive director emeritus of The North American Menopause Society (NAMS) and past-President of NAMS (2008-2009). Within the past few years, I have served as an expert advisor for the recent ACOG Clinical Practice Guidelines on Osteoporosis, the NAMS Position Statements on Hormone Therapy and Osteoporosis, and the Global Consensus on Menopause and Androgen Therapy. I received the 2022 South Atlantic Association of Obstetricians and Gynecologists Lifetime Achievement Award for my expertise and work in menopause and the NAMS 2020 Ann Voda Community Service Award for my biannual community educational symposiums. I remain active in research, currently the lead and UVA principal investigator for the Oasis 2 multicenter clinical trial, which is testing a neurokinin receptor antagonist as a nonhormone therapy for the relief of hot flashes. Serving on the OBG Management Editorial Board is an honor that allows me to use my expertise in menopause management and hormone therapy to provide practical, evidence-based guidance for clinicians.

Joseph S. Sanfilippo, MD, MBA

I feel honored and privileged to have received the Golden Apple Teaching Award from the Universityof Pittsburgh School of Medicine. I am also fortunate to be the recipient of the Faculty Educator of the Month Award for resident teaching. I have been named Top Doctor 20 years in a row. My current academic activities include, since 2007, Program Director for Reproductive Endocrinology & Infertility Fellowship at the University of Pittsburgh and Chair of the Mentor-Mentee Program at University of Pittsburgh Department of Obstetrics, Gynecology & Reproductive Sciences. I am Guest Editor for the medical malpractice section of the journal Clinical Obstetrics and Gynecology. Recently, I completed a patient-focused book, “Experts Guide to Fertility,” which will be published in May 2023 by J Hopkins University Publisher and is designed for patients going through infertility treatment. Regarding outside events, I enjoy climbing steep hills and riding far and wide on my “electric bike.” Highly recommend it!

James Simon, MD, CCD, IF, NCMP

It’s been an honor serving on the OBG Management Board for many years, as a board-certified obstetrician/gynecologist/reproductive endocrinologist, certified menopause practitioner, and sexuality counsellor. Nicknamed “The Menopause Whisperer” by Washingtonian Magazine, my solo, private practice, IntimMedicine Specialists®, one of the few such practices remaining in Washington, DC, is about 6 blocks from the White House. By virtue of my practice’s location, I care for women at the highest levels of government seeking personalized gynecological, menopause, and sexual medicine care. Some high-powered patients believe they have all the answers even before I open my mouth, so I just fall back on my experience as both the President of NAMS, and The International Society for the Study of Women’s Sexual Health, or principal investigator on more than 400 clinical research trials, or Chief Medical Officer of a pharmaceutical company, or author of more than 800 publications. I love what I do every day and cannot imagine slowing down or stopping. ●

The mission of OBG Management is to enhance the quality of reproductive health care and the professional development of obstetrician-gynecologists and all reproductive health care clinicians. As we celebrate the beginning of our 35th anniversary year, we recommit to our mission, providing the highest quality reproductive health information in both print and electronic portals. Guiding all our actions is our deep commitment to being worthy of the trust of our readers.

OBG Management is one of the most widely-read publications dedicated to obstetrician-gynecologists. We recognize that it is difficult for clinicians to keep up with the vast and growing corpus of information that is relevant to clinical practice. A priority goal of OBG Management is to ensure our readers are aware of practice-changing information. The OBG Management Board of Editors guide all aspects of the editorial work at OBG Management, alerting us to upcoming practice-changing discoveries, including new research findings, new medications, and important guidelines. As we begin our 35th anniversary year, we would like to highlight our distinguished Board of Editors. Of note, this year, Dr. Cheryl B. Iglesia was named as Deputy Editor, with an expanded responsibility to curate the gynecology content for OBG Management.

We wish all our readers a wonderful New Year and the best health possible for our patients.

Arnold P. Advincula, MD

I serve on the executive board that oversees the Fellowships in Minimally Invasive Gynecologic Surgery (FMIGS), and in January 2023 will transition into the role of President. I bring to this leadership role nearly 25 years of surgical experience, both as a clinician educator and inventor. My goal during the next 2 years will be to move toward subspecialty recognition of Complex Gynecology. 

Linda D. Bradley, MD

My passion is diagnostic and operative hysteroscopy, simple procedures that can both evaluate and treat intrauterine pathology. Recently, I was thrilled to coauthor an article on office hysteroscopy for Obstetrics & Gynecology (September 2022). I will have a chapter on operative hysteroscopy in the 2023 edition of TeLinde’s Textbook of Gynecology, and I am an author for the topic Office and Operative Hysteroscopy in UpToDate. Locally, I am known as the “foodie gynecologist”—I travel, take cooking classes, and I have more cookbooks than gynecology textbooks. Since Covid, I have embraced biking and just completed a riverboat biking cruise from Salamanca, Spain, to Lisbon, Portugal.

Amy L. Garcia, MD

I am fellowship trained as a minimally invasive gynecologic surgeon (MIGS) and have had a private surgical practice since 2005. I am involved with The American College of Obstetricians and Gynecologists (ACOG), AAGL, and international surgical education for office hysteroscopy and related practice management. I am passionate about working with start-up companies in the gynecologic medical device arena and innovation in gynecologic surgery.

Steven R. Goldstein, MD, NCMP, CCD

I just completed my term as President of the International Menopause Society. This culminated in the society’s 18th World Congress in Lisbon, attended by over 1,700 health care providers from 76 countries. I delivered the Pieter van Keep Memorial Lecture, named for one of the society’s founders who died prematurely of pancreatic cancer. I was further honored by receiving the society’s Distinguished Service Award. I am very proud to have previously received the NAMS Thomas B. Clarkson award for Outstanding Clinical and Basic Science Research in Menopause. I also have one foot in the gynecologic ultrasound world and was given the Joseph H. Holmes Pioneer Award and was the 2023 recipient of the William J. Fry Memorial Lecture Award, both from the American Institute of Ultrasound in Medicine, having written the second book ever on vaginal ultrasonography.

On a personal level, I love to play golf (in spite of my foot drop and 14 orthopedic surgeries). My season tickets show some diversity—the New York City Ballet and St. John’s basketball.

Cheryl B. Iglesia, MD

I am the 49th president of the Society of Gynecologic Surgeons, the 5th woman to hold this position, and the first of Filipino-American descent. I recognize that it is only through extraordinary mentorship and support from other giants in gynecology, like Drs. Andrew Kaunitz (fellow OBG Management Board member), Linda Brubaker, and Dee Fenner and the love, support, and encouragement of my parents, husband, and daughters that I have been able to reach this milestone. A feather in my cap is the recent appointment to Deputy Editor of Gynecology for this journal, under the tutelage of Dr. Robert Barbieri. Over the past 31 years, I have had the privilege of learning from the best experts and gynecologic surgeons and the honor of working with skilled partners as we pass on our collective knowledge to our fellows, residents, and medical students. The passion in this next generation of ObGyns is so invigorating!

PS—In the spirit of continually learning, I want to add the Argentine tango to my dancing repertoire and go on an African safari; both are on my bucket list as the pandemic eases.

Andrew M. Kaunitz, MD, NCMP

Since starting with the University of Florida College of Medicine-Jacksonville in 1984, I have enjoyed caring for patients, training residents and medical students, and being involved with publications and research. My areas of focus are menopause, contraception, gyn ultrasound and evaluation/management of women with abnormal uterine bleeding. In 2020, I received the North American Menopause Society/Leon Speroff Outstanding Educator Award. In 2021, I received the ACOG Distinguished Service Award. I enjoy spending time with my family, neighborhood bicycling, and searching for sharks’ teeth at the beach. 

Barbara Levy, MD

I have been privileged to serve on the OBG Management Editorial Board for several decades. I am passionate about delivering the best possible care for the patients we serve, and helping women’s health care professionals provide that care. Through positions at AAGL, ACOG, and the American Medical Association, I have worked hard to champion best practices and to support fair, equitable, and accessible care for our patients and reimbursement for our services. My true north is to base patient care on reliable, valid, and properly interpreted data.

Continue to: David G. Mutch, MD...

David G. Mutch, MD

I am ending my 6-year term as Chair of the National Cancer Institute’s (NCI) gynecologic cancer steering committee. That is the committee that vets all NCI-sponsored clinical trials in gynecologic oncology. I am on the International Federation of Gynecology and Obstetrics (FIGO) Cancer committee, Co-Chair of the American Joint Committee on Cancer gyn staging committee and on the Reproductive Scientist Development Program selection committee. I also am completing my term as Chair of the Foundation for Women’s Cancer; this is the C3, charitable arm, of the Society of Gynecologic Oncology. We have distributed more than $3.5 million to young investigators to help start their research careers in gynecologic oncology.

Errol R. Norwitz, MD, PhD, MBA

I am a physician-scientist with subspecialty training in high-risk obstetrics (maternal-fetal medicine). I was born and raised in Cape Town, South Africa, and I have trained/practiced in 5 countries on 3 continents. My research interests include the pathophysiology, prediction, prevention, and management of pregnancy complications, primarily preterm birth and preeclampsia. I am a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development. I am currently President & CEO of Newton-Wellesley Hospital, a comprehensive community-based academic medical center and a member of the Mass General Brigham health care system in Boston, Massachusetts.

Jaimey Pauli, MD

I am the Division Chief and Professor of Maternal-Fetal Medicine (MFM) at the Penn State College of Medicine and Penn State Health Milton S. Hershey Medical Center. I had exceptional mentoring throughout my medical career, particularly by a former member of the Editorial Board, Dr. John T. Repke. One of the biggest perks of my job is that our division provides full-scope MFM care. While I often serve as the more traditional MFM consultant and academic educator, I also provide longitudinal prenatal care and deliver many of my own patients, often through subsequent pregnancies. Serving as a member of the Editorial Board combines my passion for clinical obstetrical care with my talents (as a former English major) of reading, writing, and editing. I believe that the work we do provides accessible, evidence-based, and practical guidance for our colleagues so they can provide excellence in obstetrical care.

JoAnn Pinkerton, MD, NCMP

I am a Professor of Obstetrics and Gynecology and Division Chief of Midlife Health at the University of Virginia (UVA) Health. Passionate about menopause, I am an executive director emeritus of The North American Menopause Society (NAMS) and past-President of NAMS (2008-2009). Within the past few years, I have served as an expert advisor for the recent ACOG Clinical Practice Guidelines on Osteoporosis, the NAMS Position Statements on Hormone Therapy and Osteoporosis, and the Global Consensus on Menopause and Androgen Therapy. I received the 2022 South Atlantic Association of Obstetricians and Gynecologists Lifetime Achievement Award for my expertise and work in menopause and the NAMS 2020 Ann Voda Community Service Award for my biannual community educational symposiums. I remain active in research, currently the lead and UVA principal investigator for the Oasis 2 multicenter clinical trial, which is testing a neurokinin receptor antagonist as a nonhormone therapy for the relief of hot flashes. Serving on the OBG Management Editorial Board is an honor that allows me to use my expertise in menopause management and hormone therapy to provide practical, evidence-based guidance for clinicians.

Joseph S. Sanfilippo, MD, MBA

I feel honored and privileged to have received the Golden Apple Teaching Award from the Universityof Pittsburgh School of Medicine. I am also fortunate to be the recipient of the Faculty Educator of the Month Award for resident teaching. I have been named Top Doctor 20 years in a row. My current academic activities include, since 2007, Program Director for Reproductive Endocrinology & Infertility Fellowship at the University of Pittsburgh and Chair of the Mentor-Mentee Program at University of Pittsburgh Department of Obstetrics, Gynecology & Reproductive Sciences. I am Guest Editor for the medical malpractice section of the journal Clinical Obstetrics and Gynecology. Recently, I completed a patient-focused book, “Experts Guide to Fertility,” which will be published in May 2023 by J Hopkins University Publisher and is designed for patients going through infertility treatment. Regarding outside events, I enjoy climbing steep hills and riding far and wide on my “electric bike.” Highly recommend it!

James Simon, MD, CCD, IF, NCMP

It’s been an honor serving on the OBG Management Board for many years, as a board-certified obstetrician/gynecologist/reproductive endocrinologist, certified menopause practitioner, and sexuality counsellor. Nicknamed “The Menopause Whisperer” by Washingtonian Magazine, my solo, private practice, IntimMedicine Specialists®, one of the few such practices remaining in Washington, DC, is about 6 blocks from the White House. By virtue of my practice’s location, I care for women at the highest levels of government seeking personalized gynecological, menopause, and sexual medicine care. Some high-powered patients believe they have all the answers even before I open my mouth, so I just fall back on my experience as both the President of NAMS, and The International Society for the Study of Women’s Sexual Health, or principal investigator on more than 400 clinical research trials, or Chief Medical Officer of a pharmaceutical company, or author of more than 800 publications. I love what I do every day and cannot imagine slowing down or stopping. ●

The mission of OBG Management is to enhance the quality of reproductive health care and the professional development of obstetrician-gynecologists and all reproductive health care clinicians. As we celebrate the beginning of our 35th anniversary year, we recommit to our mission, providing the highest quality reproductive health information in both print and electronic portals. Guiding all our actions is our deep commitment to being worthy of the trust of our readers.

OBG Management is one of the most widely-read publications dedicated to obstetrician-gynecologists. We recognize that it is difficult for clinicians to keep up with the vast and growing corpus of information that is relevant to clinical practice. A priority goal of OBG Management is to ensure our readers are aware of practice-changing information. The OBG Management Board of Editors guide all aspects of the editorial work at OBG Management, alerting us to upcoming practice-changing discoveries, including new research findings, new medications, and important guidelines. As we begin our 35th anniversary year, we would like to highlight our distinguished Board of Editors. Of note, this year, Dr. Cheryl B. Iglesia was named as Deputy Editor, with an expanded responsibility to curate the gynecology content for OBG Management.

We wish all our readers a wonderful New Year and the best health possible for our patients.

Arnold P. Advincula, MD

I serve on the executive board that oversees the Fellowships in Minimally Invasive Gynecologic Surgery (FMIGS), and in January 2023 will transition into the role of President. I bring to this leadership role nearly 25 years of surgical experience, both as a clinician educator and inventor. My goal during the next 2 years will be to move toward subspecialty recognition of Complex Gynecology. 

Linda D. Bradley, MD

My passion is diagnostic and operative hysteroscopy, simple procedures that can both evaluate and treat intrauterine pathology. Recently, I was thrilled to coauthor an article on office hysteroscopy for Obstetrics & Gynecology (September 2022). I will have a chapter on operative hysteroscopy in the 2023 edition of TeLinde’s Textbook of Gynecology, and I am an author for the topic Office and Operative Hysteroscopy in UpToDate. Locally, I am known as the “foodie gynecologist”—I travel, take cooking classes, and I have more cookbooks than gynecology textbooks. Since Covid, I have embraced biking and just completed a riverboat biking cruise from Salamanca, Spain, to Lisbon, Portugal.

Amy L. Garcia, MD

I am fellowship trained as a minimally invasive gynecologic surgeon (MIGS) and have had a private surgical practice since 2005. I am involved with The American College of Obstetricians and Gynecologists (ACOG), AAGL, and international surgical education for office hysteroscopy and related practice management. I am passionate about working with start-up companies in the gynecologic medical device arena and innovation in gynecologic surgery.

Steven R. Goldstein, MD, NCMP, CCD

I just completed my term as President of the International Menopause Society. This culminated in the society’s 18th World Congress in Lisbon, attended by over 1,700 health care providers from 76 countries. I delivered the Pieter van Keep Memorial Lecture, named for one of the society’s founders who died prematurely of pancreatic cancer. I was further honored by receiving the society’s Distinguished Service Award. I am very proud to have previously received the NAMS Thomas B. Clarkson award for Outstanding Clinical and Basic Science Research in Menopause. I also have one foot in the gynecologic ultrasound world and was given the Joseph H. Holmes Pioneer Award and was the 2023 recipient of the William J. Fry Memorial Lecture Award, both from the American Institute of Ultrasound in Medicine, having written the second book ever on vaginal ultrasonography.

On a personal level, I love to play golf (in spite of my foot drop and 14 orthopedic surgeries). My season tickets show some diversity—the New York City Ballet and St. John’s basketball.

Cheryl B. Iglesia, MD

I am the 49th president of the Society of Gynecologic Surgeons, the 5th woman to hold this position, and the first of Filipino-American descent. I recognize that it is only through extraordinary mentorship and support from other giants in gynecology, like Drs. Andrew Kaunitz (fellow OBG Management Board member), Linda Brubaker, and Dee Fenner and the love, support, and encouragement of my parents, husband, and daughters that I have been able to reach this milestone. A feather in my cap is the recent appointment to Deputy Editor of Gynecology for this journal, under the tutelage of Dr. Robert Barbieri. Over the past 31 years, I have had the privilege of learning from the best experts and gynecologic surgeons and the honor of working with skilled partners as we pass on our collective knowledge to our fellows, residents, and medical students. The passion in this next generation of ObGyns is so invigorating!

PS—In the spirit of continually learning, I want to add the Argentine tango to my dancing repertoire and go on an African safari; both are on my bucket list as the pandemic eases.

Andrew M. Kaunitz, MD, NCMP

Since starting with the University of Florida College of Medicine-Jacksonville in 1984, I have enjoyed caring for patients, training residents and medical students, and being involved with publications and research. My areas of focus are menopause, contraception, gyn ultrasound and evaluation/management of women with abnormal uterine bleeding. In 2020, I received the North American Menopause Society/Leon Speroff Outstanding Educator Award. In 2021, I received the ACOG Distinguished Service Award. I enjoy spending time with my family, neighborhood bicycling, and searching for sharks’ teeth at the beach. 

Barbara Levy, MD

I have been privileged to serve on the OBG Management Editorial Board for several decades. I am passionate about delivering the best possible care for the patients we serve, and helping women’s health care professionals provide that care. Through positions at AAGL, ACOG, and the American Medical Association, I have worked hard to champion best practices and to support fair, equitable, and accessible care for our patients and reimbursement for our services. My true north is to base patient care on reliable, valid, and properly interpreted data.

Continue to: David G. Mutch, MD...

David G. Mutch, MD

I am ending my 6-year term as Chair of the National Cancer Institute’s (NCI) gynecologic cancer steering committee. That is the committee that vets all NCI-sponsored clinical trials in gynecologic oncology. I am on the International Federation of Gynecology and Obstetrics (FIGO) Cancer committee, Co-Chair of the American Joint Committee on Cancer gyn staging committee and on the Reproductive Scientist Development Program selection committee. I also am completing my term as Chair of the Foundation for Women’s Cancer; this is the C3, charitable arm, of the Society of Gynecologic Oncology. We have distributed more than $3.5 million to young investigators to help start their research careers in gynecologic oncology.

Errol R. Norwitz, MD, PhD, MBA

I am a physician-scientist with subspecialty training in high-risk obstetrics (maternal-fetal medicine). I was born and raised in Cape Town, South Africa, and I have trained/practiced in 5 countries on 3 continents. My research interests include the pathophysiology, prediction, prevention, and management of pregnancy complications, primarily preterm birth and preeclampsia. I am a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development. I am currently President & CEO of Newton-Wellesley Hospital, a comprehensive community-based academic medical center and a member of the Mass General Brigham health care system in Boston, Massachusetts.

Jaimey Pauli, MD

I am the Division Chief and Professor of Maternal-Fetal Medicine (MFM) at the Penn State College of Medicine and Penn State Health Milton S. Hershey Medical Center. I had exceptional mentoring throughout my medical career, particularly by a former member of the Editorial Board, Dr. John T. Repke. One of the biggest perks of my job is that our division provides full-scope MFM care. While I often serve as the more traditional MFM consultant and academic educator, I also provide longitudinal prenatal care and deliver many of my own patients, often through subsequent pregnancies. Serving as a member of the Editorial Board combines my passion for clinical obstetrical care with my talents (as a former English major) of reading, writing, and editing. I believe that the work we do provides accessible, evidence-based, and practical guidance for our colleagues so they can provide excellence in obstetrical care.

JoAnn Pinkerton, MD, NCMP

I am a Professor of Obstetrics and Gynecology and Division Chief of Midlife Health at the University of Virginia (UVA) Health. Passionate about menopause, I am an executive director emeritus of The North American Menopause Society (NAMS) and past-President of NAMS (2008-2009). Within the past few years, I have served as an expert advisor for the recent ACOG Clinical Practice Guidelines on Osteoporosis, the NAMS Position Statements on Hormone Therapy and Osteoporosis, and the Global Consensus on Menopause and Androgen Therapy. I received the 2022 South Atlantic Association of Obstetricians and Gynecologists Lifetime Achievement Award for my expertise and work in menopause and the NAMS 2020 Ann Voda Community Service Award for my biannual community educational symposiums. I remain active in research, currently the lead and UVA principal investigator for the Oasis 2 multicenter clinical trial, which is testing a neurokinin receptor antagonist as a nonhormone therapy for the relief of hot flashes. Serving on the OBG Management Editorial Board is an honor that allows me to use my expertise in menopause management and hormone therapy to provide practical, evidence-based guidance for clinicians.

Joseph S. Sanfilippo, MD, MBA

I feel honored and privileged to have received the Golden Apple Teaching Award from the Universityof Pittsburgh School of Medicine. I am also fortunate to be the recipient of the Faculty Educator of the Month Award for resident teaching. I have been named Top Doctor 20 years in a row. My current academic activities include, since 2007, Program Director for Reproductive Endocrinology & Infertility Fellowship at the University of Pittsburgh and Chair of the Mentor-Mentee Program at University of Pittsburgh Department of Obstetrics, Gynecology & Reproductive Sciences. I am Guest Editor for the medical malpractice section of the journal Clinical Obstetrics and Gynecology. Recently, I completed a patient-focused book, “Experts Guide to Fertility,” which will be published in May 2023 by J Hopkins University Publisher and is designed for patients going through infertility treatment. Regarding outside events, I enjoy climbing steep hills and riding far and wide on my “electric bike.” Highly recommend it!

James Simon, MD, CCD, IF, NCMP

It’s been an honor serving on the OBG Management Board for many years, as a board-certified obstetrician/gynecologist/reproductive endocrinologist, certified menopause practitioner, and sexuality counsellor. Nicknamed “The Menopause Whisperer” by Washingtonian Magazine, my solo, private practice, IntimMedicine Specialists®, one of the few such practices remaining in Washington, DC, is about 6 blocks from the White House. By virtue of my practice’s location, I care for women at the highest levels of government seeking personalized gynecological, menopause, and sexual medicine care. Some high-powered patients believe they have all the answers even before I open my mouth, so I just fall back on my experience as both the President of NAMS, and The International Society for the Study of Women’s Sexual Health, or principal investigator on more than 400 clinical research trials, or Chief Medical Officer of a pharmaceutical company, or author of more than 800 publications. I love what I do every day and cannot imagine slowing down or stopping. ●

PCOS is a common problem, with a prevalence of 6% to 10% among women of reproductive age.¹ Patients with PCOS often present with hirsutism, acne, female androgenetic alopecia, oligomenorrhea (also known as infrequent menstrual bleeding), amenorrhea, infertility, overweight, or obesity. In addition, many patients with PCOS have insulin resistance, dyslipidemia, metabolic syndrome, and an increased risk for developing type 2 diabetes mellitus (DM).² A simplified approach to the diagnosis of PCOS will save health care resources by reducing the use of low-value diagnostic tests. A simplified approach to the treatment of PCOS will support patient medication adherence and improve health outcomes.

Simplify the diagnosis of PCOS

Simplify PCOS diagnosis by focusing on the core criteria of hyperandrogenism and oligo-ovulation. There are 3 major approaches to diagnosis:

1. the 1990 National Institutes of Health (NIH) criteria³
2. the 2003 Rotterdam criteria^4,5
3. the 2008 Androgen Excess and PCOS Society (AES) criteria.⁶

Using the 1990 NIH approach, the diagnosis of PCOS is made by the presence of 2 core criteria: hyperandrogenism and oligo-ovulation, typically manifested as oligomenorrhea. In addition, other causes of hyperandrogenism should be excluded, including nonclassical adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency.³ Using the 1990 NIH criteria, PCOS can be diagnosed based on history (oligomenorrhea) and physical examination (assessment of the severity of hirsutism), but laboratory tests including total testosterone are often ordered.⁷

The Rotterdam approach to the diagnosis added a third criteria, the detection by ultrasonography of a multifollicular ovary and/or increased ovarian volume.^4,5 Using the Rotterdam approach, PCOS is diagnosed in the presence of any 2 of the following 3 criteria: hyperandrogenism, oligo-ovulation, or ultrasound imaging showing the presence of a multifollicular ovary, identified by ≥ 12 antral follicles (2 to 9 mm in diameter) in each ovary or increased ovarian volume (> 10 mL).^4,5

The Rotterdam approach using ovarian ultrasound as a criterion to diagnose PCOS is rife with serious problems, including:

• The number of small antral follicles in the normal ovary is age dependent, and many ovulatory and nonhirsute patients have ≥ 12 small antral follicles in each ovary.^8,9
• There is no consensus on the number of small antral follicles needed to diagnose a multifollicular ovary, with recommendations to use thresholds of 12^4,5 or 20 follicles¹⁰ as the diagnostic cut-off.
• Accurate counting of the number of small ovarian follicles requires transvaginal ultrasound, which is not appropriate for many young adolescent patients.
• The process of counting ovarian follicles is operator-dependent.
• The high cost of ultrasound assessment of ovarian follicles (≥ $500 per examination).

The Rotterdam approach supports the diagnosis of PCOS in a patient with oligo-ovulation plus an ultrasound showing a multifollicular ovary in the absence of any clinical or laboratory evidence of hyperandrogenism.^3,4,5 This approach to the diagnosis of PCOS is rejected by both the 1990 NIH³ and AES⁶ recommendations, which require the presence of hyperandrogenism as the sine qua non in the diagnosis of PCOS. I recommend against diagnosing PCOS in a non-hyperandrogenic patient with oligo-ovulation and a multifollicular ovary because other diagnoses are also possible, such as functional hypothalamic oligo-ovulation, especially in young patients. The Rotterdam approach also supports the diagnosis of PCOS in a patient with hyperandrogenism, an ultrasound showing a multifollicular ovary, and normal ovulation and menses.^3,4 For most patients with normal, regular ovulation and menses, the testosterone concentration is normal and the only evidence of hyperandrogenism is hirsutism. Patients with normal, regular ovulation and menses plus hirsutism usually have idiopathic hirsutism. Idiopathic hirsutism is a problem caused by excessive 5-alpha-reductase activity in the hair pilosebaceous unit, which catalyzes the conversion of weak androgens into dihydrotestosterone, a potent intracellular androgen that stimulates terminal hair growth.¹¹ In my opinion, the Rotterdam approach to diagnosing PCOS has created unnecessary confusion and complexity for both clinicians and patients. I believe we should simplify the diagnosis of PCOS and return to the 1990 NIH criteria.³

On occasion, a patient presents for a consultation and has already had an ovarian ultrasound to assess for a multifollicular ovary. I carefully read the report and, if a multifollicular ovary has been identified, I consider it as a secondary supporting finding of PCOS in my clinical assessment. But I do not base my diagnosis on the ultrasound finding. Patients often present with other laboratory tests that are secondary supporting findings of PCOS, which I carefully consider but do not use to make a diagnosis of PCOS. Secondary supporting laboratory findings consistent with PCOS include: 1) a markedly elevated anti-müllerian hormone (AMH) level,¹² 2) an elevated fasting insulin level,^2,13 and 3) an elevated luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio.^13,14 But it is not necessary to measure AMH, fasting insulin, LH, and FSH levels. To conserve health care resources, I recommend against measuring those analytes to diagnose PCOS.

Continue to: Simplify the core laboratory tests...

Simplify the core laboratory tests

Simplify the testing used to support the diagnosis of PCOS by measuring total testosterone, sex-hormone binding globulin (SHBG) and early morning 17-hydroxyprogesterone (17-OH Prog).

The core criteria for diagnosis of PCOS are hyperandrogenism and oligo-ovulation, typically manifested as oligomenorrhea or amenorrhea. Hyperandrogenism can be clinically diagnosed by assessing for the presence of hirsutism.⁷ Elevated levels of total testosterone, free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate (DHEAS) suggest the presence of hyperandrogenism. In clinical practice, the laboratory approach to the diagnosis of hyperandrogenism can be simplified to the measurement of total testosterone, SHBG, and 17-OH Prog. By measuring total testosterone and SHBG, an estimate of free testosterone can be made. If the total testosterone is elevated, it is highly likely that the free testosterone is elevated. If the SHBG is abnormally low and the total testosterone level is in the upper limit of the normal range, the free testosterone is likely to be elevated.¹⁵ Using this approach, either an elevated total testosterone or an abnormally low SHBG indicate elevated free testosterone. For patients with hyperandrogenism and oligo-ovulation, an early morning (8 to 9 AM) 17-OH Prog level ≤ 2 ng/mL rules out the presence of NCAH due to a 21-hydroxylase deficiency.¹⁶ In my practice, the core laboratory tests I order when considering the diagnosis of PCOS are a total testosterone, SHBG, and 17-OH Prog.

Additional laboratory tests may be warranted to assess the patient diagnosed with PCOS. For example, if the patient has amenorrhea due to anovulation, tests for prolactin, FSH, and thyroid-stimulating hormone levels are warranted to assess for the presence of a prolactinoma, primary ovarian insufficiency, or thyroid disease, respectively. If the patient has a body mass index (BMI) ≥ 25 kg/m², a hemoglobin A1c concentration is warranted to assess for the presence of prediabetes or DM.² Many patients with PCOS have dyslipidemia, manifested through low high-density lipoprotein cholesterol levels and elevated low-density lipoprotein cholesterol levels, and a lipid panel assessment may be indicated. Among patients with PCOS, the most common lipid abnormality is a low high-density lipoprotein cholesterol level.¹⁷

Simplify the treatment of PCOS

Simplify treatment by counseling about lifestyle changes and prescribing an estrogen-progestin contraceptive, spironolactone, and metformin.

Most patients with PCOS have dysfunction in reproductive, metabolic, and dermatologic systems. For patients who are overweight or obese, lifestyle changes, including diet and exercise, that result in a 5% to 10% decrease in weight can improve metabolic balance, reduce circulating androgens, and increase menstrual frequency.¹⁸ For patients with PCOS and weight issues, referral to nutrition counseling or a full-service weight loss program can be very beneficial. In addition to lifestyle changes, patients with PCOS benefit from treatment with estrogen-progestin medications, spironolactone, and metformin.

Combination estrogen-progestin medications will lower LH secretion, decrease ovarian androgen production, increase SHBG production, decrease free testosterone levels and, if given cyclically, cause regular withdrawal bleeding.¹⁹ Spironolactone is an antiandrogen, which blocks the intracellular action of dihydrotestosterone and improves hirsutism and acne. Spironolactone also modestly decreases circulating levels of testosterone and DHEAS.²⁰ For patients with metabolic problems, including insulin resistance and obesity, weight loss and/or treatment with metformin can help improve metabolic balance, which may result in restoration of ovulatory menses.^21,22 Metformin can be effective in restoring ovulatory menses in both obese and lean patients with PCOS.²² The most common dermatologic problem caused by PCOS are hirsutism and acne. Both combination estrogen-progestin medications and spironolactone are effective treatments for hirsutism and acne.²³

Estrogen-progestin hormones, spironolactone, and metformin are low-cost medications for the treatment of PCOS. Additional high-cost options for treatment of PCOS in obese patients include bariatric surgery and glucagon-like peptide (GLP-1) agonist medications (liraglutide and exenatide). For patients with PCOS and a body mass index (BMI) ≥ 35 kg/m², bariatric surgery often results in sufficient weight loss to resolve the patient’s hyperandrogenism and oligo-ovulation, restoring spontaneous ovulatory cycles.²⁴ In a study of more than 1,000 patients with: PCOS; mean BMI, 44 kg/m²; mean age, 31 years who were followed post-bariatric surgery for 5 years, > 90% of patients reported reductions in hirsutism and resumption of regular menses.²⁵ For patients with PCOS seeking fertility, bariatric surgery often results in spontaneous pregnancy and live birth.²⁶ GLP-1 agonists, including liraglutide or exenatide with or without metformin are effective in reducing weight, decreasing androgen levels, and restoring ovulatory menses.^27,28

In my practice, I often prescribe 2 or 3 core medications for a patient with PCOS: 1) combination estrogen-progestin used cyclically or continuously, 2) spironolactone, and 3) metformin.¹⁹ Any estrogen-progestin contraceptive will suppress LH and ovarian androgen production; however, in the treatment of patients with PCOS, I prefer to use an estrogen-progestin combination that does not contain the androgenic progestin levonorgestrel.²⁹ For the treatment of PCOS, I prefer to use an estrogen-progestin contraceptive with a non-androgenic progestin such as drospirenone, desogestrel, or gestodene. I routinely prescribe spironolactone at a dose of 100 mg, once daily, a dose near the top of the dose-response curve. A daily dose ≤ 50 mg of spironolactone is subtherapeutic for the treatment of hirsutism. A daily dose of 200 mg of spironolactone may cause bothersome breakthrough bleeding. When prescribing metformin, I usually recommend the extended-release formulation, at a dose of 750 mg with dinner. If well tolerated, I will increase the dose to 1,500 mg with dinner. Most of my patients with PCOS are taking a combination of 2 medications, either an estrogen-progestin contraceptive plus spironolactone or an estrogen-progestin contraceptive plus metformin.¹⁹ Some of my patients are taking all 3 medications. All 3 medications are very low cost.

For patients with PCOS and anovulatory infertility, letrozole treatment often results in ovulatory cycles and pregnancy with live birth. In obese PCOS patients, compared with clomiphene, letrozole results in superior live birth rates.³⁰ Unlike clomiphene, letrozole is not approved by the US Food and Drug Administration for the treatment of anovulatory infertility.

The diagnosis of PCOS is often delayed due to confusion about how to make the diagnosis.³¹ To simplify the diagnosis of PCOS and improve patient encounters for PCOS, I focus on 2 core criteria: hyperandrogenism and oligo-ovulation. I recommend against ordering ultrasound imaging to assess for the presence of a multifollicular ovary. To simplify the treatment of PCOS I frequently prescribe an estrogen-progestin contraceptive, spironolactone, and metformin. By simplifying the diagnosis and treatment of PCOS, ObGyns will reduce patient confusion, improve outcomes, and save health care resources. ●

PCOS is a common problem, with a prevalence of 6% to 10% among women of reproductive age.¹ Patients with PCOS often present with hirsutism, acne, female androgenetic alopecia, oligomenorrhea (also known as infrequent menstrual bleeding), amenorrhea, infertility, overweight, or obesity. In addition, many patients with PCOS have insulin resistance, dyslipidemia, metabolic syndrome, and an increased risk for developing type 2 diabetes mellitus (DM).² A simplified approach to the diagnosis of PCOS will save health care resources by reducing the use of low-value diagnostic tests. A simplified approach to the treatment of PCOS will support patient medication adherence and improve health outcomes.

Simplify the diagnosis of PCOS

Simplify PCOS diagnosis by focusing on the core criteria of hyperandrogenism and oligo-ovulation. There are 3 major approaches to diagnosis:

1. the 1990 National Institutes of Health (NIH) criteria³
2. the 2003 Rotterdam criteria^4,5
3. the 2008 Androgen Excess and PCOS Society (AES) criteria.⁶

Using the 1990 NIH approach, the diagnosis of PCOS is made by the presence of 2 core criteria: hyperandrogenism and oligo-ovulation, typically manifested as oligomenorrhea. In addition, other causes of hyperandrogenism should be excluded, including nonclassical adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency.³ Using the 1990 NIH criteria, PCOS can be diagnosed based on history (oligomenorrhea) and physical examination (assessment of the severity of hirsutism), but laboratory tests including total testosterone are often ordered.⁷

The Rotterdam approach to the diagnosis added a third criteria, the detection by ultrasonography of a multifollicular ovary and/or increased ovarian volume.^4,5 Using the Rotterdam approach, PCOS is diagnosed in the presence of any 2 of the following 3 criteria: hyperandrogenism, oligo-ovulation, or ultrasound imaging showing the presence of a multifollicular ovary, identified by ≥ 12 antral follicles (2 to 9 mm in diameter) in each ovary or increased ovarian volume (> 10 mL).^4,5

The Rotterdam approach using ovarian ultrasound as a criterion to diagnose PCOS is rife with serious problems, including:

• The number of small antral follicles in the normal ovary is age dependent, and many ovulatory and nonhirsute patients have ≥ 12 small antral follicles in each ovary.^8,9
• There is no consensus on the number of small antral follicles needed to diagnose a multifollicular ovary, with recommendations to use thresholds of 12^4,5 or 20 follicles¹⁰ as the diagnostic cut-off.
• Accurate counting of the number of small ovarian follicles requires transvaginal ultrasound, which is not appropriate for many young adolescent patients.
• The process of counting ovarian follicles is operator-dependent.
• The high cost of ultrasound assessment of ovarian follicles (≥ $500 per examination).

The Rotterdam approach supports the diagnosis of PCOS in a patient with oligo-ovulation plus an ultrasound showing a multifollicular ovary in the absence of any clinical or laboratory evidence of hyperandrogenism.^3,4,5 This approach to the diagnosis of PCOS is rejected by both the 1990 NIH³ and AES⁶ recommendations, which require the presence of hyperandrogenism as the sine qua non in the diagnosis of PCOS. I recommend against diagnosing PCOS in a non-hyperandrogenic patient with oligo-ovulation and a multifollicular ovary because other diagnoses are also possible, such as functional hypothalamic oligo-ovulation, especially in young patients. The Rotterdam approach also supports the diagnosis of PCOS in a patient with hyperandrogenism, an ultrasound showing a multifollicular ovary, and normal ovulation and menses.^3,4 For most patients with normal, regular ovulation and menses, the testosterone concentration is normal and the only evidence of hyperandrogenism is hirsutism. Patients with normal, regular ovulation and menses plus hirsutism usually have idiopathic hirsutism. Idiopathic hirsutism is a problem caused by excessive 5-alpha-reductase activity in the hair pilosebaceous unit, which catalyzes the conversion of weak androgens into dihydrotestosterone, a potent intracellular androgen that stimulates terminal hair growth.¹¹ In my opinion, the Rotterdam approach to diagnosing PCOS has created unnecessary confusion and complexity for both clinicians and patients. I believe we should simplify the diagnosis of PCOS and return to the 1990 NIH criteria.³

On occasion, a patient presents for a consultation and has already had an ovarian ultrasound to assess for a multifollicular ovary. I carefully read the report and, if a multifollicular ovary has been identified, I consider it as a secondary supporting finding of PCOS in my clinical assessment. But I do not base my diagnosis on the ultrasound finding. Patients often present with other laboratory tests that are secondary supporting findings of PCOS, which I carefully consider but do not use to make a diagnosis of PCOS. Secondary supporting laboratory findings consistent with PCOS include: 1) a markedly elevated anti-müllerian hormone (AMH) level,¹² 2) an elevated fasting insulin level,^2,13 and 3) an elevated luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio.^13,14 But it is not necessary to measure AMH, fasting insulin, LH, and FSH levels. To conserve health care resources, I recommend against measuring those analytes to diagnose PCOS.

Continue to: Simplify the core laboratory tests...

Simplify the core laboratory tests

Simplify the testing used to support the diagnosis of PCOS by measuring total testosterone, sex-hormone binding globulin (SHBG) and early morning 17-hydroxyprogesterone (17-OH Prog).

The core criteria for diagnosis of PCOS are hyperandrogenism and oligo-ovulation, typically manifested as oligomenorrhea or amenorrhea. Hyperandrogenism can be clinically diagnosed by assessing for the presence of hirsutism.⁷ Elevated levels of total testosterone, free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate (DHEAS) suggest the presence of hyperandrogenism. In clinical practice, the laboratory approach to the diagnosis of hyperandrogenism can be simplified to the measurement of total testosterone, SHBG, and 17-OH Prog. By measuring total testosterone and SHBG, an estimate of free testosterone can be made. If the total testosterone is elevated, it is highly likely that the free testosterone is elevated. If the SHBG is abnormally low and the total testosterone level is in the upper limit of the normal range, the free testosterone is likely to be elevated.¹⁵ Using this approach, either an elevated total testosterone or an abnormally low SHBG indicate elevated free testosterone. For patients with hyperandrogenism and oligo-ovulation, an early morning (8 to 9 AM) 17-OH Prog level ≤ 2 ng/mL rules out the presence of NCAH due to a 21-hydroxylase deficiency.¹⁶ In my practice, the core laboratory tests I order when considering the diagnosis of PCOS are a total testosterone, SHBG, and 17-OH Prog.

Additional laboratory tests may be warranted to assess the patient diagnosed with PCOS. For example, if the patient has amenorrhea due to anovulation, tests for prolactin, FSH, and thyroid-stimulating hormone levels are warranted to assess for the presence of a prolactinoma, primary ovarian insufficiency, or thyroid disease, respectively. If the patient has a body mass index (BMI) ≥ 25 kg/m², a hemoglobin A1c concentration is warranted to assess for the presence of prediabetes or DM.² Many patients with PCOS have dyslipidemia, manifested through low high-density lipoprotein cholesterol levels and elevated low-density lipoprotein cholesterol levels, and a lipid panel assessment may be indicated. Among patients with PCOS, the most common lipid abnormality is a low high-density lipoprotein cholesterol level.¹⁷

Simplify the treatment of PCOS

Simplify treatment by counseling about lifestyle changes and prescribing an estrogen-progestin contraceptive, spironolactone, and metformin.

Most patients with PCOS have dysfunction in reproductive, metabolic, and dermatologic systems. For patients who are overweight or obese, lifestyle changes, including diet and exercise, that result in a 5% to 10% decrease in weight can improve metabolic balance, reduce circulating androgens, and increase menstrual frequency.¹⁸ For patients with PCOS and weight issues, referral to nutrition counseling or a full-service weight loss program can be very beneficial. In addition to lifestyle changes, patients with PCOS benefit from treatment with estrogen-progestin medications, spironolactone, and metformin.

Combination estrogen-progestin medications will lower LH secretion, decrease ovarian androgen production, increase SHBG production, decrease free testosterone levels and, if given cyclically, cause regular withdrawal bleeding.¹⁹ Spironolactone is an antiandrogen, which blocks the intracellular action of dihydrotestosterone and improves hirsutism and acne. Spironolactone also modestly decreases circulating levels of testosterone and DHEAS.²⁰ For patients with metabolic problems, including insulin resistance and obesity, weight loss and/or treatment with metformin can help improve metabolic balance, which may result in restoration of ovulatory menses.^21,22 Metformin can be effective in restoring ovulatory menses in both obese and lean patients with PCOS.²² The most common dermatologic problem caused by PCOS are hirsutism and acne. Both combination estrogen-progestin medications and spironolactone are effective treatments for hirsutism and acne.²³

Estrogen-progestin hormones, spironolactone, and metformin are low-cost medications for the treatment of PCOS. Additional high-cost options for treatment of PCOS in obese patients include bariatric surgery and glucagon-like peptide (GLP-1) agonist medications (liraglutide and exenatide). For patients with PCOS and a body mass index (BMI) ≥ 35 kg/m², bariatric surgery often results in sufficient weight loss to resolve the patient’s hyperandrogenism and oligo-ovulation, restoring spontaneous ovulatory cycles.²⁴ In a study of more than 1,000 patients with: PCOS; mean BMI, 44 kg/m²; mean age, 31 years who were followed post-bariatric surgery for 5 years, > 90% of patients reported reductions in hirsutism and resumption of regular menses.²⁵ For patients with PCOS seeking fertility, bariatric surgery often results in spontaneous pregnancy and live birth.²⁶ GLP-1 agonists, including liraglutide or exenatide with or without metformin are effective in reducing weight, decreasing androgen levels, and restoring ovulatory menses.^27,28

In my practice, I often prescribe 2 or 3 core medications for a patient with PCOS: 1) combination estrogen-progestin used cyclically or continuously, 2) spironolactone, and 3) metformin.¹⁹ Any estrogen-progestin contraceptive will suppress LH and ovarian androgen production; however, in the treatment of patients with PCOS, I prefer to use an estrogen-progestin combination that does not contain the androgenic progestin levonorgestrel.²⁹ For the treatment of PCOS, I prefer to use an estrogen-progestin contraceptive with a non-androgenic progestin such as drospirenone, desogestrel, or gestodene. I routinely prescribe spironolactone at a dose of 100 mg, once daily, a dose near the top of the dose-response curve. A daily dose ≤ 50 mg of spironolactone is subtherapeutic for the treatment of hirsutism. A daily dose of 200 mg of spironolactone may cause bothersome breakthrough bleeding. When prescribing metformin, I usually recommend the extended-release formulation, at a dose of 750 mg with dinner. If well tolerated, I will increase the dose to 1,500 mg with dinner. Most of my patients with PCOS are taking a combination of 2 medications, either an estrogen-progestin contraceptive plus spironolactone or an estrogen-progestin contraceptive plus metformin.¹⁹ Some of my patients are taking all 3 medications. All 3 medications are very low cost.

For patients with PCOS and anovulatory infertility, letrozole treatment often results in ovulatory cycles and pregnancy with live birth. In obese PCOS patients, compared with clomiphene, letrozole results in superior live birth rates.³⁰ Unlike clomiphene, letrozole is not approved by the US Food and Drug Administration for the treatment of anovulatory infertility.

The diagnosis of PCOS is often delayed due to confusion about how to make the diagnosis.³¹ To simplify the diagnosis of PCOS and improve patient encounters for PCOS, I focus on 2 core criteria: hyperandrogenism and oligo-ovulation. I recommend against ordering ultrasound imaging to assess for the presence of a multifollicular ovary. To simplify the treatment of PCOS I frequently prescribe an estrogen-progestin contraceptive, spironolactone, and metformin. By simplifying the diagnosis and treatment of PCOS, ObGyns will reduce patient confusion, improve outcomes, and save health care resources. ●

PCOS is a common problem, with a prevalence of 6% to 10% among women of reproductive age.¹ Patients with PCOS often present with hirsutism, acne, female androgenetic alopecia, oligomenorrhea (also known as infrequent menstrual bleeding), amenorrhea, infertility, overweight, or obesity. In addition, many patients with PCOS have insulin resistance, dyslipidemia, metabolic syndrome, and an increased risk for developing type 2 diabetes mellitus (DM).² A simplified approach to the diagnosis of PCOS will save health care resources by reducing the use of low-value diagnostic tests. A simplified approach to the treatment of PCOS will support patient medication adherence and improve health outcomes.

Simplify the diagnosis of PCOS

Simplify PCOS diagnosis by focusing on the core criteria of hyperandrogenism and oligo-ovulation. There are 3 major approaches to diagnosis:

1. the 1990 National Institutes of Health (NIH) criteria³
2. the 2003 Rotterdam criteria^4,5
3. the 2008 Androgen Excess and PCOS Society (AES) criteria.⁶

Using the 1990 NIH approach, the diagnosis of PCOS is made by the presence of 2 core criteria: hyperandrogenism and oligo-ovulation, typically manifested as oligomenorrhea. In addition, other causes of hyperandrogenism should be excluded, including nonclassical adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency.³ Using the 1990 NIH criteria, PCOS can be diagnosed based on history (oligomenorrhea) and physical examination (assessment of the severity of hirsutism), but laboratory tests including total testosterone are often ordered.⁷

The Rotterdam approach to the diagnosis added a third criteria, the detection by ultrasonography of a multifollicular ovary and/or increased ovarian volume.^4,5 Using the Rotterdam approach, PCOS is diagnosed in the presence of any 2 of the following 3 criteria: hyperandrogenism, oligo-ovulation, or ultrasound imaging showing the presence of a multifollicular ovary, identified by ≥ 12 antral follicles (2 to 9 mm in diameter) in each ovary or increased ovarian volume (> 10 mL).^4,5

The Rotterdam approach using ovarian ultrasound as a criterion to diagnose PCOS is rife with serious problems, including:

• The number of small antral follicles in the normal ovary is age dependent, and many ovulatory and nonhirsute patients have ≥ 12 small antral follicles in each ovary.^8,9
• There is no consensus on the number of small antral follicles needed to diagnose a multifollicular ovary, with recommendations to use thresholds of 12^4,5 or 20 follicles¹⁰ as the diagnostic cut-off.
• Accurate counting of the number of small ovarian follicles requires transvaginal ultrasound, which is not appropriate for many young adolescent patients.
• The process of counting ovarian follicles is operator-dependent.
• The high cost of ultrasound assessment of ovarian follicles (≥ $500 per examination).

The Rotterdam approach supports the diagnosis of PCOS in a patient with oligo-ovulation plus an ultrasound showing a multifollicular ovary in the absence of any clinical or laboratory evidence of hyperandrogenism.^3,4,5 This approach to the diagnosis of PCOS is rejected by both the 1990 NIH³ and AES⁶ recommendations, which require the presence of hyperandrogenism as the sine qua non in the diagnosis of PCOS. I recommend against diagnosing PCOS in a non-hyperandrogenic patient with oligo-ovulation and a multifollicular ovary because other diagnoses are also possible, such as functional hypothalamic oligo-ovulation, especially in young patients. The Rotterdam approach also supports the diagnosis of PCOS in a patient with hyperandrogenism, an ultrasound showing a multifollicular ovary, and normal ovulation and menses.^3,4 For most patients with normal, regular ovulation and menses, the testosterone concentration is normal and the only evidence of hyperandrogenism is hirsutism. Patients with normal, regular ovulation and menses plus hirsutism usually have idiopathic hirsutism. Idiopathic hirsutism is a problem caused by excessive 5-alpha-reductase activity in the hair pilosebaceous unit, which catalyzes the conversion of weak androgens into dihydrotestosterone, a potent intracellular androgen that stimulates terminal hair growth.¹¹ In my opinion, the Rotterdam approach to diagnosing PCOS has created unnecessary confusion and complexity for both clinicians and patients. I believe we should simplify the diagnosis of PCOS and return to the 1990 NIH criteria.³

On occasion, a patient presents for a consultation and has already had an ovarian ultrasound to assess for a multifollicular ovary. I carefully read the report and, if a multifollicular ovary has been identified, I consider it as a secondary supporting finding of PCOS in my clinical assessment. But I do not base my diagnosis on the ultrasound finding. Patients often present with other laboratory tests that are secondary supporting findings of PCOS, which I carefully consider but do not use to make a diagnosis of PCOS. Secondary supporting laboratory findings consistent with PCOS include: 1) a markedly elevated anti-müllerian hormone (AMH) level,¹² 2) an elevated fasting insulin level,^2,13 and 3) an elevated luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio.^13,14 But it is not necessary to measure AMH, fasting insulin, LH, and FSH levels. To conserve health care resources, I recommend against measuring those analytes to diagnose PCOS.

Continue to: Simplify the core laboratory tests...

Simplify the core laboratory tests

Simplify the testing used to support the diagnosis of PCOS by measuring total testosterone, sex-hormone binding globulin (SHBG) and early morning 17-hydroxyprogesterone (17-OH Prog).

The core criteria for diagnosis of PCOS are hyperandrogenism and oligo-ovulation, typically manifested as oligomenorrhea or amenorrhea. Hyperandrogenism can be clinically diagnosed by assessing for the presence of hirsutism.⁷ Elevated levels of total testosterone, free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate (DHEAS) suggest the presence of hyperandrogenism. In clinical practice, the laboratory approach to the diagnosis of hyperandrogenism can be simplified to the measurement of total testosterone, SHBG, and 17-OH Prog. By measuring total testosterone and SHBG, an estimate of free testosterone can be made. If the total testosterone is elevated, it is highly likely that the free testosterone is elevated. If the SHBG is abnormally low and the total testosterone level is in the upper limit of the normal range, the free testosterone is likely to be elevated.¹⁵ Using this approach, either an elevated total testosterone or an abnormally low SHBG indicate elevated free testosterone. For patients with hyperandrogenism and oligo-ovulation, an early morning (8 to 9 AM) 17-OH Prog level ≤ 2 ng/mL rules out the presence of NCAH due to a 21-hydroxylase deficiency.¹⁶ In my practice, the core laboratory tests I order when considering the diagnosis of PCOS are a total testosterone, SHBG, and 17-OH Prog.

Additional laboratory tests may be warranted to assess the patient diagnosed with PCOS. For example, if the patient has amenorrhea due to anovulation, tests for prolactin, FSH, and thyroid-stimulating hormone levels are warranted to assess for the presence of a prolactinoma, primary ovarian insufficiency, or thyroid disease, respectively. If the patient has a body mass index (BMI) ≥ 25 kg/m², a hemoglobin A1c concentration is warranted to assess for the presence of prediabetes or DM.² Many patients with PCOS have dyslipidemia, manifested through low high-density lipoprotein cholesterol levels and elevated low-density lipoprotein cholesterol levels, and a lipid panel assessment may be indicated. Among patients with PCOS, the most common lipid abnormality is a low high-density lipoprotein cholesterol level.¹⁷

Simplify the treatment of PCOS

Simplify treatment by counseling about lifestyle changes and prescribing an estrogen-progestin contraceptive, spironolactone, and metformin.

Most patients with PCOS have dysfunction in reproductive, metabolic, and dermatologic systems. For patients who are overweight or obese, lifestyle changes, including diet and exercise, that result in a 5% to 10% decrease in weight can improve metabolic balance, reduce circulating androgens, and increase menstrual frequency.¹⁸ For patients with PCOS and weight issues, referral to nutrition counseling or a full-service weight loss program can be very beneficial. In addition to lifestyle changes, patients with PCOS benefit from treatment with estrogen-progestin medications, spironolactone, and metformin.

Combination estrogen-progestin medications will lower LH secretion, decrease ovarian androgen production, increase SHBG production, decrease free testosterone levels and, if given cyclically, cause regular withdrawal bleeding.¹⁹ Spironolactone is an antiandrogen, which blocks the intracellular action of dihydrotestosterone and improves hirsutism and acne. Spironolactone also modestly decreases circulating levels of testosterone and DHEAS.²⁰ For patients with metabolic problems, including insulin resistance and obesity, weight loss and/or treatment with metformin can help improve metabolic balance, which may result in restoration of ovulatory menses.^21,22 Metformin can be effective in restoring ovulatory menses in both obese and lean patients with PCOS.²² The most common dermatologic problem caused by PCOS are hirsutism and acne. Both combination estrogen-progestin medications and spironolactone are effective treatments for hirsutism and acne.²³

Estrogen-progestin hormones, spironolactone, and metformin are low-cost medications for the treatment of PCOS. Additional high-cost options for treatment of PCOS in obese patients include bariatric surgery and glucagon-like peptide (GLP-1) agonist medications (liraglutide and exenatide). For patients with PCOS and a body mass index (BMI) ≥ 35 kg/m², bariatric surgery often results in sufficient weight loss to resolve the patient’s hyperandrogenism and oligo-ovulation, restoring spontaneous ovulatory cycles.²⁴ In a study of more than 1,000 patients with: PCOS; mean BMI, 44 kg/m²; mean age, 31 years who were followed post-bariatric surgery for 5 years, > 90% of patients reported reductions in hirsutism and resumption of regular menses.²⁵ For patients with PCOS seeking fertility, bariatric surgery often results in spontaneous pregnancy and live birth.²⁶ GLP-1 agonists, including liraglutide or exenatide with or without metformin are effective in reducing weight, decreasing androgen levels, and restoring ovulatory menses.^27,28

In my practice, I often prescribe 2 or 3 core medications for a patient with PCOS: 1) combination estrogen-progestin used cyclically or continuously, 2) spironolactone, and 3) metformin.¹⁹ Any estrogen-progestin contraceptive will suppress LH and ovarian androgen production; however, in the treatment of patients with PCOS, I prefer to use an estrogen-progestin combination that does not contain the androgenic progestin levonorgestrel.²⁹ For the treatment of PCOS, I prefer to use an estrogen-progestin contraceptive with a non-androgenic progestin such as drospirenone, desogestrel, or gestodene. I routinely prescribe spironolactone at a dose of 100 mg, once daily, a dose near the top of the dose-response curve. A daily dose ≤ 50 mg of spironolactone is subtherapeutic for the treatment of hirsutism. A daily dose of 200 mg of spironolactone may cause bothersome breakthrough bleeding. When prescribing metformin, I usually recommend the extended-release formulation, at a dose of 750 mg with dinner. If well tolerated, I will increase the dose to 1,500 mg with dinner. Most of my patients with PCOS are taking a combination of 2 medications, either an estrogen-progestin contraceptive plus spironolactone or an estrogen-progestin contraceptive plus metformin.¹⁹ Some of my patients are taking all 3 medications. All 3 medications are very low cost.

For patients with PCOS and anovulatory infertility, letrozole treatment often results in ovulatory cycles and pregnancy with live birth. In obese PCOS patients, compared with clomiphene, letrozole results in superior live birth rates.³⁰ Unlike clomiphene, letrozole is not approved by the US Food and Drug Administration for the treatment of anovulatory infertility.

The diagnosis of PCOS is often delayed due to confusion about how to make the diagnosis.³¹ To simplify the diagnosis of PCOS and improve patient encounters for PCOS, I focus on 2 core criteria: hyperandrogenism and oligo-ovulation. I recommend against ordering ultrasound imaging to assess for the presence of a multifollicular ovary. To simplify the treatment of PCOS I frequently prescribe an estrogen-progestin contraceptive, spironolactone, and metformin. By simplifying the diagnosis and treatment of PCOS, ObGyns will reduce patient confusion, improve outcomes, and save health care resources. ●

Cesarean birth is one of the most common major surgical procedures performed in developed countries¹ with over 1,170,000 cesarean births in the United States in 2021.² Many surgeons and anesthesiologists believe that Enhanced Recovery after Surgery (ERAS) pathways improve surgical outcomes.^3,4 Important goals of ERAS include setting patient expectations for the surgical procedure, accelerating patient recovery to full function, and minimizing perioperative complications such as severe nausea, aspiration, surgical site infection, wound complications, and perioperative anemia. The ERAS Society in 2018^5-7 and the Society for Obstetric Anesthesia and Perinatology (SOAP) in 2021⁸ proposed ERAS pathways for cesarean birth. Both societies recommended that obstetric units consider adopting an ERAS pathway compatible with local clinical resources. In addition, the American College of Obstetricians and Gynecologists (ACOG) has provided guidance for implementing ERAS pathways for gynecologic surgery.⁹ The consistent use of standardized protocols to improve surgical care in obstetrics should lead to a reduction in care variation and improve health equity outcomes.

The clinical interventions recommended for ERAS cesarean birth occur sequentially in the preoperative, intraoperative, and postoperative phases of care. The recommendations associated with each of these phases are reviewed below. It is important to note that each obstetric unit should use a multidisciplinary process to develop an ERAS pathway that best supports local practice given clinician preferences, patient characteristics, and resource availability.
 

Preoperative components of ERAS

Standardized patient education (SPE). SPE is an important component of ERAS, although evidence to support the recommendation is limited. At a minimum a written handout describing steps in the cesarean birth process, or a patient-education video should be part of patient education. The University of Michigan Medical Center has produced a 3-minute video for patients explaining ERAS cesarean birth.¹⁰ The University of Maryland Medical Center has produced a 2.5-minute video in English and Spanish, explaining ERAS cesarean birth for patients.¹¹ Some surgeons place a telephone call to patients the evening before surgery to help orient the patient to ERAS cesarean birth.

Breastfeeding education. An important goal of obstetric care is to optimize the rate of exclusive breastfeeding at birth. Breastfeeding education, including a commitment to support the initiation of breastfeeding within 1 hour of birth, may enhance the rate of exclusive breastfeeding. There are numerous videos available for patients about breastfeeding after cesarean birth (as an example, see: https://www.youtube.com/watch?v=9iOGn85NdTg).

Limit fasting. In the past, surgical guidelines recommended fasting after midnight prior to surgery. The ERAS Society recommends that patients should be encouraged to drink clear fluids up to 2 hours before surgery and may have a light meal up to 6 hours before surgery (Part 1).

Carbohydrate loading. Surgery causes a metabolic stress that is increased by fasting. Carbohydrate loading prior to surgery reduces the magnitude of the catabolic state caused by the combination of surgery and fasting.¹² SOAP and the ERAS Society recommend oral carbohydrate fluid supplementation 2 hours before surgery for nondiabetic patients. SOAP suggests 32 oz of Gatorade or 16 oz of clear apple juice as options for carbohydrate loading. For diabetic patients, the carbohydrate load can be omitted. In fasting pregnant patients at term, gastric emptying was near complete 2 hours after consumption of 400 mL of a carbohydrate drink.¹³ In one study, consumption of 400 mL of a carbohydrate drink 2 hours before cesarean resulted in a 7% increase in the newborn blood glucose level at 20 min after delivery.¹⁴

Minimize preoperative anemia. Approximately 50% of pregnant women are iron deficient and approximately 10% are anemic in the third trimester.^15,16 Cesarean birth is associated with significant blood loss necessitating the need to optimize red blood cell mass before surgery. Measuring ferritin to identify patients with iron deficiency and aggressive iron replacement, including intravenous iron if necessary, will reduce the prevalence of anemia prior to cesarean birth.¹⁷ Another cause of anemia in pregnancy is vitamin B12 (cobalamin) deficiency. Low vitamin B12 is especially common in pregnant patients who have previously had bariatric surgery. One study reported that, of 113 pregnant patients who were, on average, 3 years from a bariatric surgery procedure, 12% had vitamin B12 circulating levels < 130 pg/mL.¹⁸ Among pregnant patients who are anemic, and do not have a hemoglobinopathy, measuring ferritin, folic acid, and vitamin B12 will help identify the cause of anemia and guide treatment.¹⁹

Optimize preoperative physical condition. Improving healthy behaviors and reducing unhealthy behaviors preoperatively may enhance patient recovery to full function. In the weeks before scheduled cesarean birth, cessation of the use of tobacco products, optimizing activity and improving diet quality, including increasing protein intake, may best prepare patients for the metabolic stress of surgery.

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

Reduce the risk of surgical site infection (SSI) and wound complications. Bundles that include antibiotics, chlorhexidine (or an alternative antibacterial soap) and clippers have been shown to reduce SSI.²⁰ Routine administration of preoperative antibiotics is a consensus recommendation and there is high adherence with this recommendation in the United States. Chlorhexidine-alcohol is the preferred solution for skin preparation. Vaginal preparation with povidine-iodine or chlorhexidine may be considered.⁶

Surgical technique. Blunt extension of a transverse hysterotomy may reduce blood loss. Closure of the hysterotomy incision in 2 layers is recommended to reduce uterine scar dehiscence in a subsequent pregnancy. If the patient has ≥2 cm of subcutaneous tissue, this layer should be approximated with sutures. Skin closure should be with subcuticular suture.⁶

Optimize uterotonic administration. Routine use of uterotonics reduces the risk of blood loss, transfusion, and postoperative anemia. There is high adherence with the use of uterotonic administration after birth in the United States.^6,8

Ensure normothermia. Many patients become hypothermic during a cesarean birth. Active warming of the patient with an in-line IV fluid warmer and forced air warming over the patient’s body can reduce the risk of hypothermia.⁸

Initiate multimodal anesthesia. Anesthesiologists often use intrathecal or epidural morphine to enhance analgesia. Ketorolac administration prior to completion of the cesarean procedure and perioperative administration of acetaminophen may reduce postoperative pain.⁸ The use of preoperative antiemetics will reduce intraoperative and postoperative nausea and vomiting.

Initiate VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁶

Postoperative components of ERAS

Patient education to prepare for discharge home when ready. Patient education focused on home when ready is important in preparing the patient for discharge home.⁷ Completion of required newborn testing, lactation education, and contraception planning plus coordination of newborn pediatric follow-up is necessary before discharge.

Support early return of bowel function. Early return of bowel function is best supported by a multimodal approach including initiation of clear fluid intake immediately following surgery, encouraging consumption of a regular diet within 2⁷ to 4 hours⁸ following surgery. Gum chewing for at least 5 minutes 3 times daily accelerates return of bowel function.⁸ In a meta-analysis of 10 randomized studies examining the effect of gum chewing after cesarean, the investigators reported that gum chewing shortened the time to passage of flatus and defecation.²¹

Early ambulation.

Sequentially advanced activity, starting with sitting on the edge of the bed, sitting in a chair, and ambulation within 8 hours of surgery, is recommended to facilitate faster recovery, reduce rates of complications, and enable transition to home.⁸

Early removal of the urinary catheter. It is recommended that the urinary catheter be removed within 12 hours after cesarean birth.⁸ Early removal of the urinary catheter increases patient mobility and reduces the length of hospitalization. Early removal of the urinary catheter may be associated with postoperative urinary retention and recatheterization in a small number of patients.

Prescribe routinely scheduled acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and ketorolac. A key component of ERAS cesarean birth is the standardized administration of nonopioid pain medicines, alternating doses of acetaminophen and an NSAID. ERAS cesarean birth is likely to result in a reduction in inpatient and postdischarge opioid use.^22-24

VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁸

Auditing and reporting adherence with components of ERAS

In clinical practice there may be a gap between a clinician’s subjective perception of their performance and an independent audit of their clinical performance. ERAS pathways should be implemented with a commitment to performing audits and providing quantitative feedback to clinicians. Consistent use of measurement, feedback, and coaching can improve performance and reduce variation among individual clinicians. As an example, in one study of the use of a surgical safety checklist, 99% of the surgeons reported that they routinely used a surgical safety checklist, but the audit showed that the checklist was used in only 60% of cases.²⁵ Gaps between self-reported performance and audited performance are common in clinical practice. Audits with feedback are critical to improving adherence with the components of an ERAS pathway.

Three independent systematic reviews and meta-analyses report that ERAS pathways reduce hospital length of stay without increasing the readmission rate.^26-28 One meta-analysis reported that ERAS may also reduce time to first mobilization and result in earlier removal of the urinary catheter.²⁶ ERAS pathways also may reduce postoperative complications, lower pain scores, and decrease opioid use.²⁷ The general consensus among quality and safety experts is that reducing variation through standardization of pathways is generally associated with improved quality and enhanced safety. ERAS pathways have been widely accepted in multiple surgical fields. ERAS pathways should become the standard for performing cesarean procedures.●

Cesarean birth is one of the most common major surgical procedures performed in developed countries¹ with over 1,170,000 cesarean births in the United States in 2021.² Many surgeons and anesthesiologists believe that Enhanced Recovery after Surgery (ERAS) pathways improve surgical outcomes.^3,4 Important goals of ERAS include setting patient expectations for the surgical procedure, accelerating patient recovery to full function, and minimizing perioperative complications such as severe nausea, aspiration, surgical site infection, wound complications, and perioperative anemia. The ERAS Society in 2018^5-7 and the Society for Obstetric Anesthesia and Perinatology (SOAP) in 2021⁸ proposed ERAS pathways for cesarean birth. Both societies recommended that obstetric units consider adopting an ERAS pathway compatible with local clinical resources. In addition, the American College of Obstetricians and Gynecologists (ACOG) has provided guidance for implementing ERAS pathways for gynecologic surgery.⁹ The consistent use of standardized protocols to improve surgical care in obstetrics should lead to a reduction in care variation and improve health equity outcomes.

The clinical interventions recommended for ERAS cesarean birth occur sequentially in the preoperative, intraoperative, and postoperative phases of care. The recommendations associated with each of these phases are reviewed below. It is important to note that each obstetric unit should use a multidisciplinary process to develop an ERAS pathway that best supports local practice given clinician preferences, patient characteristics, and resource availability.
 

Preoperative components of ERAS

Standardized patient education (SPE). SPE is an important component of ERAS, although evidence to support the recommendation is limited. At a minimum a written handout describing steps in the cesarean birth process, or a patient-education video should be part of patient education. The University of Michigan Medical Center has produced a 3-minute video for patients explaining ERAS cesarean birth.¹⁰ The University of Maryland Medical Center has produced a 2.5-minute video in English and Spanish, explaining ERAS cesarean birth for patients.¹¹ Some surgeons place a telephone call to patients the evening before surgery to help orient the patient to ERAS cesarean birth.

Breastfeeding education. An important goal of obstetric care is to optimize the rate of exclusive breastfeeding at birth. Breastfeeding education, including a commitment to support the initiation of breastfeeding within 1 hour of birth, may enhance the rate of exclusive breastfeeding. There are numerous videos available for patients about breastfeeding after cesarean birth (as an example, see: https://www.youtube.com/watch?v=9iOGn85NdTg).

Limit fasting. In the past, surgical guidelines recommended fasting after midnight prior to surgery. The ERAS Society recommends that patients should be encouraged to drink clear fluids up to 2 hours before surgery and may have a light meal up to 6 hours before surgery (Part 1).

Carbohydrate loading. Surgery causes a metabolic stress that is increased by fasting. Carbohydrate loading prior to surgery reduces the magnitude of the catabolic state caused by the combination of surgery and fasting.¹² SOAP and the ERAS Society recommend oral carbohydrate fluid supplementation 2 hours before surgery for nondiabetic patients. SOAP suggests 32 oz of Gatorade or 16 oz of clear apple juice as options for carbohydrate loading. For diabetic patients, the carbohydrate load can be omitted. In fasting pregnant patients at term, gastric emptying was near complete 2 hours after consumption of 400 mL of a carbohydrate drink.¹³ In one study, consumption of 400 mL of a carbohydrate drink 2 hours before cesarean resulted in a 7% increase in the newborn blood glucose level at 20 min after delivery.¹⁴

Minimize preoperative anemia. Approximately 50% of pregnant women are iron deficient and approximately 10% are anemic in the third trimester.^15,16 Cesarean birth is associated with significant blood loss necessitating the need to optimize red blood cell mass before surgery. Measuring ferritin to identify patients with iron deficiency and aggressive iron replacement, including intravenous iron if necessary, will reduce the prevalence of anemia prior to cesarean birth.¹⁷ Another cause of anemia in pregnancy is vitamin B12 (cobalamin) deficiency. Low vitamin B12 is especially common in pregnant patients who have previously had bariatric surgery. One study reported that, of 113 pregnant patients who were, on average, 3 years from a bariatric surgery procedure, 12% had vitamin B12 circulating levels < 130 pg/mL.¹⁸ Among pregnant patients who are anemic, and do not have a hemoglobinopathy, measuring ferritin, folic acid, and vitamin B12 will help identify the cause of anemia and guide treatment.¹⁹

Optimize preoperative physical condition. Improving healthy behaviors and reducing unhealthy behaviors preoperatively may enhance patient recovery to full function. In the weeks before scheduled cesarean birth, cessation of the use of tobacco products, optimizing activity and improving diet quality, including increasing protein intake, may best prepare patients for the metabolic stress of surgery.

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

Reduce the risk of surgical site infection (SSI) and wound complications. Bundles that include antibiotics, chlorhexidine (or an alternative antibacterial soap) and clippers have been shown to reduce SSI.²⁰ Routine administration of preoperative antibiotics is a consensus recommendation and there is high adherence with this recommendation in the United States. Chlorhexidine-alcohol is the preferred solution for skin preparation. Vaginal preparation with povidine-iodine or chlorhexidine may be considered.⁶

Surgical technique. Blunt extension of a transverse hysterotomy may reduce blood loss. Closure of the hysterotomy incision in 2 layers is recommended to reduce uterine scar dehiscence in a subsequent pregnancy. If the patient has ≥2 cm of subcutaneous tissue, this layer should be approximated with sutures. Skin closure should be with subcuticular suture.⁶

Optimize uterotonic administration. Routine use of uterotonics reduces the risk of blood loss, transfusion, and postoperative anemia. There is high adherence with the use of uterotonic administration after birth in the United States.^6,8

Ensure normothermia. Many patients become hypothermic during a cesarean birth. Active warming of the patient with an in-line IV fluid warmer and forced air warming over the patient’s body can reduce the risk of hypothermia.⁸

Initiate multimodal anesthesia. Anesthesiologists often use intrathecal or epidural morphine to enhance analgesia. Ketorolac administration prior to completion of the cesarean procedure and perioperative administration of acetaminophen may reduce postoperative pain.⁸ The use of preoperative antiemetics will reduce intraoperative and postoperative nausea and vomiting.

Initiate VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁶

Postoperative components of ERAS

Patient education to prepare for discharge home when ready. Patient education focused on home when ready is important in preparing the patient for discharge home.⁷ Completion of required newborn testing, lactation education, and contraception planning plus coordination of newborn pediatric follow-up is necessary before discharge.

Support early return of bowel function. Early return of bowel function is best supported by a multimodal approach including initiation of clear fluid intake immediately following surgery, encouraging consumption of a regular diet within 2⁷ to 4 hours⁸ following surgery. Gum chewing for at least 5 minutes 3 times daily accelerates return of bowel function.⁸ In a meta-analysis of 10 randomized studies examining the effect of gum chewing after cesarean, the investigators reported that gum chewing shortened the time to passage of flatus and defecation.²¹

Early ambulation.

Sequentially advanced activity, starting with sitting on the edge of the bed, sitting in a chair, and ambulation within 8 hours of surgery, is recommended to facilitate faster recovery, reduce rates of complications, and enable transition to home.⁸

Early removal of the urinary catheter. It is recommended that the urinary catheter be removed within 12 hours after cesarean birth.⁸ Early removal of the urinary catheter increases patient mobility and reduces the length of hospitalization. Early removal of the urinary catheter may be associated with postoperative urinary retention and recatheterization in a small number of patients.

Prescribe routinely scheduled acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and ketorolac. A key component of ERAS cesarean birth is the standardized administration of nonopioid pain medicines, alternating doses of acetaminophen and an NSAID. ERAS cesarean birth is likely to result in a reduction in inpatient and postdischarge opioid use.^22-24

VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁸

Auditing and reporting adherence with components of ERAS

In clinical practice there may be a gap between a clinician’s subjective perception of their performance and an independent audit of their clinical performance. ERAS pathways should be implemented with a commitment to performing audits and providing quantitative feedback to clinicians. Consistent use of measurement, feedback, and coaching can improve performance and reduce variation among individual clinicians. As an example, in one study of the use of a surgical safety checklist, 99% of the surgeons reported that they routinely used a surgical safety checklist, but the audit showed that the checklist was used in only 60% of cases.²⁵ Gaps between self-reported performance and audited performance are common in clinical practice. Audits with feedback are critical to improving adherence with the components of an ERAS pathway.

Three independent systematic reviews and meta-analyses report that ERAS pathways reduce hospital length of stay without increasing the readmission rate.^26-28 One meta-analysis reported that ERAS may also reduce time to first mobilization and result in earlier removal of the urinary catheter.²⁶ ERAS pathways also may reduce postoperative complications, lower pain scores, and decrease opioid use.²⁷ The general consensus among quality and safety experts is that reducing variation through standardization of pathways is generally associated with improved quality and enhanced safety. ERAS pathways have been widely accepted in multiple surgical fields. ERAS pathways should become the standard for performing cesarean procedures.●

Cesarean birth is one of the most common major surgical procedures performed in developed countries¹ with over 1,170,000 cesarean births in the United States in 2021.² Many surgeons and anesthesiologists believe that Enhanced Recovery after Surgery (ERAS) pathways improve surgical outcomes.^3,4 Important goals of ERAS include setting patient expectations for the surgical procedure, accelerating patient recovery to full function, and minimizing perioperative complications such as severe nausea, aspiration, surgical site infection, wound complications, and perioperative anemia. The ERAS Society in 2018^5-7 and the Society for Obstetric Anesthesia and Perinatology (SOAP) in 2021⁸ proposed ERAS pathways for cesarean birth. Both societies recommended that obstetric units consider adopting an ERAS pathway compatible with local clinical resources. In addition, the American College of Obstetricians and Gynecologists (ACOG) has provided guidance for implementing ERAS pathways for gynecologic surgery.⁹ The consistent use of standardized protocols to improve surgical care in obstetrics should lead to a reduction in care variation and improve health equity outcomes.

The clinical interventions recommended for ERAS cesarean birth occur sequentially in the preoperative, intraoperative, and postoperative phases of care. The recommendations associated with each of these phases are reviewed below. It is important to note that each obstetric unit should use a multidisciplinary process to develop an ERAS pathway that best supports local practice given clinician preferences, patient characteristics, and resource availability.
 

Preoperative components of ERAS

Standardized patient education (SPE). SPE is an important component of ERAS, although evidence to support the recommendation is limited. At a minimum a written handout describing steps in the cesarean birth process, or a patient-education video should be part of patient education. The University of Michigan Medical Center has produced a 3-minute video for patients explaining ERAS cesarean birth.¹⁰ The University of Maryland Medical Center has produced a 2.5-minute video in English and Spanish, explaining ERAS cesarean birth for patients.¹¹ Some surgeons place a telephone call to patients the evening before surgery to help orient the patient to ERAS cesarean birth.

Breastfeeding education. An important goal of obstetric care is to optimize the rate of exclusive breastfeeding at birth. Breastfeeding education, including a commitment to support the initiation of breastfeeding within 1 hour of birth, may enhance the rate of exclusive breastfeeding. There are numerous videos available for patients about breastfeeding after cesarean birth (as an example, see: https://www.youtube.com/watch?v=9iOGn85NdTg).

Limit fasting. In the past, surgical guidelines recommended fasting after midnight prior to surgery. The ERAS Society recommends that patients should be encouraged to drink clear fluids up to 2 hours before surgery and may have a light meal up to 6 hours before surgery (Part 1).

Carbohydrate loading. Surgery causes a metabolic stress that is increased by fasting. Carbohydrate loading prior to surgery reduces the magnitude of the catabolic state caused by the combination of surgery and fasting.¹² SOAP and the ERAS Society recommend oral carbohydrate fluid supplementation 2 hours before surgery for nondiabetic patients. SOAP suggests 32 oz of Gatorade or 16 oz of clear apple juice as options for carbohydrate loading. For diabetic patients, the carbohydrate load can be omitted. In fasting pregnant patients at term, gastric emptying was near complete 2 hours after consumption of 400 mL of a carbohydrate drink.¹³ In one study, consumption of 400 mL of a carbohydrate drink 2 hours before cesarean resulted in a 7% increase in the newborn blood glucose level at 20 min after delivery.¹⁴

Minimize preoperative anemia. Approximately 50% of pregnant women are iron deficient and approximately 10% are anemic in the third trimester.^15,16 Cesarean birth is associated with significant blood loss necessitating the need to optimize red blood cell mass before surgery. Measuring ferritin to identify patients with iron deficiency and aggressive iron replacement, including intravenous iron if necessary, will reduce the prevalence of anemia prior to cesarean birth.¹⁷ Another cause of anemia in pregnancy is vitamin B12 (cobalamin) deficiency. Low vitamin B12 is especially common in pregnant patients who have previously had bariatric surgery. One study reported that, of 113 pregnant patients who were, on average, 3 years from a bariatric surgery procedure, 12% had vitamin B12 circulating levels < 130 pg/mL.¹⁸ Among pregnant patients who are anemic, and do not have a hemoglobinopathy, measuring ferritin, folic acid, and vitamin B12 will help identify the cause of anemia and guide treatment.¹⁹

Optimize preoperative physical condition. Improving healthy behaviors and reducing unhealthy behaviors preoperatively may enhance patient recovery to full function. In the weeks before scheduled cesarean birth, cessation of the use of tobacco products, optimizing activity and improving diet quality, including increasing protein intake, may best prepare patients for the metabolic stress of surgery.

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

Reduce the risk of surgical site infection (SSI) and wound complications. Bundles that include antibiotics, chlorhexidine (or an alternative antibacterial soap) and clippers have been shown to reduce SSI.²⁰ Routine administration of preoperative antibiotics is a consensus recommendation and there is high adherence with this recommendation in the United States. Chlorhexidine-alcohol is the preferred solution for skin preparation. Vaginal preparation with povidine-iodine or chlorhexidine may be considered.⁶

Surgical technique. Blunt extension of a transverse hysterotomy may reduce blood loss. Closure of the hysterotomy incision in 2 layers is recommended to reduce uterine scar dehiscence in a subsequent pregnancy. If the patient has ≥2 cm of subcutaneous tissue, this layer should be approximated with sutures. Skin closure should be with subcuticular suture.⁶

Optimize uterotonic administration. Routine use of uterotonics reduces the risk of blood loss, transfusion, and postoperative anemia. There is high adherence with the use of uterotonic administration after birth in the United States.^6,8

Ensure normothermia. Many patients become hypothermic during a cesarean birth. Active warming of the patient with an in-line IV fluid warmer and forced air warming over the patient’s body can reduce the risk of hypothermia.⁸

Initiate multimodal anesthesia. Anesthesiologists often use intrathecal or epidural morphine to enhance analgesia. Ketorolac administration prior to completion of the cesarean procedure and perioperative administration of acetaminophen may reduce postoperative pain.⁸ The use of preoperative antiemetics will reduce intraoperative and postoperative nausea and vomiting.

Initiate VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁶

Postoperative components of ERAS

Patient education to prepare for discharge home when ready. Patient education focused on home when ready is important in preparing the patient for discharge home.⁷ Completion of required newborn testing, lactation education, and contraception planning plus coordination of newborn pediatric follow-up is necessary before discharge.

Support early return of bowel function. Early return of bowel function is best supported by a multimodal approach including initiation of clear fluid intake immediately following surgery, encouraging consumption of a regular diet within 2⁷ to 4 hours⁸ following surgery. Gum chewing for at least 5 minutes 3 times daily accelerates return of bowel function.⁸ In a meta-analysis of 10 randomized studies examining the effect of gum chewing after cesarean, the investigators reported that gum chewing shortened the time to passage of flatus and defecation.²¹

Early ambulation.

Sequentially advanced activity, starting with sitting on the edge of the bed, sitting in a chair, and ambulation within 8 hours of surgery, is recommended to facilitate faster recovery, reduce rates of complications, and enable transition to home.⁸

Early removal of the urinary catheter. It is recommended that the urinary catheter be removed within 12 hours after cesarean birth.⁸ Early removal of the urinary catheter increases patient mobility and reduces the length of hospitalization. Early removal of the urinary catheter may be associated with postoperative urinary retention and recatheterization in a small number of patients.

Prescribe routinely scheduled acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and ketorolac. A key component of ERAS cesarean birth is the standardized administration of nonopioid pain medicines, alternating doses of acetaminophen and an NSAID. ERAS cesarean birth is likely to result in a reduction in inpatient and postdischarge opioid use.^22-24

VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁸

Auditing and reporting adherence with components of ERAS

In clinical practice there may be a gap between a clinician’s subjective perception of their performance and an independent audit of their clinical performance. ERAS pathways should be implemented with a commitment to performing audits and providing quantitative feedback to clinicians. Consistent use of measurement, feedback, and coaching can improve performance and reduce variation among individual clinicians. As an example, in one study of the use of a surgical safety checklist, 99% of the surgeons reported that they routinely used a surgical safety checklist, but the audit showed that the checklist was used in only 60% of cases.²⁵ Gaps between self-reported performance and audited performance are common in clinical practice. Audits with feedback are critical to improving adherence with the components of an ERAS pathway.

Three independent systematic reviews and meta-analyses report that ERAS pathways reduce hospital length of stay without increasing the readmission rate.^26-28 One meta-analysis reported that ERAS may also reduce time to first mobilization and result in earlier removal of the urinary catheter.²⁶ ERAS pathways also may reduce postoperative complications, lower pain scores, and decrease opioid use.²⁷ The general consensus among quality and safety experts is that reducing variation through standardization of pathways is generally associated with improved quality and enhanced safety. ERAS pathways have been widely accepted in multiple surgical fields. ERAS pathways should become the standard for performing cesarean procedures.●

Hypertension is a prevalent medical problem among US women, with a higher prevalence among Black women, than among White, Hispanic, or Asian women (TABLE 1).¹ Among US women aged 55 to 64 years, approximately 50% have hypertension or are taking a hypertension medicine.¹ Hypertension is an important risk factor for cardiovascular disease, including stroke, coronary heart disease, heart failure, atrial fibrillation, and peripheral vascular disease.^1,2 In a study of 1.3 million people, blood pressure (BP) ≥ 130/80 mm Hg was associated with an increased risk of a cardiovascular event, including myocardial infarction and stroke.² Excessive sodium intake is an important risk factor for developing hypertension.³ In 2015–2016, 87% of US adults consumed >2,300 mg/d of sodium,⁴ an amount that is considered excessive.¹ Less well known is the association between low potassium intake and hypertension. This editorial reviews the evidence that diets high in sodium and low in potassium contribute to the development of hypertension and cardiovascular disease.

Sodium and potassium dueling cations

Many cohort studies report that diets high in sodium and low in potassium are associated with hypertension and an increased risk of cardiovascular disease. For example, in a cohort of 146,000 Chinese people, high sodium and low potassium intake was positively correlated with higher BP.⁵ In addition, the impact of increasing sodium intake or decreasing potassium intake was greater for people with a BMI ≥24 kg/m², than people with a BMI <24 kg/m². In a cohort of 11,095 US adults, high sodium and low potassium intake was associated with an increased risk of hypertension.⁶

In a study of 13,696 women, high potassium intake was associated with lower BP in participants with either a low or high sodium intake.⁷ In addition, over a 19-year follow up, higher potassium intake was associated with a lower risk of cardiovascular events.⁷ Comparing the highest (5,773 mg/d) vs lowest (2,783 mg/d) tertile of potassium intake, the decreased risk of a cardiovascular event was 0.89 (95% confidence interval [CI], 0.83–0.95).⁷

In a meta-analysis of data culled from 6 cohort studies, 10,709 adults with a mean age of 52 years, 54% of whom identified as women, were followed for a median of 8.8 years.⁸ Each adult contributed at least two 24-hour urine samples for measurement of sodium and potassium content. (Measurement of sodium and potassium in multiple 24-hour urine specimens from the same participant is thought to be the best way to assess sodium and potassium consumption.) The primary outcome was a cardiovascular event, including heart attack, stroke, or undergoing coronary revascularization procedures. In this study increasing consumption of sodium was associated with an increase in cardiovascular events, and increasing consumption of potassium was associated with a decrease in cardiovascular events. The hazard ratio for a cardiovascular event comparing high versus low consumption of sodium was 1.60 (95% CI, 1.19–2.14), and comparing high versus low consumption of potassium was 0.69 (95% CI, 0.51–0.91) (TABLE 2).⁸

Continue to: Clinical trial data on decreasing Na and/or increasing K consumption on CV outcomes...

Clinical trial data on decreasing Na and/or increasing K consumption on CV outcomes

Building on the cohort studies reporting that diets high in sodium and low in potassium are associated with hypertension and cardiovascular disease, clinical trials report that decreasing dietary sodium intake reduces BP and the risk of a cardiovascular event. For example, in a meta-analysis of 85 clinical trials studying the link between sodium and BP, the investigators concluded that there was a linear relationship between sodium intake and BP, with larger reductions in sodium intake associated with greater reductions in BP, down to a daily sodium intake of 1,000 to 1,500 mg.⁹ The effect of sodium reduction on BP was greatest in study participants with higher BP at baseline.

In a cluster-randomized clinical trial in China, people living in 600 villages were assigned to a control group, continuing to use sodium chloride in their food preparation or an experimental intervention, replacing sodium chloride with a substitute product containing 75% sodium chloride and 25% potassium chloride by weight.¹⁰ The inclusion criteria included people ≥60 years of age with high BP or a history of stroke. The mean duration of follow-up was 4.7 years. Half of the participants were female. A total of 73% of the participants had a history of stroke and 88% had hypertension. In this study, the rate of death was lower in the group that used the salt substitute than in the group using sodium chloride (39 vs 45 deaths per 1,000 person-years; rate ratio (RR) 0.88; 95% CI, 0.82–0.95, P<.001). The rate of major cardiovascular events (nonfatal stroke, nonfatal acute coronary syndrome or death from vascular causes) was decreased in the group that used salt substitute compared with the group using sodium chloride (49 vs 56 events per 1,000 person-years, rate ratio (RR), 0.87; 95% CI, 0.80–0.94; P<.001). Similarly, the rate of stroke was decreased in the group that used salt substitute compared with the group using sodium chloride (29 vs 34 events per 1,000 person-years; rate ratio (RR), 0.86; 95% CI, 0.77–0.96; P = .006). This study shows that by decreasing sodium intake and increasing potassium, cardiovascular outcomes are improved in people at high risk for a cardiovascular event.¹⁰ People with kidney disease or taking medications that decrease renal excretion of potassium should consult with their health care provider before using potassium chloride containing salt substitutes.

What is your daily intake of sodium and potassium?

Almost all packaged prepared foods have labels indicating the amount of sodium in one serving. Many packaged foods also report the amount of potassium in one serving. Many processed foods contain high amounts of sodium and low amounts of potassium. Processed and ultra-processed foods are a major dietary source of sodium.¹¹ In contrast to processed foods, fresh fruits, vegetables, and milk have high quantities of potassium and low amounts of sodium. As an example, a major brand of canned chicken broth has 750 mg of sodium and 40 mg of potassium per one-half cup, a ratio of sodium to potassium of 19:1. By contrast, canned red kidney beans have 135 mg of sodium and 425 mg of potassium in one-half cup, a ratio of sodium to potassium of 1:3. Patients can better understand their daily sodium and potassium intake by reading the food labels. Calculating a sodium to potassium ratio for a food may help people better understand their salt intake and identify foods associated with positive health outcomes.

The optimal target for daily consumption of sodium and potassium is controversial (TABLE 2). The mean daily intakes of sodium and potassium in the United States are approximately 3,380 mg and 2,499 mg,respectively.¹² The American College of Cardiology (ACC) recommends that an optimal diet contains <1,500 mg/d of sodium, a stringent target.¹ If that target is unattainable, people should at least aim for a 1,000 mg/d-reduction in their current sodium intake.¹ The World Health Organization strongly recommends that adults consume <2,000 mg/d of sodium.¹³ The National Academy of Science recommends adults seeking to reduce the risk of cardiovascular disease consume <2,300 mg/d of sodium.¹⁴ The top dietary sources of sodium include deli meat, pizza, burritos and tacos, soups, savory snacks (chips, crackers, popcorn), fried poultry, burgers, and eggs.¹⁵

The optimal target for daily consumption of potassium is controversial. The ACC recommends that an optimal diet contains 3,500–5,000 mg/d of potassium.¹ The World Health Organization recommends that adults consume >3,510 mg/d of potassium.¹⁶ The top dietary sources of potassium include milk, fruit, vegetables, coffee, savory snacks (chips, crackers, popcorn), fruit juice, white potatoes, deli meats, burritos, and tacos.¹⁵ The foods with the greatest amount of potassium include banana, avocado, acorn squash, spinach, sweet potatoes, salmon, apricots, grapefruit, broccoli, and white beans. People with kidney disease or those who are taking medications that interfere with renal excretion of potassium should consult with their health care provider before adding more potassium to their diet.

The ACC also recommends¹:

• Maintaining an optimal weight (a 1-kg reduction in weight is associated with a 1-mm Hg reduction in BP).
• Eating a healthy diet rich in fruits, vegetables, whole grains, and low-fat dairy products with reduced saturated and total fat.
• Regular aerobic physical activity 90 to 150 min/wk.
• Moderation in alcohol consumption, with men limiting consumption ≤ 2 drinks/d and women limiting consumption to ≤ 1 drink/d.
• Smoking cessation.

Most adults in the US have too much sodium and too little potassium in their daily diet. Diets high in sodium and low in potassium increase the risk of hypertension. In turn, this increases the risk of cardiovascular disease, including myocardial infarction and stroke. Many personal choices and societal factors contribute to our current imbalanced and unhealthy diet, rich in sodium and deficient in potassium. Our best approach to improve health and reduce cardiovascular disease is to guide people to modify unhealthy lifestyle behaviors.¹⁷ For patients who are ready to change, a counseling intervention using the 5 A’s (including assess risk behaviors, advise change, agree on goals/action plan, assist with treatment, and arrange follow-up) has been shown to result in improved dietary choices, increased physical activity, and reduced use of tobacco products.¹⁸ ●

Hypertension is a prevalent medical problem among US women, with a higher prevalence among Black women, than among White, Hispanic, or Asian women (TABLE 1).¹ Among US women aged 55 to 64 years, approximately 50% have hypertension or are taking a hypertension medicine.¹ Hypertension is an important risk factor for cardiovascular disease, including stroke, coronary heart disease, heart failure, atrial fibrillation, and peripheral vascular disease.^1,2 In a study of 1.3 million people, blood pressure (BP) ≥ 130/80 mm Hg was associated with an increased risk of a cardiovascular event, including myocardial infarction and stroke.² Excessive sodium intake is an important risk factor for developing hypertension.³ In 2015–2016, 87% of US adults consumed >2,300 mg/d of sodium,⁴ an amount that is considered excessive.¹ Less well known is the association between low potassium intake and hypertension. This editorial reviews the evidence that diets high in sodium and low in potassium contribute to the development of hypertension and cardiovascular disease.

Sodium and potassium dueling cations

Many cohort studies report that diets high in sodium and low in potassium are associated with hypertension and an increased risk of cardiovascular disease. For example, in a cohort of 146,000 Chinese people, high sodium and low potassium intake was positively correlated with higher BP.⁵ In addition, the impact of increasing sodium intake or decreasing potassium intake was greater for people with a BMI ≥24 kg/m², than people with a BMI <24 kg/m². In a cohort of 11,095 US adults, high sodium and low potassium intake was associated with an increased risk of hypertension.⁶

In a study of 13,696 women, high potassium intake was associated with lower BP in participants with either a low or high sodium intake.⁷ In addition, over a 19-year follow up, higher potassium intake was associated with a lower risk of cardiovascular events.⁷ Comparing the highest (5,773 mg/d) vs lowest (2,783 mg/d) tertile of potassium intake, the decreased risk of a cardiovascular event was 0.89 (95% confidence interval [CI], 0.83–0.95).⁷

In a meta-analysis of data culled from 6 cohort studies, 10,709 adults with a mean age of 52 years, 54% of whom identified as women, were followed for a median of 8.8 years.⁸ Each adult contributed at least two 24-hour urine samples for measurement of sodium and potassium content. (Measurement of sodium and potassium in multiple 24-hour urine specimens from the same participant is thought to be the best way to assess sodium and potassium consumption.) The primary outcome was a cardiovascular event, including heart attack, stroke, or undergoing coronary revascularization procedures. In this study increasing consumption of sodium was associated with an increase in cardiovascular events, and increasing consumption of potassium was associated with a decrease in cardiovascular events. The hazard ratio for a cardiovascular event comparing high versus low consumption of sodium was 1.60 (95% CI, 1.19–2.14), and comparing high versus low consumption of potassium was 0.69 (95% CI, 0.51–0.91) (TABLE 2).⁸

Continue to: Clinical trial data on decreasing Na and/or increasing K consumption on CV outcomes...

Clinical trial data on decreasing Na and/or increasing K consumption on CV outcomes

Building on the cohort studies reporting that diets high in sodium and low in potassium are associated with hypertension and cardiovascular disease, clinical trials report that decreasing dietary sodium intake reduces BP and the risk of a cardiovascular event. For example, in a meta-analysis of 85 clinical trials studying the link between sodium and BP, the investigators concluded that there was a linear relationship between sodium intake and BP, with larger reductions in sodium intake associated with greater reductions in BP, down to a daily sodium intake of 1,000 to 1,500 mg.⁹ The effect of sodium reduction on BP was greatest in study participants with higher BP at baseline.

In a cluster-randomized clinical trial in China, people living in 600 villages were assigned to a control group, continuing to use sodium chloride in their food preparation or an experimental intervention, replacing sodium chloride with a substitute product containing 75% sodium chloride and 25% potassium chloride by weight.¹⁰ The inclusion criteria included people ≥60 years of age with high BP or a history of stroke. The mean duration of follow-up was 4.7 years. Half of the participants were female. A total of 73% of the participants had a history of stroke and 88% had hypertension. In this study, the rate of death was lower in the group that used the salt substitute than in the group using sodium chloride (39 vs 45 deaths per 1,000 person-years; rate ratio (RR) 0.88; 95% CI, 0.82–0.95, P<.001). The rate of major cardiovascular events (nonfatal stroke, nonfatal acute coronary syndrome or death from vascular causes) was decreased in the group that used salt substitute compared with the group using sodium chloride (49 vs 56 events per 1,000 person-years, rate ratio (RR), 0.87; 95% CI, 0.80–0.94; P<.001). Similarly, the rate of stroke was decreased in the group that used salt substitute compared with the group using sodium chloride (29 vs 34 events per 1,000 person-years; rate ratio (RR), 0.86; 95% CI, 0.77–0.96; P = .006). This study shows that by decreasing sodium intake and increasing potassium, cardiovascular outcomes are improved in people at high risk for a cardiovascular event.¹⁰ People with kidney disease or taking medications that decrease renal excretion of potassium should consult with their health care provider before using potassium chloride containing salt substitutes.

What is your daily intake of sodium and potassium?

Almost all packaged prepared foods have labels indicating the amount of sodium in one serving. Many packaged foods also report the amount of potassium in one serving. Many processed foods contain high amounts of sodium and low amounts of potassium. Processed and ultra-processed foods are a major dietary source of sodium.¹¹ In contrast to processed foods, fresh fruits, vegetables, and milk have high quantities of potassium and low amounts of sodium. As an example, a major brand of canned chicken broth has 750 mg of sodium and 40 mg of potassium per one-half cup, a ratio of sodium to potassium of 19:1. By contrast, canned red kidney beans have 135 mg of sodium and 425 mg of potassium in one-half cup, a ratio of sodium to potassium of 1:3. Patients can better understand their daily sodium and potassium intake by reading the food labels. Calculating a sodium to potassium ratio for a food may help people better understand their salt intake and identify foods associated with positive health outcomes.

The optimal target for daily consumption of sodium and potassium is controversial (TABLE 2). The mean daily intakes of sodium and potassium in the United States are approximately 3,380 mg and 2,499 mg,respectively.¹² The American College of Cardiology (ACC) recommends that an optimal diet contains <1,500 mg/d of sodium, a stringent target.¹ If that target is unattainable, people should at least aim for a 1,000 mg/d-reduction in their current sodium intake.¹ The World Health Organization strongly recommends that adults consume <2,000 mg/d of sodium.¹³ The National Academy of Science recommends adults seeking to reduce the risk of cardiovascular disease consume <2,300 mg/d of sodium.¹⁴ The top dietary sources of sodium include deli meat, pizza, burritos and tacos, soups, savory snacks (chips, crackers, popcorn), fried poultry, burgers, and eggs.¹⁵

The optimal target for daily consumption of potassium is controversial. The ACC recommends that an optimal diet contains 3,500–5,000 mg/d of potassium.¹ The World Health Organization recommends that adults consume >3,510 mg/d of potassium.¹⁶ The top dietary sources of potassium include milk, fruit, vegetables, coffee, savory snacks (chips, crackers, popcorn), fruit juice, white potatoes, deli meats, burritos, and tacos.¹⁵ The foods with the greatest amount of potassium include banana, avocado, acorn squash, spinach, sweet potatoes, salmon, apricots, grapefruit, broccoli, and white beans. People with kidney disease or those who are taking medications that interfere with renal excretion of potassium should consult with their health care provider before adding more potassium to their diet.

The ACC also recommends¹:

• Maintaining an optimal weight (a 1-kg reduction in weight is associated with a 1-mm Hg reduction in BP).
• Eating a healthy diet rich in fruits, vegetables, whole grains, and low-fat dairy products with reduced saturated and total fat.
• Regular aerobic physical activity 90 to 150 min/wk.
• Moderation in alcohol consumption, with men limiting consumption ≤ 2 drinks/d and women limiting consumption to ≤ 1 drink/d.
• Smoking cessation.

Most adults in the US have too much sodium and too little potassium in their daily diet. Diets high in sodium and low in potassium increase the risk of hypertension. In turn, this increases the risk of cardiovascular disease, including myocardial infarction and stroke. Many personal choices and societal factors contribute to our current imbalanced and unhealthy diet, rich in sodium and deficient in potassium. Our best approach to improve health and reduce cardiovascular disease is to guide people to modify unhealthy lifestyle behaviors.¹⁷ For patients who are ready to change, a counseling intervention using the 5 A’s (including assess risk behaviors, advise change, agree on goals/action plan, assist with treatment, and arrange follow-up) has been shown to result in improved dietary choices, increased physical activity, and reduced use of tobacco products.¹⁸ ●

Hypertension is a prevalent medical problem among US women, with a higher prevalence among Black women, than among White, Hispanic, or Asian women (TABLE 1).¹ Among US women aged 55 to 64 years, approximately 50% have hypertension or are taking a hypertension medicine.¹ Hypertension is an important risk factor for cardiovascular disease, including stroke, coronary heart disease, heart failure, atrial fibrillation, and peripheral vascular disease.^1,2 In a study of 1.3 million people, blood pressure (BP) ≥ 130/80 mm Hg was associated with an increased risk of a cardiovascular event, including myocardial infarction and stroke.² Excessive sodium intake is an important risk factor for developing hypertension.³ In 2015–2016, 87% of US adults consumed >2,300 mg/d of sodium,⁴ an amount that is considered excessive.¹ Less well known is the association between low potassium intake and hypertension. This editorial reviews the evidence that diets high in sodium and low in potassium contribute to the development of hypertension and cardiovascular disease.

Sodium and potassium dueling cations

Many cohort studies report that diets high in sodium and low in potassium are associated with hypertension and an increased risk of cardiovascular disease. For example, in a cohort of 146,000 Chinese people, high sodium and low potassium intake was positively correlated with higher BP.⁵ In addition, the impact of increasing sodium intake or decreasing potassium intake was greater for people with a BMI ≥24 kg/m², than people with a BMI <24 kg/m². In a cohort of 11,095 US adults, high sodium and low potassium intake was associated with an increased risk of hypertension.⁶

In a study of 13,696 women, high potassium intake was associated with lower BP in participants with either a low or high sodium intake.⁷ In addition, over a 19-year follow up, higher potassium intake was associated with a lower risk of cardiovascular events.⁷ Comparing the highest (5,773 mg/d) vs lowest (2,783 mg/d) tertile of potassium intake, the decreased risk of a cardiovascular event was 0.89 (95% confidence interval [CI], 0.83–0.95).⁷

In a meta-analysis of data culled from 6 cohort studies, 10,709 adults with a mean age of 52 years, 54% of whom identified as women, were followed for a median of 8.8 years.⁸ Each adult contributed at least two 24-hour urine samples for measurement of sodium and potassium content. (Measurement of sodium and potassium in multiple 24-hour urine specimens from the same participant is thought to be the best way to assess sodium and potassium consumption.) The primary outcome was a cardiovascular event, including heart attack, stroke, or undergoing coronary revascularization procedures. In this study increasing consumption of sodium was associated with an increase in cardiovascular events, and increasing consumption of potassium was associated with a decrease in cardiovascular events. The hazard ratio for a cardiovascular event comparing high versus low consumption of sodium was 1.60 (95% CI, 1.19–2.14), and comparing high versus low consumption of potassium was 0.69 (95% CI, 0.51–0.91) (TABLE 2).⁸

Continue to: Clinical trial data on decreasing Na and/or increasing K consumption on CV outcomes...

Clinical trial data on decreasing Na and/or increasing K consumption on CV outcomes

Building on the cohort studies reporting that diets high in sodium and low in potassium are associated with hypertension and cardiovascular disease, clinical trials report that decreasing dietary sodium intake reduces BP and the risk of a cardiovascular event. For example, in a meta-analysis of 85 clinical trials studying the link between sodium and BP, the investigators concluded that there was a linear relationship between sodium intake and BP, with larger reductions in sodium intake associated with greater reductions in BP, down to a daily sodium intake of 1,000 to 1,500 mg.⁹ The effect of sodium reduction on BP was greatest in study participants with higher BP at baseline.

In a cluster-randomized clinical trial in China, people living in 600 villages were assigned to a control group, continuing to use sodium chloride in their food preparation or an experimental intervention, replacing sodium chloride with a substitute product containing 75% sodium chloride and 25% potassium chloride by weight.¹⁰ The inclusion criteria included people ≥60 years of age with high BP or a history of stroke. The mean duration of follow-up was 4.7 years. Half of the participants were female. A total of 73% of the participants had a history of stroke and 88% had hypertension. In this study, the rate of death was lower in the group that used the salt substitute than in the group using sodium chloride (39 vs 45 deaths per 1,000 person-years; rate ratio (RR) 0.88; 95% CI, 0.82–0.95, P<.001). The rate of major cardiovascular events (nonfatal stroke, nonfatal acute coronary syndrome or death from vascular causes) was decreased in the group that used salt substitute compared with the group using sodium chloride (49 vs 56 events per 1,000 person-years, rate ratio (RR), 0.87; 95% CI, 0.80–0.94; P<.001). Similarly, the rate of stroke was decreased in the group that used salt substitute compared with the group using sodium chloride (29 vs 34 events per 1,000 person-years; rate ratio (RR), 0.86; 95% CI, 0.77–0.96; P = .006). This study shows that by decreasing sodium intake and increasing potassium, cardiovascular outcomes are improved in people at high risk for a cardiovascular event.¹⁰ People with kidney disease or taking medications that decrease renal excretion of potassium should consult with their health care provider before using potassium chloride containing salt substitutes.

What is your daily intake of sodium and potassium?

Almost all packaged prepared foods have labels indicating the amount of sodium in one serving. Many packaged foods also report the amount of potassium in one serving. Many processed foods contain high amounts of sodium and low amounts of potassium. Processed and ultra-processed foods are a major dietary source of sodium.¹¹ In contrast to processed foods, fresh fruits, vegetables, and milk have high quantities of potassium and low amounts of sodium. As an example, a major brand of canned chicken broth has 750 mg of sodium and 40 mg of potassium per one-half cup, a ratio of sodium to potassium of 19:1. By contrast, canned red kidney beans have 135 mg of sodium and 425 mg of potassium in one-half cup, a ratio of sodium to potassium of 1:3. Patients can better understand their daily sodium and potassium intake by reading the food labels. Calculating a sodium to potassium ratio for a food may help people better understand their salt intake and identify foods associated with positive health outcomes.

The optimal target for daily consumption of sodium and potassium is controversial (TABLE 2). The mean daily intakes of sodium and potassium in the United States are approximately 3,380 mg and 2,499 mg,respectively.¹² The American College of Cardiology (ACC) recommends that an optimal diet contains <1,500 mg/d of sodium, a stringent target.¹ If that target is unattainable, people should at least aim for a 1,000 mg/d-reduction in their current sodium intake.¹ The World Health Organization strongly recommends that adults consume <2,000 mg/d of sodium.¹³ The National Academy of Science recommends adults seeking to reduce the risk of cardiovascular disease consume <2,300 mg/d of sodium.¹⁴ The top dietary sources of sodium include deli meat, pizza, burritos and tacos, soups, savory snacks (chips, crackers, popcorn), fried poultry, burgers, and eggs.¹⁵

The optimal target for daily consumption of potassium is controversial. The ACC recommends that an optimal diet contains 3,500–5,000 mg/d of potassium.¹ The World Health Organization recommends that adults consume >3,510 mg/d of potassium.¹⁶ The top dietary sources of potassium include milk, fruit, vegetables, coffee, savory snacks (chips, crackers, popcorn), fruit juice, white potatoes, deli meats, burritos, and tacos.¹⁵ The foods with the greatest amount of potassium include banana, avocado, acorn squash, spinach, sweet potatoes, salmon, apricots, grapefruit, broccoli, and white beans. People with kidney disease or those who are taking medications that interfere with renal excretion of potassium should consult with their health care provider before adding more potassium to their diet.

The ACC also recommends¹:

• Maintaining an optimal weight (a 1-kg reduction in weight is associated with a 1-mm Hg reduction in BP).
• Eating a healthy diet rich in fruits, vegetables, whole grains, and low-fat dairy products with reduced saturated and total fat.
• Regular aerobic physical activity 90 to 150 min/wk.
• Moderation in alcohol consumption, with men limiting consumption ≤ 2 drinks/d and women limiting consumption to ≤ 1 drink/d.
• Smoking cessation.

Most adults in the US have too much sodium and too little potassium in their daily diet. Diets high in sodium and low in potassium increase the risk of hypertension. In turn, this increases the risk of cardiovascular disease, including myocardial infarction and stroke. Many personal choices and societal factors contribute to our current imbalanced and unhealthy diet, rich in sodium and deficient in potassium. Our best approach to improve health and reduce cardiovascular disease is to guide people to modify unhealthy lifestyle behaviors.¹⁷ For patients who are ready to change, a counseling intervention using the 5 A’s (including assess risk behaviors, advise change, agree on goals/action plan, assist with treatment, and arrange follow-up) has been shown to result in improved dietary choices, increased physical activity, and reduced use of tobacco products.¹⁸ ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

Hypertension in pregnancy is a major challenge in current obstetric practice. Based on an analysis of the National Inpatient Sample, the Centers for Disease Control and Prevention (CDC) recently reported that from 2017 to 2019 the prevalence of hypertensive disorders in pregnancy increased from 13.3% to 15.9% of hospital deliveries.¹ During that same time period, the prevalence of pregnancy-associated hypertension, which includes preeclampsia, eclampsia, and gestational hypertension, increased from 10.8% to 13.0%.¹ The prevalence of chronic hypertension increased from 2.0% to 2.3%.¹ In 2017 and 2019, unspecified maternal hypertension was diagnosed in 0.5% and 0.6% of the sample, respectively.¹

Bruno and colleagues reported a 3-fold increase in the prevalence of HDPs from 1989 to 2020, with an acceleration in the rate of increase from 2010 to 2020.² The increase in prevalence of HDPs may be caused by an increase in the prevalence of advanced maternal age, obesity, and diabetes. Black patients are disproportionately impacted by both pregnancy-associated hypertension and chronic hypertension.¹ In 2019, the prevalence of pregnancy-associated hypertension was greater among Black patients (15.6%), than White (12.1%), Hispanic (10.6%), or Asian or Pacific Islander patients (7.7%).¹ Similarly, the prevalence of chronic hypertension was greater among Black patients (4.3%) than among White (2.0%), Hispanic (1.5%), or Asian or Pacific Islander patients (1.2%).¹ Racial/ethnic differences in HDPs may be influenced by poverty; structural racism; or lack of access to care, diet, and obesity.^3,4

HDPs are major contributors to maternal morbidity and mortality. The CDC reported that among maternal deaths occurring during the delivery hospitalization, 32% of the decedents had documented hypertension.¹ HDPs are associated with an approximately 2.5-fold increased risk of a severe morbidity, a composite measure that includes blood transfusion, acute kidney injury, disseminated intravascular coagulation, sepsis, shock, and pulmonary edema.⁵ A history of HDPs is associated with an approximately 67% increase in the lifetime risk of cardiovascular disease, including coronary artery disease, stroke, peripheral vascular disease, and heart failure.^6,7

What are the best antihypertensive medications for pregnancy?

All clinicians know that the use of angiotensin-converting-enzyme inhibitors (ACE-Is) and angiotensin-receptor-blockers (ARBs) are contraindicated in pregnancy because they cause major congenital anomalies, with an odds ratio of 1.8 (95% confidence interval [CI], 1.42-2.34), compared with no exposure.⁸ In addition, ACE-Is and ARBs increase the risk of stillbirth, with an odds ratio of 1.75 (95% CI, 1.21-2.53).⁸ No increase in congenital anomalies were detected for patients exposed to other antihypertensive medications.⁸ Prior to attempting conception, patients with chronic hypertension should discontinue ACE-Is and ARBs and initiate an alternative medication.

The most commonly used antihypertensive medications in pregnancy are labetalol, nifedipine, and methyldopa.⁹ Labetalol blocks the beta-1, beta-2, and alpha-1 adrenergic receptors.¹⁰ Nifedipine blocks calcium entry into cells through the L-type calcium channel.¹¹ Methyldopa is a central nervous system alpha-2 adrenergic agonist.¹² The dose range for these commonly used medications are labetalol 400 mg to 2,400 mg daily in divided doses every 8 to 12 hours, nifedipine extended-release 30 mg to 120 mg daily, and methyldopa 500 mg to 2 g daily in 2 to 4 divided doses. Some clinicians recommend prescribing divided doses of nifedipine extended release at doses ≥ 60 mg for patients who have bothersome adverse effects, hypotension following a single daily dose, or hypertension between single daily doses. The nifedipine extended release tablets should not be divided. If monotherapy with the maximal daily dose of labetalol does not achieve the blood pressure (BP) target, adding nifedipine as a second agent is an option.⁹ Similarly, if monotherapy with the maximal daily dose of nifedipine extended release does not achieve the BP target, adding labetalol as a second agent is an option.⁹

In a network meta-analysis of antihypertensive medications used in pregnancy, that included 61 trials and 6,923 participants, all the medications studied reduced the risk of developing severe hypertension by 30% to 70%.¹³ Sufficient data was available to also report that labetalol used to treat hypertension in pregnancy reduced the risk of developing proteinuria.¹³ Given similar efficacy among antihypertensive medications, patient comorbidities may influence the medication choice. For example, labetalol may not be the optimal medication for a patient with poorly controlled asthma due to its ability to cause bronchospasm.^14,15 Methyldopa may not be the optimal medication for a patient with depression.¹⁶ Based on the available data, labetalol, nifedipine, and methyldopa are the best antihypertensive medications for pregnant patients.

Continue to: What is an optimal BP target when treating chronic hypertension in pregnancy?...

What is an optimal BP target when treating chronic hypertension in pregnancy?

When treating chronic hypertension in pregnant patients, a concern is that reducing maternal BP may decrease uteroplacental perfusion and result in fetal growth restriction. However, a recent trial reported that a BP treatment target < 140/90 mm Hg is associated with better outcomes for both mother and newborn than withholding antihypertension medications. In the trial, 2,408 women with chronic hypertension diagnosed before 20 weeks of gestation were randomly assigned to an active treatment group with prescription of antihypertension medicines to achieve a BP target of < 140/90 mm Hg; or to a control group where no antihypertension or no additional antihypertension treatment was prescribed unless BP was ≥ 160 mm Hg systolic or ≥ 105 mm Hg diastolic.⁹ The hypertension medications prescribed to the patients in the active treatment group were labetalol (63.2%), nifedipine (33.4%), amlodipine (1.7%), methyldopa (0.5%), hydrochlorothiazide (0.3%), metoprolol (0.2%), and missing/unknown/other (0.7%).⁹

If a patient in the control group developed severe hypertension, they were started on an antihypertension medicine and the BP treatment target was < 140/90 mm Hg. Compared with the control regimen, active treatment resulted in a significant decrease in the development of preeclampsia (24.4% vs 31.1%; risk ratio [RR], 0.79; 95% CI, 0.69-0.89), severe hypertension (36.1% vs 44.3%; RR, 0.82; 95% CI, 0.74-0.90), preterm birth < 37 weeks’ gestation (27.5% vs 31.4%; RR, 0.87; 95% CI, 0.77-0.99), preterm birth < 35 weeks’ gestation (12.2% vs 16.7%; odds ratio [OR], 0.69; 95% CI, 0.55-0.88), and low birth-weight (< 2,500 g) newborns (19.2% vs 23.1%; RR, 0.83; 95% CI, 0.71-0.97).⁹ The percentage of small for gestational age birth weight below the 10th percentile was similar in the treatment and control groups, 11.2% and 10.4%, respectively (adjusted RR, 1.04; 95% CI, 0.82-1.31).⁹ The number of patients who would need to be treated to prevent one primary-outcome event was 15.⁹ The investigators concluded that for pregnant patients with chronic hypertension, the optimal BP target is < 140/90 mm Hg.⁹

When does BP reach a postpartum peak?

In pregnant patients with hypertension, BP may decrease immediately after birth. Following birth, BP tends to increase, reaching a peak 3 to 6 days postpartum.^17,18 This pattern was observed in patients with and without preeclampsia in the index pregnancy. Among 136 patients without antepartum preeclampsia, the prevalence of a diastolic BP > 89 mm Hg was 5% and 15% on postpartum days 1 and 3, respectively.¹⁷ The postpartum rise in BP may be due to mobilization of water from the extravascular to the intravascular space and excretion of total body sodium that accumulated during pregnancy.¹⁹ In one study of 998 consecutive singleton cesarean births, 7.7% of the patients with no recorded elevated BP before delivery developed de novo hypertension postpartum.²⁰ Compared with patients without antepartum or new onset postpartum hypertension, the patients who developed postpartum hypertension had a higher body mass index, were more likely to be Black and to have a history of type 2 diabetes. Compared with patients without antepartum or postpartum hypertension, the patients who developed de novo postpartum hypertension, had significantly elevated soluble fms-like tyrosine kinase-1 and significantly decreased placental growth factor, a pattern seen with preeclampsia.²⁰ These results suggest that de novo postpartum hypertension may have molecular causes similar to preeclampsia.²⁰

Postpartum hypertension should be treated with a medication that is thought to be safe for breastfeeding patients, including labetalol, nifedipine, or enalapril.^21-23 The relative infant dose of labetalol, nifedipine, and enalapril is approximately 3.6%, ≤ 3.2%, and 1.1%, respectively.²⁴ If the relative infant dose of a medication is < 10% it is generally considered to be compatible with breastfeeding.²⁵

Many obstetricians have seldom prescribed enalapril, an ACE-I. The initial dose of enalapril is 5 mg or 10 mg daily. After initiation of treatment, the dose can be adjusted based on BP measurement. The maximal daily dose is 40 mg daily in one dose or two divided doses. Similar to other hypertension medicines, enalapril therapy may cause hypotension and dizziness. Enalapril should not be used by pregnant patients because it is associated with an increased risk of congenital anomalies and fetal demise.

Does a HDP increase the risk of developing chronic hypertension?

All obstetricians know that a patient with a history of a HDP is at an increased risk for developing chronic hypertension treated with a medication, but the magnitude of the risk is less well known. In a nationwide study in Denmark, the prevalence of chronic hypertension treated with medication 10 years after delivery among patients with a history of a HDP in their first pregnancy, was 14%, 21%, and 32%, if the first pregnancy occurred in the patient’s 20s, 30s, or 40s, respectively.²⁶ The corresponding prevalence of chronic hypertension in patients without a history of a HDP was 4%, 6%, and 11%, if the first pregnancy occurred in the 20s, 30s, or 40s, respectively.²⁶ Maternal age is an important predictor of who will develop chronic hypertension within 10 years following a pregnancy with a HDP.

In modern obstetric practice, the hypertensive disorders of pregnancy are prevalent and associated with increased maternal and newborn morbidity. Appropriate treatment of hypertension with labetalol, nifedipine, or methyldopa improves maternal and newborn health. Available evidence suggests that maintaining BP < 140/90 mm Hg during pregnancy for most patients is a practical goal with significant benefit. A significant public-health concern is that an increase in the prevalence of HDPs will eventually translate into an increase in chronic hypertension and the attendant complications of heart attack, heart failure, stroke, and renal insufficiency. Recognizing the increased prevalence of HDPs, ObGyns will need to alert patients to their long-term health risks and coordinate appropriate follow-up and treatment to optimize the future health of their patients. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

Hypertension in pregnancy is a major challenge in current obstetric practice. Based on an analysis of the National Inpatient Sample, the Centers for Disease Control and Prevention (CDC) recently reported that from 2017 to 2019 the prevalence of hypertensive disorders in pregnancy increased from 13.3% to 15.9% of hospital deliveries.¹ During that same time period, the prevalence of pregnancy-associated hypertension, which includes preeclampsia, eclampsia, and gestational hypertension, increased from 10.8% to 13.0%.¹ The prevalence of chronic hypertension increased from 2.0% to 2.3%.¹ In 2017 and 2019, unspecified maternal hypertension was diagnosed in 0.5% and 0.6% of the sample, respectively.¹

Bruno and colleagues reported a 3-fold increase in the prevalence of HDPs from 1989 to 2020, with an acceleration in the rate of increase from 2010 to 2020.² The increase in prevalence of HDPs may be caused by an increase in the prevalence of advanced maternal age, obesity, and diabetes. Black patients are disproportionately impacted by both pregnancy-associated hypertension and chronic hypertension.¹ In 2019, the prevalence of pregnancy-associated hypertension was greater among Black patients (15.6%), than White (12.1%), Hispanic (10.6%), or Asian or Pacific Islander patients (7.7%).¹ Similarly, the prevalence of chronic hypertension was greater among Black patients (4.3%) than among White (2.0%), Hispanic (1.5%), or Asian or Pacific Islander patients (1.2%).¹ Racial/ethnic differences in HDPs may be influenced by poverty; structural racism; or lack of access to care, diet, and obesity.^3,4

HDPs are major contributors to maternal morbidity and mortality. The CDC reported that among maternal deaths occurring during the delivery hospitalization, 32% of the decedents had documented hypertension.¹ HDPs are associated with an approximately 2.5-fold increased risk of a severe morbidity, a composite measure that includes blood transfusion, acute kidney injury, disseminated intravascular coagulation, sepsis, shock, and pulmonary edema.⁵ A history of HDPs is associated with an approximately 67% increase in the lifetime risk of cardiovascular disease, including coronary artery disease, stroke, peripheral vascular disease, and heart failure.^6,7

What are the best antihypertensive medications for pregnancy?

All clinicians know that the use of angiotensin-converting-enzyme inhibitors (ACE-Is) and angiotensin-receptor-blockers (ARBs) are contraindicated in pregnancy because they cause major congenital anomalies, with an odds ratio of 1.8 (95% confidence interval [CI], 1.42-2.34), compared with no exposure.⁸ In addition, ACE-Is and ARBs increase the risk of stillbirth, with an odds ratio of 1.75 (95% CI, 1.21-2.53).⁸ No increase in congenital anomalies were detected for patients exposed to other antihypertensive medications.⁸ Prior to attempting conception, patients with chronic hypertension should discontinue ACE-Is and ARBs and initiate an alternative medication.

The most commonly used antihypertensive medications in pregnancy are labetalol, nifedipine, and methyldopa.⁹ Labetalol blocks the beta-1, beta-2, and alpha-1 adrenergic receptors.¹⁰ Nifedipine blocks calcium entry into cells through the L-type calcium channel.¹¹ Methyldopa is a central nervous system alpha-2 adrenergic agonist.¹² The dose range for these commonly used medications are labetalol 400 mg to 2,400 mg daily in divided doses every 8 to 12 hours, nifedipine extended-release 30 mg to 120 mg daily, and methyldopa 500 mg to 2 g daily in 2 to 4 divided doses. Some clinicians recommend prescribing divided doses of nifedipine extended release at doses ≥ 60 mg for patients who have bothersome adverse effects, hypotension following a single daily dose, or hypertension between single daily doses. The nifedipine extended release tablets should not be divided. If monotherapy with the maximal daily dose of labetalol does not achieve the blood pressure (BP) target, adding nifedipine as a second agent is an option.⁹ Similarly, if monotherapy with the maximal daily dose of nifedipine extended release does not achieve the BP target, adding labetalol as a second agent is an option.⁹

In a network meta-analysis of antihypertensive medications used in pregnancy, that included 61 trials and 6,923 participants, all the medications studied reduced the risk of developing severe hypertension by 30% to 70%.¹³ Sufficient data was available to also report that labetalol used to treat hypertension in pregnancy reduced the risk of developing proteinuria.¹³ Given similar efficacy among antihypertensive medications, patient comorbidities may influence the medication choice. For example, labetalol may not be the optimal medication for a patient with poorly controlled asthma due to its ability to cause bronchospasm.^14,15 Methyldopa may not be the optimal medication for a patient with depression.¹⁶ Based on the available data, labetalol, nifedipine, and methyldopa are the best antihypertensive medications for pregnant patients.

Continue to: What is an optimal BP target when treating chronic hypertension in pregnancy?...

What is an optimal BP target when treating chronic hypertension in pregnancy?

When treating chronic hypertension in pregnant patients, a concern is that reducing maternal BP may decrease uteroplacental perfusion and result in fetal growth restriction. However, a recent trial reported that a BP treatment target < 140/90 mm Hg is associated with better outcomes for both mother and newborn than withholding antihypertension medications. In the trial, 2,408 women with chronic hypertension diagnosed before 20 weeks of gestation were randomly assigned to an active treatment group with prescription of antihypertension medicines to achieve a BP target of < 140/90 mm Hg; or to a control group where no antihypertension or no additional antihypertension treatment was prescribed unless BP was ≥ 160 mm Hg systolic or ≥ 105 mm Hg diastolic.⁹ The hypertension medications prescribed to the patients in the active treatment group were labetalol (63.2%), nifedipine (33.4%), amlodipine (1.7%), methyldopa (0.5%), hydrochlorothiazide (0.3%), metoprolol (0.2%), and missing/unknown/other (0.7%).⁹

If a patient in the control group developed severe hypertension, they were started on an antihypertension medicine and the BP treatment target was < 140/90 mm Hg. Compared with the control regimen, active treatment resulted in a significant decrease in the development of preeclampsia (24.4% vs 31.1%; risk ratio [RR], 0.79; 95% CI, 0.69-0.89), severe hypertension (36.1% vs 44.3%; RR, 0.82; 95% CI, 0.74-0.90), preterm birth < 37 weeks’ gestation (27.5% vs 31.4%; RR, 0.87; 95% CI, 0.77-0.99), preterm birth < 35 weeks’ gestation (12.2% vs 16.7%; odds ratio [OR], 0.69; 95% CI, 0.55-0.88), and low birth-weight (< 2,500 g) newborns (19.2% vs 23.1%; RR, 0.83; 95% CI, 0.71-0.97).⁹ The percentage of small for gestational age birth weight below the 10th percentile was similar in the treatment and control groups, 11.2% and 10.4%, respectively (adjusted RR, 1.04; 95% CI, 0.82-1.31).⁹ The number of patients who would need to be treated to prevent one primary-outcome event was 15.⁹ The investigators concluded that for pregnant patients with chronic hypertension, the optimal BP target is < 140/90 mm Hg.⁹

When does BP reach a postpartum peak?

In pregnant patients with hypertension, BP may decrease immediately after birth. Following birth, BP tends to increase, reaching a peak 3 to 6 days postpartum.^17,18 This pattern was observed in patients with and without preeclampsia in the index pregnancy. Among 136 patients without antepartum preeclampsia, the prevalence of a diastolic BP > 89 mm Hg was 5% and 15% on postpartum days 1 and 3, respectively.¹⁷ The postpartum rise in BP may be due to mobilization of water from the extravascular to the intravascular space and excretion of total body sodium that accumulated during pregnancy.¹⁹ In one study of 998 consecutive singleton cesarean births, 7.7% of the patients with no recorded elevated BP before delivery developed de novo hypertension postpartum.²⁰ Compared with patients without antepartum or new onset postpartum hypertension, the patients who developed postpartum hypertension had a higher body mass index, were more likely to be Black and to have a history of type 2 diabetes. Compared with patients without antepartum or postpartum hypertension, the patients who developed de novo postpartum hypertension, had significantly elevated soluble fms-like tyrosine kinase-1 and significantly decreased placental growth factor, a pattern seen with preeclampsia.²⁰ These results suggest that de novo postpartum hypertension may have molecular causes similar to preeclampsia.²⁰

Postpartum hypertension should be treated with a medication that is thought to be safe for breastfeeding patients, including labetalol, nifedipine, or enalapril.^21-23 The relative infant dose of labetalol, nifedipine, and enalapril is approximately 3.6%, ≤ 3.2%, and 1.1%, respectively.²⁴ If the relative infant dose of a medication is < 10% it is generally considered to be compatible with breastfeeding.²⁵

Many obstetricians have seldom prescribed enalapril, an ACE-I. The initial dose of enalapril is 5 mg or 10 mg daily. After initiation of treatment, the dose can be adjusted based on BP measurement. The maximal daily dose is 40 mg daily in one dose or two divided doses. Similar to other hypertension medicines, enalapril therapy may cause hypotension and dizziness. Enalapril should not be used by pregnant patients because it is associated with an increased risk of congenital anomalies and fetal demise.

Does a HDP increase the risk of developing chronic hypertension?

All obstetricians know that a patient with a history of a HDP is at an increased risk for developing chronic hypertension treated with a medication, but the magnitude of the risk is less well known. In a nationwide study in Denmark, the prevalence of chronic hypertension treated with medication 10 years after delivery among patients with a history of a HDP in their first pregnancy, was 14%, 21%, and 32%, if the first pregnancy occurred in the patient’s 20s, 30s, or 40s, respectively.²⁶ The corresponding prevalence of chronic hypertension in patients without a history of a HDP was 4%, 6%, and 11%, if the first pregnancy occurred in the 20s, 30s, or 40s, respectively.²⁶ Maternal age is an important predictor of who will develop chronic hypertension within 10 years following a pregnancy with a HDP.

In modern obstetric practice, the hypertensive disorders of pregnancy are prevalent and associated with increased maternal and newborn morbidity. Appropriate treatment of hypertension with labetalol, nifedipine, or methyldopa improves maternal and newborn health. Available evidence suggests that maintaining BP < 140/90 mm Hg during pregnancy for most patients is a practical goal with significant benefit. A significant public-health concern is that an increase in the prevalence of HDPs will eventually translate into an increase in chronic hypertension and the attendant complications of heart attack, heart failure, stroke, and renal insufficiency. Recognizing the increased prevalence of HDPs, ObGyns will need to alert patients to their long-term health risks and coordinate appropriate follow-up and treatment to optimize the future health of their patients. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

Hypertension in pregnancy is a major challenge in current obstetric practice. Based on an analysis of the National Inpatient Sample, the Centers for Disease Control and Prevention (CDC) recently reported that from 2017 to 2019 the prevalence of hypertensive disorders in pregnancy increased from 13.3% to 15.9% of hospital deliveries.¹ During that same time period, the prevalence of pregnancy-associated hypertension, which includes preeclampsia, eclampsia, and gestational hypertension, increased from 10.8% to 13.0%.¹ The prevalence of chronic hypertension increased from 2.0% to 2.3%.¹ In 2017 and 2019, unspecified maternal hypertension was diagnosed in 0.5% and 0.6% of the sample, respectively.¹

Bruno and colleagues reported a 3-fold increase in the prevalence of HDPs from 1989 to 2020, with an acceleration in the rate of increase from 2010 to 2020.² The increase in prevalence of HDPs may be caused by an increase in the prevalence of advanced maternal age, obesity, and diabetes. Black patients are disproportionately impacted by both pregnancy-associated hypertension and chronic hypertension.¹ In 2019, the prevalence of pregnancy-associated hypertension was greater among Black patients (15.6%), than White (12.1%), Hispanic (10.6%), or Asian or Pacific Islander patients (7.7%).¹ Similarly, the prevalence of chronic hypertension was greater among Black patients (4.3%) than among White (2.0%), Hispanic (1.5%), or Asian or Pacific Islander patients (1.2%).¹ Racial/ethnic differences in HDPs may be influenced by poverty; structural racism; or lack of access to care, diet, and obesity.^3,4

HDPs are major contributors to maternal morbidity and mortality. The CDC reported that among maternal deaths occurring during the delivery hospitalization, 32% of the decedents had documented hypertension.¹ HDPs are associated with an approximately 2.5-fold increased risk of a severe morbidity, a composite measure that includes blood transfusion, acute kidney injury, disseminated intravascular coagulation, sepsis, shock, and pulmonary edema.⁵ A history of HDPs is associated with an approximately 67% increase in the lifetime risk of cardiovascular disease, including coronary artery disease, stroke, peripheral vascular disease, and heart failure.^6,7

What are the best antihypertensive medications for pregnancy?

All clinicians know that the use of angiotensin-converting-enzyme inhibitors (ACE-Is) and angiotensin-receptor-blockers (ARBs) are contraindicated in pregnancy because they cause major congenital anomalies, with an odds ratio of 1.8 (95% confidence interval [CI], 1.42-2.34), compared with no exposure.⁸ In addition, ACE-Is and ARBs increase the risk of stillbirth, with an odds ratio of 1.75 (95% CI, 1.21-2.53).⁸ No increase in congenital anomalies were detected for patients exposed to other antihypertensive medications.⁸ Prior to attempting conception, patients with chronic hypertension should discontinue ACE-Is and ARBs and initiate an alternative medication.

The most commonly used antihypertensive medications in pregnancy are labetalol, nifedipine, and methyldopa.⁹ Labetalol blocks the beta-1, beta-2, and alpha-1 adrenergic receptors.¹⁰ Nifedipine blocks calcium entry into cells through the L-type calcium channel.¹¹ Methyldopa is a central nervous system alpha-2 adrenergic agonist.¹² The dose range for these commonly used medications are labetalol 400 mg to 2,400 mg daily in divided doses every 8 to 12 hours, nifedipine extended-release 30 mg to 120 mg daily, and methyldopa 500 mg to 2 g daily in 2 to 4 divided doses. Some clinicians recommend prescribing divided doses of nifedipine extended release at doses ≥ 60 mg for patients who have bothersome adverse effects, hypotension following a single daily dose, or hypertension between single daily doses. The nifedipine extended release tablets should not be divided. If monotherapy with the maximal daily dose of labetalol does not achieve the blood pressure (BP) target, adding nifedipine as a second agent is an option.⁹ Similarly, if monotherapy with the maximal daily dose of nifedipine extended release does not achieve the BP target, adding labetalol as a second agent is an option.⁹

In a network meta-analysis of antihypertensive medications used in pregnancy, that included 61 trials and 6,923 participants, all the medications studied reduced the risk of developing severe hypertension by 30% to 70%.¹³ Sufficient data was available to also report that labetalol used to treat hypertension in pregnancy reduced the risk of developing proteinuria.¹³ Given similar efficacy among antihypertensive medications, patient comorbidities may influence the medication choice. For example, labetalol may not be the optimal medication for a patient with poorly controlled asthma due to its ability to cause bronchospasm.^14,15 Methyldopa may not be the optimal medication for a patient with depression.¹⁶ Based on the available data, labetalol, nifedipine, and methyldopa are the best antihypertensive medications for pregnant patients.

Continue to: What is an optimal BP target when treating chronic hypertension in pregnancy?...

What is an optimal BP target when treating chronic hypertension in pregnancy?

When treating chronic hypertension in pregnant patients, a concern is that reducing maternal BP may decrease uteroplacental perfusion and result in fetal growth restriction. However, a recent trial reported that a BP treatment target < 140/90 mm Hg is associated with better outcomes for both mother and newborn than withholding antihypertension medications. In the trial, 2,408 women with chronic hypertension diagnosed before 20 weeks of gestation were randomly assigned to an active treatment group with prescription of antihypertension medicines to achieve a BP target of < 140/90 mm Hg; or to a control group where no antihypertension or no additional antihypertension treatment was prescribed unless BP was ≥ 160 mm Hg systolic or ≥ 105 mm Hg diastolic.⁹ The hypertension medications prescribed to the patients in the active treatment group were labetalol (63.2%), nifedipine (33.4%), amlodipine (1.7%), methyldopa (0.5%), hydrochlorothiazide (0.3%), metoprolol (0.2%), and missing/unknown/other (0.7%).⁹

If a patient in the control group developed severe hypertension, they were started on an antihypertension medicine and the BP treatment target was < 140/90 mm Hg. Compared with the control regimen, active treatment resulted in a significant decrease in the development of preeclampsia (24.4% vs 31.1%; risk ratio [RR], 0.79; 95% CI, 0.69-0.89), severe hypertension (36.1% vs 44.3%; RR, 0.82; 95% CI, 0.74-0.90), preterm birth < 37 weeks’ gestation (27.5% vs 31.4%; RR, 0.87; 95% CI, 0.77-0.99), preterm birth < 35 weeks’ gestation (12.2% vs 16.7%; odds ratio [OR], 0.69; 95% CI, 0.55-0.88), and low birth-weight (< 2,500 g) newborns (19.2% vs 23.1%; RR, 0.83; 95% CI, 0.71-0.97).⁹ The percentage of small for gestational age birth weight below the 10th percentile was similar in the treatment and control groups, 11.2% and 10.4%, respectively (adjusted RR, 1.04; 95% CI, 0.82-1.31).⁹ The number of patients who would need to be treated to prevent one primary-outcome event was 15.⁹ The investigators concluded that for pregnant patients with chronic hypertension, the optimal BP target is < 140/90 mm Hg.⁹

When does BP reach a postpartum peak?

In pregnant patients with hypertension, BP may decrease immediately after birth. Following birth, BP tends to increase, reaching a peak 3 to 6 days postpartum.^17,18 This pattern was observed in patients with and without preeclampsia in the index pregnancy. Among 136 patients without antepartum preeclampsia, the prevalence of a diastolic BP > 89 mm Hg was 5% and 15% on postpartum days 1 and 3, respectively.¹⁷ The postpartum rise in BP may be due to mobilization of water from the extravascular to the intravascular space and excretion of total body sodium that accumulated during pregnancy.¹⁹ In one study of 998 consecutive singleton cesarean births, 7.7% of the patients with no recorded elevated BP before delivery developed de novo hypertension postpartum.²⁰ Compared with patients without antepartum or new onset postpartum hypertension, the patients who developed postpartum hypertension had a higher body mass index, were more likely to be Black and to have a history of type 2 diabetes. Compared with patients without antepartum or postpartum hypertension, the patients who developed de novo postpartum hypertension, had significantly elevated soluble fms-like tyrosine kinase-1 and significantly decreased placental growth factor, a pattern seen with preeclampsia.²⁰ These results suggest that de novo postpartum hypertension may have molecular causes similar to preeclampsia.²⁰

Postpartum hypertension should be treated with a medication that is thought to be safe for breastfeeding patients, including labetalol, nifedipine, or enalapril.^21-23 The relative infant dose of labetalol, nifedipine, and enalapril is approximately 3.6%, ≤ 3.2%, and 1.1%, respectively.²⁴ If the relative infant dose of a medication is < 10% it is generally considered to be compatible with breastfeeding.²⁵

Many obstetricians have seldom prescribed enalapril, an ACE-I. The initial dose of enalapril is 5 mg or 10 mg daily. After initiation of treatment, the dose can be adjusted based on BP measurement. The maximal daily dose is 40 mg daily in one dose or two divided doses. Similar to other hypertension medicines, enalapril therapy may cause hypotension and dizziness. Enalapril should not be used by pregnant patients because it is associated with an increased risk of congenital anomalies and fetal demise.

Does a HDP increase the risk of developing chronic hypertension?

All obstetricians know that a patient with a history of a HDP is at an increased risk for developing chronic hypertension treated with a medication, but the magnitude of the risk is less well known. In a nationwide study in Denmark, the prevalence of chronic hypertension treated with medication 10 years after delivery among patients with a history of a HDP in their first pregnancy, was 14%, 21%, and 32%, if the first pregnancy occurred in the patient’s 20s, 30s, or 40s, respectively.²⁶ The corresponding prevalence of chronic hypertension in patients without a history of a HDP was 4%, 6%, and 11%, if the first pregnancy occurred in the 20s, 30s, or 40s, respectively.²⁶ Maternal age is an important predictor of who will develop chronic hypertension within 10 years following a pregnancy with a HDP.

In modern obstetric practice, the hypertensive disorders of pregnancy are prevalent and associated with increased maternal and newborn morbidity. Appropriate treatment of hypertension with labetalol, nifedipine, or methyldopa improves maternal and newborn health. Available evidence suggests that maintaining BP < 140/90 mm Hg during pregnancy for most patients is a practical goal with significant benefit. A significant public-health concern is that an increase in the prevalence of HDPs will eventually translate into an increase in chronic hypertension and the attendant complications of heart attack, heart failure, stroke, and renal insufficiency. Recognizing the increased prevalence of HDPs, ObGyns will need to alert patients to their long-term health risks and coordinate appropriate follow-up and treatment to optimize the future health of their patients. ●

In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.¹ Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.² Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.^3,4

It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.³ Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.⁴

Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.⁵ In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.⁶

Pharmacology of mifepristone

Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.⁷ At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.

Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.^8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.

The terminal half-life of mifepristone is 18 hours.¹¹ Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.

Continue to: Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac...

Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac

For patients with a miscarriage, the treatment options to resolve the pregnancy loss are expectant management, medication, or surgery.¹² Joint decision-making is recommended to establish a management plan that supports the patient’s values. Expectant management is most likely to result in a multi-week process to achieve completion of the miscarriage. A surgical procedure is most likely to result in rapid resolution of the miscarriage with the greatest rate of success. Surgical evacuation of the uterus may be the preferred option for patients who have excessive uterine bleeding or concerning vital signs. Both medical and surgical management are more likely than expectant management to successfully resolve the miscarriage.¹³

In the past, the standard approach to medication management of a miscarriage was the administration of one or more doses of misoprostol, a synthetic prostaglandin E1. However, two large trials have reported that the dual-medication sequence of mifepristone followed 24 to 48 hours later by misoprostol is more effective than misoprostol alone for resolving a miscarriage.^14,15 This is probably due to mifepristone making the uterus more responsive to the effects of misoprostol.

Schreiber and colleagues¹⁴ reported a study of 300 patients with an anembryonic gestation or embryonic demise, between 5 and 12 completed weeks of gestation, who were randomly assigned to treatment with mifepristone (200 mg) followed in 24 to 48 hours with vaginal misoprostol (800 µg) or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09–1.43).

Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment than with misoprostol monotherapy—9% and 24%, respectively (RR, 0.37; 95% CI, 0.21–0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁶ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹⁷

Chu and colleagues¹⁵ reported a study of medication treatment of missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route, but 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. In this study, mifepristone-misoprostol resulted in fewer patients who did not pass the gestational sac within 7 days after entry into the study than placebo (mifepristone-misoprostol, 17% vs placebo-misoprostol, 24% (P=.043). Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53–0.95; P=.021). A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostol alone for the management of missed miscarriages.¹⁸

Misoprostol can be administered by an oral, buccal, rectal, or vaginal route.^19,20 Vaginal administration results in higher circulating concentrations of misoprostol than buccal administration, but both routes of administration produce similar mean uterine tone and mean uterine activity as measured by an intrauterine pressure transducer over 5 hours.²¹ Hence, at our institution, we most often use buccal administration of misoprostol. To assess effectiveness of mifepristone-misoprostol treatment, 1 week after treatment with a pelvic ultrasound to detect expulsion of the gestational sac. Alternatively, a urine pregnancy test can be performed 3 weeks following medication treatment. The mifepristone-misoprostol regimen is not approved by the US Food and Drug Administration for the treatment of miscarriage.

Continue to: Mifepristone-misoprostol for the treatment of fetal demise...

Mifepristone-misoprostol for the treatment of fetal demise

Fetal loss in the second or third trimesters is a devastating experience for most patients, painfully echoing in the heart and mind for years. Empathic and effective treatment of fetal loss may reduce the adverse impact of the event. Multiple studies have reported that combinations of mifepristone and misoprostol reduced the time from initiation of labor contractions to birth compared with misoprostol alone.^22-28 In addition, the combination of mifepristone-misoprostol reduced the amount of misoprostol needed to achieve delivery.^22,23

In one clinical trial, 66 patients with fetal demise between 14 and 28 weeks’ gestation were randomized to receive mifepristone 200 mg or placebo.²² Twenty-four to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 14 to 23 completed weeks of gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24 to 28 weeks gestation, the misoprostol dose was 200 µg vaginally every 4 hours. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P=.002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage—4 in the placebo group and 1 in the mifepristone group.²²

In a second clinical trial, 110 patients with fetal demise after 20 weeks of gestation were randomized to receive mifepristone 200 mg or placebo.²³ Thirty-six to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostol dose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients ≥26 weeks gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours. (P=.001).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg, P<.001).

Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among the patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²³

Miscarriage and fetal demise frequently cause patients to experience a range of emotions including denial, numbness, grief, anger, guilt, and depression. It may take months or years for people to progress to a tentative acceptance of the loss, refocusing on future aspirations. Empathic care and timely and effective medical intervention to resolve the pregnancy loss optimize outcomes. For medication treatment of miscarriage and fetal demise, mifepristone is an important agent because it improves the success rate for resolution of miscarriage without surgery and it shortens the time of labor for inductions for fetal demise. Obstetrician-gynecologists are the specialists leading advances in treatment of miscarriage and fetal demise. I encourage you to use mifepristone in your care of appropriate patients with miscarriage and fetal demise. ●

In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.¹ Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.² Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.^3,4

It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.³ Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.⁴

Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.⁵ In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.⁶

Pharmacology of mifepristone

Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.⁷ At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.

Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.^8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.

The terminal half-life of mifepristone is 18 hours.¹¹ Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.

Continue to: Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac...

Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac

For patients with a miscarriage, the treatment options to resolve the pregnancy loss are expectant management, medication, or surgery.¹² Joint decision-making is recommended to establish a management plan that supports the patient’s values. Expectant management is most likely to result in a multi-week process to achieve completion of the miscarriage. A surgical procedure is most likely to result in rapid resolution of the miscarriage with the greatest rate of success. Surgical evacuation of the uterus may be the preferred option for patients who have excessive uterine bleeding or concerning vital signs. Both medical and surgical management are more likely than expectant management to successfully resolve the miscarriage.¹³

In the past, the standard approach to medication management of a miscarriage was the administration of one or more doses of misoprostol, a synthetic prostaglandin E1. However, two large trials have reported that the dual-medication sequence of mifepristone followed 24 to 48 hours later by misoprostol is more effective than misoprostol alone for resolving a miscarriage.^14,15 This is probably due to mifepristone making the uterus more responsive to the effects of misoprostol.

Schreiber and colleagues¹⁴ reported a study of 300 patients with an anembryonic gestation or embryonic demise, between 5 and 12 completed weeks of gestation, who were randomly assigned to treatment with mifepristone (200 mg) followed in 24 to 48 hours with vaginal misoprostol (800 µg) or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09–1.43).

Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment than with misoprostol monotherapy—9% and 24%, respectively (RR, 0.37; 95% CI, 0.21–0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁶ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹⁷

Chu and colleagues¹⁵ reported a study of medication treatment of missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route, but 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. In this study, mifepristone-misoprostol resulted in fewer patients who did not pass the gestational sac within 7 days after entry into the study than placebo (mifepristone-misoprostol, 17% vs placebo-misoprostol, 24% (P=.043). Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53–0.95; P=.021). A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostol alone for the management of missed miscarriages.¹⁸

Misoprostol can be administered by an oral, buccal, rectal, or vaginal route.^19,20 Vaginal administration results in higher circulating concentrations of misoprostol than buccal administration, but both routes of administration produce similar mean uterine tone and mean uterine activity as measured by an intrauterine pressure transducer over 5 hours.²¹ Hence, at our institution, we most often use buccal administration of misoprostol. To assess effectiveness of mifepristone-misoprostol treatment, 1 week after treatment with a pelvic ultrasound to detect expulsion of the gestational sac. Alternatively, a urine pregnancy test can be performed 3 weeks following medication treatment. The mifepristone-misoprostol regimen is not approved by the US Food and Drug Administration for the treatment of miscarriage.

Continue to: Mifepristone-misoprostol for the treatment of fetal demise...

Mifepristone-misoprostol for the treatment of fetal demise

Fetal loss in the second or third trimesters is a devastating experience for most patients, painfully echoing in the heart and mind for years. Empathic and effective treatment of fetal loss may reduce the adverse impact of the event. Multiple studies have reported that combinations of mifepristone and misoprostol reduced the time from initiation of labor contractions to birth compared with misoprostol alone.^22-28 In addition, the combination of mifepristone-misoprostol reduced the amount of misoprostol needed to achieve delivery.^22,23

In one clinical trial, 66 patients with fetal demise between 14 and 28 weeks’ gestation were randomized to receive mifepristone 200 mg or placebo.²² Twenty-four to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 14 to 23 completed weeks of gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24 to 28 weeks gestation, the misoprostol dose was 200 µg vaginally every 4 hours. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P=.002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage—4 in the placebo group and 1 in the mifepristone group.²²

In a second clinical trial, 110 patients with fetal demise after 20 weeks of gestation were randomized to receive mifepristone 200 mg or placebo.²³ Thirty-six to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostol dose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients ≥26 weeks gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours. (P=.001).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg, P<.001).

Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among the patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²³

Miscarriage and fetal demise frequently cause patients to experience a range of emotions including denial, numbness, grief, anger, guilt, and depression. It may take months or years for people to progress to a tentative acceptance of the loss, refocusing on future aspirations. Empathic care and timely and effective medical intervention to resolve the pregnancy loss optimize outcomes. For medication treatment of miscarriage and fetal demise, mifepristone is an important agent because it improves the success rate for resolution of miscarriage without surgery and it shortens the time of labor for inductions for fetal demise. Obstetrician-gynecologists are the specialists leading advances in treatment of miscarriage and fetal demise. I encourage you to use mifepristone in your care of appropriate patients with miscarriage and fetal demise. ●

In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.¹ Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.² Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.^3,4

It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.³ Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.⁴

Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.⁵ In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.⁶

Pharmacology of mifepristone

Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.⁷ At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.

Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.^8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.

The terminal half-life of mifepristone is 18 hours.¹¹ Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.

Continue to: Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac...

Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac

For patients with a miscarriage, the treatment options to resolve the pregnancy loss are expectant management, medication, or surgery.¹² Joint decision-making is recommended to establish a management plan that supports the patient’s values. Expectant management is most likely to result in a multi-week process to achieve completion of the miscarriage. A surgical procedure is most likely to result in rapid resolution of the miscarriage with the greatest rate of success. Surgical evacuation of the uterus may be the preferred option for patients who have excessive uterine bleeding or concerning vital signs. Both medical and surgical management are more likely than expectant management to successfully resolve the miscarriage.¹³

In the past, the standard approach to medication management of a miscarriage was the administration of one or more doses of misoprostol, a synthetic prostaglandin E1. However, two large trials have reported that the dual-medication sequence of mifepristone followed 24 to 48 hours later by misoprostol is more effective than misoprostol alone for resolving a miscarriage.^14,15 This is probably due to mifepristone making the uterus more responsive to the effects of misoprostol.

Schreiber and colleagues¹⁴ reported a study of 300 patients with an anembryonic gestation or embryonic demise, between 5 and 12 completed weeks of gestation, who were randomly assigned to treatment with mifepristone (200 mg) followed in 24 to 48 hours with vaginal misoprostol (800 µg) or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09–1.43).

Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment than with misoprostol monotherapy—9% and 24%, respectively (RR, 0.37; 95% CI, 0.21–0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁶ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹⁷

Chu and colleagues¹⁵ reported a study of medication treatment of missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route, but 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. In this study, mifepristone-misoprostol resulted in fewer patients who did not pass the gestational sac within 7 days after entry into the study than placebo (mifepristone-misoprostol, 17% vs placebo-misoprostol, 24% (P=.043). Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53–0.95; P=.021). A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostol alone for the management of missed miscarriages.¹⁸

Misoprostol can be administered by an oral, buccal, rectal, or vaginal route.^19,20 Vaginal administration results in higher circulating concentrations of misoprostol than buccal administration, but both routes of administration produce similar mean uterine tone and mean uterine activity as measured by an intrauterine pressure transducer over 5 hours.²¹ Hence, at our institution, we most often use buccal administration of misoprostol. To assess effectiveness of mifepristone-misoprostol treatment, 1 week after treatment with a pelvic ultrasound to detect expulsion of the gestational sac. Alternatively, a urine pregnancy test can be performed 3 weeks following medication treatment. The mifepristone-misoprostol regimen is not approved by the US Food and Drug Administration for the treatment of miscarriage.

Continue to: Mifepristone-misoprostol for the treatment of fetal demise...

Mifepristone-misoprostol for the treatment of fetal demise

Fetal loss in the second or third trimesters is a devastating experience for most patients, painfully echoing in the heart and mind for years. Empathic and effective treatment of fetal loss may reduce the adverse impact of the event. Multiple studies have reported that combinations of mifepristone and misoprostol reduced the time from initiation of labor contractions to birth compared with misoprostol alone.^22-28 In addition, the combination of mifepristone-misoprostol reduced the amount of misoprostol needed to achieve delivery.^22,23

In one clinical trial, 66 patients with fetal demise between 14 and 28 weeks’ gestation were randomized to receive mifepristone 200 mg or placebo.²² Twenty-four to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 14 to 23 completed weeks of gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24 to 28 weeks gestation, the misoprostol dose was 200 µg vaginally every 4 hours. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P=.002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage—4 in the placebo group and 1 in the mifepristone group.²²

In a second clinical trial, 110 patients with fetal demise after 20 weeks of gestation were randomized to receive mifepristone 200 mg or placebo.²³ Thirty-six to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostol dose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients ≥26 weeks gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours. (P=.001).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg, P<.001).

Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among the patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²³

Miscarriage and fetal demise frequently cause patients to experience a range of emotions including denial, numbness, grief, anger, guilt, and depression. It may take months or years for people to progress to a tentative acceptance of the loss, refocusing on future aspirations. Empathic care and timely and effective medical intervention to resolve the pregnancy loss optimize outcomes. For medication treatment of miscarriage and fetal demise, mifepristone is an important agent because it improves the success rate for resolution of miscarriage without surgery and it shortens the time of labor for inductions for fetal demise. Obstetrician-gynecologists are the specialists leading advances in treatment of miscarriage and fetal demise. I encourage you to use mifepristone in your care of appropriate patients with miscarriage and fetal demise. ●

Oxytocin and prostaglandins are critically important regulators of uterine contraction. Obstetrician-gynecologists commonly prescribe oxytocin and prostaglandin agonists (misoprostol, dinoprostone) to stimulate uterine contraction for the induction of labor, prevention and treatment of postpartum hemorrhage, and treatment of miscarriage and fetal demise. The focus of this editorial is the clinical pharmacology of misoprostol.

Misoprostol is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of nonsteroidal anti-inflammatory drug–induced gastric ulcers and for patients at high risk for gastric ulcers, including those with a history of gastric ulcers. The approved misoprostol route and dose for this indication is oral administration of 200 µg four times daily with food.¹ Recent food intake and antacid use reduces the absorption of orally administered misoprostol. There are no FDA-approved indications for the use of misoprostol as a single agent in obstetrics and gynecology. The FDA has approved the combination of mifepristone and misoprostol for medication abortion in the first trimester. In contrast to misoprostol, PGE2 (dinoprostone) is approved by the FDA as a vaginal insert containing 10 mg of dinoprostone for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetric indication for induction of labor (Cervidil; Ferring Pharmaceuticals Inc, Parsippany, New Jersey).²

Pharmacology of misoprostol

Misoprostol is a prostaglandin E1 (PGE1) agonist analogue. Prostaglandin E1 (alprostadil) is rapidly metabolized, has a half-life in the range of minutes and is not orally active, requiring administration by intravenous infusion or injection. It is indicated to maintain a patent ductus arteriosus in newborns with ductal-dependent circulation and to treat erectile dysfunction.³ In contrast to PGE1, misoprostol has a methyl ester group at carbon-1 (C-1) that increases potency and duration of action. Misoprostol also has no hydroxyl group at C-15, replacing that moiety with the addition of both a methyl- and hydroxyl- group at C-16 (FIGURE). These molecular changes improve oral activity and increase duration of action.⁴ Pure misoprostol is a viscous oil. It is formulated into tables by dispersing the oil on hydroxypropyl methyl cellulose before compounding into tablets. Unlike naturally occurring prostaglandins (PGE1), misoprostol tablets are stabile at room temperature for years.⁴

Following absorption, the methyl ester at C-1 is enzymatically cleaved, yielding misoprostol acid, the active drug.⁴ Misoprostol binds to the E prostanoid receptor 3 (EP-3).⁵ Activation of myometrial EP-3 receptor induces an increase in intracellular phosphoinositol turnover and calcium mobilization, resulting in an increase in intracellular-free calcium, triggering actin-myosin contractility.⁶ The increase in free calcium is propagated cell-to-cell through gap junctions that link the myometrial cells to facilitate the generation of a coordinated contraction.

Misoprostol: Various routes of administration are not equal

Misoprostol can be given by an oral, buccal, vaginal, or rectal route of administration. To study the effect of the route of administration on uterine tone and contractility, investigators randomly assigned patients at 8 to 11 weeks’ gestation to receive misoprostol 400 µg as a single dose by the oral or vaginal route. Uterine tone and contractility were measured using an intrauterine pressure transducer. Compared to vaginal administration, oral administration of misprostol was associated with rapid attainment of peak plasma level at 30 minutes, followed by a decline in concentration by 60 minutes. This rapid onset and rapid offset of plasma concentration was paralleled by the onset of uterine tone within 8 minutes, but surprisingly no sustained uterine contractions.⁷ By contrast, following vaginal administration of misoprostol, serum levels rose slowly and peaked in 1 to 2 hours. Uterine tone increased within 21 minutes, and sustained uterine contractions were recorded for 4 hours.⁷ The rapid rise and fall in plasma misoprostol following oral administration and the more sustained plasma misoprostol concentration over 4 hours has been previously reported.⁸ In a second study involving patients 8 to 11 weeks’ gestation, the effect of a single dose of misoprostol 400 µg by an oral or vaginal route on uterine contractility was compared using an intrauterine pressure transducer.⁹ Confirming previous results, the time from misoprostol administration to increased uterine tone was more rapid with oral than with vaginal administration (8 min vs 19 min). Over the course of 4 hours, uterine contraction activity was greater with vaginal than with oral administration (454 vs 166 Montevideo units).⁹

Both studies reported that oral administration of misoprostol resulted in more rapid onset and offset of action than vaginal administration. Oral administration of a single dose of misoprostol 400 µg did not result in sustained uterine contractions in most patients in the first trimester. Vaginal administration produced a slower onset of increased uterine tone but sustained uterine contractions over 4 hours. Compared with vaginal administration of misoprostol, the rapid onset and offset of action of oral misoprostol may reduce the rate of tachysystole and changes in fetal heart rate observed with vaginal administration.¹⁰

An important finding is that buccal and vaginal administration of misoprostol have similar effects on uterine tone in the first trimester.¹¹ To study the effect of buccal and vaginal administration of misoprostol on uterine tone, patients 6 to 13 weeks’ gestation were randomly allocated to receive a single dose of misoprostol 400 µg by a buccal or vaginal route.¹¹ Uterine activity over 5 hours following administration was assessed using an intrauterine pressure transducer. Uterine tone 20 to 30 minutes after buccal or vaginal administration of misoprostol (400 µg) was 27 and 28 mm Hg, respectively. Peak uterine tone, as measured by an intrauterine pressure transducer, for buccal and vaginal administration of misoprostol was 49 mm Hg and 54 mm Hg, respectively. Total Alexandria units (AU) over 5 hours following buccal or vaginal administration was 6,537 AU and 6,090 AU, respectively.¹¹

An AU is calculated as the average amplitude of the contractions (mm Hg) multiplied by the average duration of the contractions (min) multiplied by average frequency of contraction over 10 minutes.¹² By contrast, a Montevideo unit does not include an assessment of contraction duration and is calculated as average amplitude of contractions (mm Hg) multiplied by frequency of uterine contractions over 10 minutes.¹²

In contrast to buccal or vaginal administration, rectal administration of misoprostol resulted in much lower peak uterine tone and contractility as measured by a pressure transducer. Uterine tone 20 to 30 minutes after vaginal and rectal administration of misoprostol (400 µg) was 28 and 19 mm Hg, respectively.¹¹ Peak uterine tone, as measured by an intrauterine pressure transducer, for vaginal and rectal administration of misoprostol was 54 and 31 mm Hg, respectively. AUs over 5 hours following vaginal and rectal administration was 6,090 AU and 2,768 AU, respectively.¹¹ Compared with buccal and vaginal administration of misoprostol, rectal administration produced less sustained uterine contractions in the first trimester of pregnancy. To achieve maximal sustained uterine contractions, buccal and vaginal routes of administration are superior to oral and rectal administration.

Continue to: Misoprostol and cervical ripening...

Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.¹³ The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.¹³ Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.

Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.¹³ Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.^14,15

An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.¹⁶ Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.¹⁶

Bottom line

Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●

Oxytocin and prostaglandins are critically important regulators of uterine contraction. Obstetrician-gynecologists commonly prescribe oxytocin and prostaglandin agonists (misoprostol, dinoprostone) to stimulate uterine contraction for the induction of labor, prevention and treatment of postpartum hemorrhage, and treatment of miscarriage and fetal demise. The focus of this editorial is the clinical pharmacology of misoprostol.

Misoprostol is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of nonsteroidal anti-inflammatory drug–induced gastric ulcers and for patients at high risk for gastric ulcers, including those with a history of gastric ulcers. The approved misoprostol route and dose for this indication is oral administration of 200 µg four times daily with food.¹ Recent food intake and antacid use reduces the absorption of orally administered misoprostol. There are no FDA-approved indications for the use of misoprostol as a single agent in obstetrics and gynecology. The FDA has approved the combination of mifepristone and misoprostol for medication abortion in the first trimester. In contrast to misoprostol, PGE2 (dinoprostone) is approved by the FDA as a vaginal insert containing 10 mg of dinoprostone for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetric indication for induction of labor (Cervidil; Ferring Pharmaceuticals Inc, Parsippany, New Jersey).²

Pharmacology of misoprostol

Misoprostol is a prostaglandin E1 (PGE1) agonist analogue. Prostaglandin E1 (alprostadil) is rapidly metabolized, has a half-life in the range of minutes and is not orally active, requiring administration by intravenous infusion or injection. It is indicated to maintain a patent ductus arteriosus in newborns with ductal-dependent circulation and to treat erectile dysfunction.³ In contrast to PGE1, misoprostol has a methyl ester group at carbon-1 (C-1) that increases potency and duration of action. Misoprostol also has no hydroxyl group at C-15, replacing that moiety with the addition of both a methyl- and hydroxyl- group at C-16 (FIGURE). These molecular changes improve oral activity and increase duration of action.⁴ Pure misoprostol is a viscous oil. It is formulated into tables by dispersing the oil on hydroxypropyl methyl cellulose before compounding into tablets. Unlike naturally occurring prostaglandins (PGE1), misoprostol tablets are stabile at room temperature for years.⁴

Following absorption, the methyl ester at C-1 is enzymatically cleaved, yielding misoprostol acid, the active drug.⁴ Misoprostol binds to the E prostanoid receptor 3 (EP-3).⁵ Activation of myometrial EP-3 receptor induces an increase in intracellular phosphoinositol turnover and calcium mobilization, resulting in an increase in intracellular-free calcium, triggering actin-myosin contractility.⁶ The increase in free calcium is propagated cell-to-cell through gap junctions that link the myometrial cells to facilitate the generation of a coordinated contraction.

Misoprostol: Various routes of administration are not equal

Misoprostol can be given by an oral, buccal, vaginal, or rectal route of administration. To study the effect of the route of administration on uterine tone and contractility, investigators randomly assigned patients at 8 to 11 weeks’ gestation to receive misoprostol 400 µg as a single dose by the oral or vaginal route. Uterine tone and contractility were measured using an intrauterine pressure transducer. Compared to vaginal administration, oral administration of misprostol was associated with rapid attainment of peak plasma level at 30 minutes, followed by a decline in concentration by 60 minutes. This rapid onset and rapid offset of plasma concentration was paralleled by the onset of uterine tone within 8 minutes, but surprisingly no sustained uterine contractions.⁷ By contrast, following vaginal administration of misoprostol, serum levels rose slowly and peaked in 1 to 2 hours. Uterine tone increased within 21 minutes, and sustained uterine contractions were recorded for 4 hours.⁷ The rapid rise and fall in plasma misoprostol following oral administration and the more sustained plasma misoprostol concentration over 4 hours has been previously reported.⁸ In a second study involving patients 8 to 11 weeks’ gestation, the effect of a single dose of misoprostol 400 µg by an oral or vaginal route on uterine contractility was compared using an intrauterine pressure transducer.⁹ Confirming previous results, the time from misoprostol administration to increased uterine tone was more rapid with oral than with vaginal administration (8 min vs 19 min). Over the course of 4 hours, uterine contraction activity was greater with vaginal than with oral administration (454 vs 166 Montevideo units).⁹

Both studies reported that oral administration of misoprostol resulted in more rapid onset and offset of action than vaginal administration. Oral administration of a single dose of misoprostol 400 µg did not result in sustained uterine contractions in most patients in the first trimester. Vaginal administration produced a slower onset of increased uterine tone but sustained uterine contractions over 4 hours. Compared with vaginal administration of misoprostol, the rapid onset and offset of action of oral misoprostol may reduce the rate of tachysystole and changes in fetal heart rate observed with vaginal administration.¹⁰

An important finding is that buccal and vaginal administration of misoprostol have similar effects on uterine tone in the first trimester.¹¹ To study the effect of buccal and vaginal administration of misoprostol on uterine tone, patients 6 to 13 weeks’ gestation were randomly allocated to receive a single dose of misoprostol 400 µg by a buccal or vaginal route.¹¹ Uterine activity over 5 hours following administration was assessed using an intrauterine pressure transducer. Uterine tone 20 to 30 minutes after buccal or vaginal administration of misoprostol (400 µg) was 27 and 28 mm Hg, respectively. Peak uterine tone, as measured by an intrauterine pressure transducer, for buccal and vaginal administration of misoprostol was 49 mm Hg and 54 mm Hg, respectively. Total Alexandria units (AU) over 5 hours following buccal or vaginal administration was 6,537 AU and 6,090 AU, respectively.¹¹

An AU is calculated as the average amplitude of the contractions (mm Hg) multiplied by the average duration of the contractions (min) multiplied by average frequency of contraction over 10 minutes.¹² By contrast, a Montevideo unit does not include an assessment of contraction duration and is calculated as average amplitude of contractions (mm Hg) multiplied by frequency of uterine contractions over 10 minutes.¹²

In contrast to buccal or vaginal administration, rectal administration of misoprostol resulted in much lower peak uterine tone and contractility as measured by a pressure transducer. Uterine tone 20 to 30 minutes after vaginal and rectal administration of misoprostol (400 µg) was 28 and 19 mm Hg, respectively.¹¹ Peak uterine tone, as measured by an intrauterine pressure transducer, for vaginal and rectal administration of misoprostol was 54 and 31 mm Hg, respectively. AUs over 5 hours following vaginal and rectal administration was 6,090 AU and 2,768 AU, respectively.¹¹ Compared with buccal and vaginal administration of misoprostol, rectal administration produced less sustained uterine contractions in the first trimester of pregnancy. To achieve maximal sustained uterine contractions, buccal and vaginal routes of administration are superior to oral and rectal administration.

Continue to: Misoprostol and cervical ripening...

Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.¹³ The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.¹³ Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.

Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.¹³ Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.^14,15

An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.¹⁶ Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.¹⁶

Bottom line

Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●

Oxytocin and prostaglandins are critically important regulators of uterine contraction. Obstetrician-gynecologists commonly prescribe oxytocin and prostaglandin agonists (misoprostol, dinoprostone) to stimulate uterine contraction for the induction of labor, prevention and treatment of postpartum hemorrhage, and treatment of miscarriage and fetal demise. The focus of this editorial is the clinical pharmacology of misoprostol.

Misoprostol is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of nonsteroidal anti-inflammatory drug–induced gastric ulcers and for patients at high risk for gastric ulcers, including those with a history of gastric ulcers. The approved misoprostol route and dose for this indication is oral administration of 200 µg four times daily with food.¹ Recent food intake and antacid use reduces the absorption of orally administered misoprostol. There are no FDA-approved indications for the use of misoprostol as a single agent in obstetrics and gynecology. The FDA has approved the combination of mifepristone and misoprostol for medication abortion in the first trimester. In contrast to misoprostol, PGE2 (dinoprostone) is approved by the FDA as a vaginal insert containing 10 mg of dinoprostone for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetric indication for induction of labor (Cervidil; Ferring Pharmaceuticals Inc, Parsippany, New Jersey).²

Pharmacology of misoprostol

Misoprostol is a prostaglandin E1 (PGE1) agonist analogue. Prostaglandin E1 (alprostadil) is rapidly metabolized, has a half-life in the range of minutes and is not orally active, requiring administration by intravenous infusion or injection. It is indicated to maintain a patent ductus arteriosus in newborns with ductal-dependent circulation and to treat erectile dysfunction.³ In contrast to PGE1, misoprostol has a methyl ester group at carbon-1 (C-1) that increases potency and duration of action. Misoprostol also has no hydroxyl group at C-15, replacing that moiety with the addition of both a methyl- and hydroxyl- group at C-16 (FIGURE). These molecular changes improve oral activity and increase duration of action.⁴ Pure misoprostol is a viscous oil. It is formulated into tables by dispersing the oil on hydroxypropyl methyl cellulose before compounding into tablets. Unlike naturally occurring prostaglandins (PGE1), misoprostol tablets are stabile at room temperature for years.⁴

Following absorption, the methyl ester at C-1 is enzymatically cleaved, yielding misoprostol acid, the active drug.⁴ Misoprostol binds to the E prostanoid receptor 3 (EP-3).⁵ Activation of myometrial EP-3 receptor induces an increase in intracellular phosphoinositol turnover and calcium mobilization, resulting in an increase in intracellular-free calcium, triggering actin-myosin contractility.⁶ The increase in free calcium is propagated cell-to-cell through gap junctions that link the myometrial cells to facilitate the generation of a coordinated contraction.

Misoprostol: Various routes of administration are not equal

Misoprostol can be given by an oral, buccal, vaginal, or rectal route of administration. To study the effect of the route of administration on uterine tone and contractility, investigators randomly assigned patients at 8 to 11 weeks’ gestation to receive misoprostol 400 µg as a single dose by the oral or vaginal route. Uterine tone and contractility were measured using an intrauterine pressure transducer. Compared to vaginal administration, oral administration of misprostol was associated with rapid attainment of peak plasma level at 30 minutes, followed by a decline in concentration by 60 minutes. This rapid onset and rapid offset of plasma concentration was paralleled by the onset of uterine tone within 8 minutes, but surprisingly no sustained uterine contractions.⁷ By contrast, following vaginal administration of misoprostol, serum levels rose slowly and peaked in 1 to 2 hours. Uterine tone increased within 21 minutes, and sustained uterine contractions were recorded for 4 hours.⁷ The rapid rise and fall in plasma misoprostol following oral administration and the more sustained plasma misoprostol concentration over 4 hours has been previously reported.⁸ In a second study involving patients 8 to 11 weeks’ gestation, the effect of a single dose of misoprostol 400 µg by an oral or vaginal route on uterine contractility was compared using an intrauterine pressure transducer.⁹ Confirming previous results, the time from misoprostol administration to increased uterine tone was more rapid with oral than with vaginal administration (8 min vs 19 min). Over the course of 4 hours, uterine contraction activity was greater with vaginal than with oral administration (454 vs 166 Montevideo units).⁹

Both studies reported that oral administration of misoprostol resulted in more rapid onset and offset of action than vaginal administration. Oral administration of a single dose of misoprostol 400 µg did not result in sustained uterine contractions in most patients in the first trimester. Vaginal administration produced a slower onset of increased uterine tone but sustained uterine contractions over 4 hours. Compared with vaginal administration of misoprostol, the rapid onset and offset of action of oral misoprostol may reduce the rate of tachysystole and changes in fetal heart rate observed with vaginal administration.¹⁰

An important finding is that buccal and vaginal administration of misoprostol have similar effects on uterine tone in the first trimester.¹¹ To study the effect of buccal and vaginal administration of misoprostol on uterine tone, patients 6 to 13 weeks’ gestation were randomly allocated to receive a single dose of misoprostol 400 µg by a buccal or vaginal route.¹¹ Uterine activity over 5 hours following administration was assessed using an intrauterine pressure transducer. Uterine tone 20 to 30 minutes after buccal or vaginal administration of misoprostol (400 µg) was 27 and 28 mm Hg, respectively. Peak uterine tone, as measured by an intrauterine pressure transducer, for buccal and vaginal administration of misoprostol was 49 mm Hg and 54 mm Hg, respectively. Total Alexandria units (AU) over 5 hours following buccal or vaginal administration was 6,537 AU and 6,090 AU, respectively.¹¹

An AU is calculated as the average amplitude of the contractions (mm Hg) multiplied by the average duration of the contractions (min) multiplied by average frequency of contraction over 10 minutes.¹² By contrast, a Montevideo unit does not include an assessment of contraction duration and is calculated as average amplitude of contractions (mm Hg) multiplied by frequency of uterine contractions over 10 minutes.¹²

In contrast to buccal or vaginal administration, rectal administration of misoprostol resulted in much lower peak uterine tone and contractility as measured by a pressure transducer. Uterine tone 20 to 30 minutes after vaginal and rectal administration of misoprostol (400 µg) was 28 and 19 mm Hg, respectively.¹¹ Peak uterine tone, as measured by an intrauterine pressure transducer, for vaginal and rectal administration of misoprostol was 54 and 31 mm Hg, respectively. AUs over 5 hours following vaginal and rectal administration was 6,090 AU and 2,768 AU, respectively.¹¹ Compared with buccal and vaginal administration of misoprostol, rectal administration produced less sustained uterine contractions in the first trimester of pregnancy. To achieve maximal sustained uterine contractions, buccal and vaginal routes of administration are superior to oral and rectal administration.

Continue to: Misoprostol and cervical ripening...

Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.¹³ The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.¹³ Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.

Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.¹³ Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.^14,15

An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.¹⁶ Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.¹⁶

Bottom line

Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●

The 1973 Supreme Court of the United States (SCOTUS) decision in Roe v Wade was a landmark ruling,¹ establishing that the United States Constitution provides a fundamental “right to privacy,” protecting pregnant people’s freedom to access all available reproductive health care options. Recognizing that the right to abortion was not absolute, the majority of justices supported a trimester system. In the first trimester, decisions about abortion care are fully controlled by patients and clinicians, and no government could place restrictions on access to abortion. In the second trimester, SCOTUS ruled that states may choose to regulate abortion to protect maternal health. (As an example of such state restrictions, in Massachusetts, for many years, but no longer, the state required that abortions occur in a hospital when the patient was between 18 and 24 weeks’ gestation in order to facilitate comprehensive emergency care for complications.) Beginning in the third trimester, a point at which a fetus could be viable, the Court ruled that a government could prohibit abortion except when an abortion was necessary to protect the life or health of the pregnant person. In 1992, the SCOTUS decision in Planned Parenthood v Casey² rejected the trimester system, reaffirming the right to an abortion before fetal viability, and adopting a new standard that states may not create an undue burden on a person seeking an abortion before fetal viability. SCOTUS ruled that an undue burden exists if the purpose of a regulation is to place substantial obstacles in the path of a person seeking an abortion.

If, as anticipated, the 2022 SCOTUS decision in Dobbs v Jackson Women’s Health Organization³ overturns the precedents set in Roe v Wade and Planned Parenthood v Casey, decisions on abortion law will be relegated to elected legislators and state courts.⁴ It is expected that at least 26 state legislatures and governors will enact stringent new restrictions on access to abortion. This cataclysmic reversal of judicial opinion creates a historic challenge to obstetrician-gynecologists and their patients and could threaten access to other vital reproductive services beyond abortion, like contraception. We will be fighting, state by state, for people’s right to access all available reproductive health procedures. This will also significantly affect the ability for providers in women’s reproductive health to obtain appropriate and necessary education and training in a critical skills. If access to safe abortion is restricted, we fear patients may be forced to consider unsafe abortion, raising the specter of a return to the 1960s, when an epidemic of unsafe abortion caused countless injuries and deaths.^5,6

How do we best prepare for these challenges?

• We will need to be flexible and continually evolve our clinical practices to be adherent with state and local legislation and regulation.
• To reduce unintended pregnancies, we need to strengthen our efforts to ensure that every patient has ready access to all available contraceptive options with no out-of-pocket cost.
• When a contraceptive is desired, we will focus on educating people about effectiveness, and offering them highly reliable contraception, such as the implant or intrauterine devices.
• We need to ensure timely access to abortion if state-based laws permit abortion before 6 or 7 weeks’ gestation. Providing medication abortion without an in-person visit using a telehealth option would be one option to expand rapid access to early first trimester abortion.
• Clinicians in states with access to abortion services will need to collaborate with colleagues in states with restrictions on abortion services to improve patient access across state borders.

On a national level, advancing our effective advocacy in Congress may lead to national legislation passed and signed by the President. This could supersede most state laws prohibiting access to comprehensive women’s reproductive health and create a unified, national approach to abortion care, allowing for the appropriate training of all obstetrician-gynecologists. We will also need to develop teams in every state capable of advocating for laws that ensure access to all reproductive health care options. The American College of Obstetricians and Gynecologists has leaders trained and tasked with legislative advocacy in every state.⁷ This network will be a foundation upon which to build additional advocacy efforts.

As women’s health care professionals, our responsibility to our patients, is to work to ensure universal access to safe and effective comprehensive reproductive options, and to ensure that our workforce is prepared to meet the needs of our patients by defending the patient-clinician relationship. Abortion care saves lives of pregnant patients and reduces maternal morbidity.⁸ Access to safe abortion care as part of comprehensive reproductive services is an important component of health care. ●

The 1973 Supreme Court of the United States (SCOTUS) decision in Roe v Wade was a landmark ruling,¹ establishing that the United States Constitution provides a fundamental “right to privacy,” protecting pregnant people’s freedom to access all available reproductive health care options. Recognizing that the right to abortion was not absolute, the majority of justices supported a trimester system. In the first trimester, decisions about abortion care are fully controlled by patients and clinicians, and no government could place restrictions on access to abortion. In the second trimester, SCOTUS ruled that states may choose to regulate abortion to protect maternal health. (As an example of such state restrictions, in Massachusetts, for many years, but no longer, the state required that abortions occur in a hospital when the patient was between 18 and 24 weeks’ gestation in order to facilitate comprehensive emergency care for complications.) Beginning in the third trimester, a point at which a fetus could be viable, the Court ruled that a government could prohibit abortion except when an abortion was necessary to protect the life or health of the pregnant person. In 1992, the SCOTUS decision in Planned Parenthood v Casey² rejected the trimester system, reaffirming the right to an abortion before fetal viability, and adopting a new standard that states may not create an undue burden on a person seeking an abortion before fetal viability. SCOTUS ruled that an undue burden exists if the purpose of a regulation is to place substantial obstacles in the path of a person seeking an abortion.

If, as anticipated, the 2022 SCOTUS decision in Dobbs v Jackson Women’s Health Organization³ overturns the precedents set in Roe v Wade and Planned Parenthood v Casey, decisions on abortion law will be relegated to elected legislators and state courts.⁴ It is expected that at least 26 state legislatures and governors will enact stringent new restrictions on access to abortion. This cataclysmic reversal of judicial opinion creates a historic challenge to obstetrician-gynecologists and their patients and could threaten access to other vital reproductive services beyond abortion, like contraception. We will be fighting, state by state, for people’s right to access all available reproductive health procedures. This will also significantly affect the ability for providers in women’s reproductive health to obtain appropriate and necessary education and training in a critical skills. If access to safe abortion is restricted, we fear patients may be forced to consider unsafe abortion, raising the specter of a return to the 1960s, when an epidemic of unsafe abortion caused countless injuries and deaths.^5,6

How do we best prepare for these challenges?

• We will need to be flexible and continually evolve our clinical practices to be adherent with state and local legislation and regulation.
• To reduce unintended pregnancies, we need to strengthen our efforts to ensure that every patient has ready access to all available contraceptive options with no out-of-pocket cost.
• When a contraceptive is desired, we will focus on educating people about effectiveness, and offering them highly reliable contraception, such as the implant or intrauterine devices.
• We need to ensure timely access to abortion if state-based laws permit abortion before 6 or 7 weeks’ gestation. Providing medication abortion without an in-person visit using a telehealth option would be one option to expand rapid access to early first trimester abortion.
• Clinicians in states with access to abortion services will need to collaborate with colleagues in states with restrictions on abortion services to improve patient access across state borders.

On a national level, advancing our effective advocacy in Congress may lead to national legislation passed and signed by the President. This could supersede most state laws prohibiting access to comprehensive women’s reproductive health and create a unified, national approach to abortion care, allowing for the appropriate training of all obstetrician-gynecologists. We will also need to develop teams in every state capable of advocating for laws that ensure access to all reproductive health care options. The American College of Obstetricians and Gynecologists has leaders trained and tasked with legislative advocacy in every state.⁷ This network will be a foundation upon which to build additional advocacy efforts.

As women’s health care professionals, our responsibility to our patients, is to work to ensure universal access to safe and effective comprehensive reproductive options, and to ensure that our workforce is prepared to meet the needs of our patients by defending the patient-clinician relationship. Abortion care saves lives of pregnant patients and reduces maternal morbidity.⁸ Access to safe abortion care as part of comprehensive reproductive services is an important component of health care. ●

The 1973 Supreme Court of the United States (SCOTUS) decision in Roe v Wade was a landmark ruling,¹ establishing that the United States Constitution provides a fundamental “right to privacy,” protecting pregnant people’s freedom to access all available reproductive health care options. Recognizing that the right to abortion was not absolute, the majority of justices supported a trimester system. In the first trimester, decisions about abortion care are fully controlled by patients and clinicians, and no government could place restrictions on access to abortion. In the second trimester, SCOTUS ruled that states may choose to regulate abortion to protect maternal health. (As an example of such state restrictions, in Massachusetts, for many years, but no longer, the state required that abortions occur in a hospital when the patient was between 18 and 24 weeks’ gestation in order to facilitate comprehensive emergency care for complications.) Beginning in the third trimester, a point at which a fetus could be viable, the Court ruled that a government could prohibit abortion except when an abortion was necessary to protect the life or health of the pregnant person. In 1992, the SCOTUS decision in Planned Parenthood v Casey² rejected the trimester system, reaffirming the right to an abortion before fetal viability, and adopting a new standard that states may not create an undue burden on a person seeking an abortion before fetal viability. SCOTUS ruled that an undue burden exists if the purpose of a regulation is to place substantial obstacles in the path of a person seeking an abortion.

If, as anticipated, the 2022 SCOTUS decision in Dobbs v Jackson Women’s Health Organization³ overturns the precedents set in Roe v Wade and Planned Parenthood v Casey, decisions on abortion law will be relegated to elected legislators and state courts.⁴ It is expected that at least 26 state legislatures and governors will enact stringent new restrictions on access to abortion. This cataclysmic reversal of judicial opinion creates a historic challenge to obstetrician-gynecologists and their patients and could threaten access to other vital reproductive services beyond abortion, like contraception. We will be fighting, state by state, for people’s right to access all available reproductive health procedures. This will also significantly affect the ability for providers in women’s reproductive health to obtain appropriate and necessary education and training in a critical skills. If access to safe abortion is restricted, we fear patients may be forced to consider unsafe abortion, raising the specter of a return to the 1960s, when an epidemic of unsafe abortion caused countless injuries and deaths.^5,6

How do we best prepare for these challenges?

• We will need to be flexible and continually evolve our clinical practices to be adherent with state and local legislation and regulation.
• To reduce unintended pregnancies, we need to strengthen our efforts to ensure that every patient has ready access to all available contraceptive options with no out-of-pocket cost.
• When a contraceptive is desired, we will focus on educating people about effectiveness, and offering them highly reliable contraception, such as the implant or intrauterine devices.
• We need to ensure timely access to abortion if state-based laws permit abortion before 6 or 7 weeks’ gestation. Providing medication abortion without an in-person visit using a telehealth option would be one option to expand rapid access to early first trimester abortion.
• Clinicians in states with access to abortion services will need to collaborate with colleagues in states with restrictions on abortion services to improve patient access across state borders.

On a national level, advancing our effective advocacy in Congress may lead to national legislation passed and signed by the President. This could supersede most state laws prohibiting access to comprehensive women’s reproductive health and create a unified, national approach to abortion care, allowing for the appropriate training of all obstetrician-gynecologists. We will also need to develop teams in every state capable of advocating for laws that ensure access to all reproductive health care options. The American College of Obstetricians and Gynecologists has leaders trained and tasked with legislative advocacy in every state.⁷ This network will be a foundation upon which to build additional advocacy efforts.

As women’s health care professionals, our responsibility to our patients, is to work to ensure universal access to safe and effective comprehensive reproductive options, and to ensure that our workforce is prepared to meet the needs of our patients by defending the patient-clinician relationship. Abortion care saves lives of pregnant patients and reduces maternal morbidity.⁸ Access to safe abortion care as part of comprehensive reproductive services is an important component of health care. ●

During pregnancy, anemia and iron deficiency are prevalent because the fetus depletes maternal iron stores. Iron deficiency and iron deficiency anemia are not synonymous. Effective screening for iron deficiency in the first trimester of pregnancy requires the measurement of a sensitive and specific biomarker of iron deficiency, such as ferritin. Limiting the measurement of ferritin to the subset of patients with anemia will result in missing many cases of iron deficiency. By the time iron deficiency causes anemia, a severe deficiency is present. Detecting iron deficiency in pregnancy and promptly treating the deficiency will reduce the number of women with anemia in the third trimester and at birth.

Diagnosis of anemia

Anemia in pregnancy is diagnosed by a hemoglobin level and hematocrit concentration below 11 g/dL and 33%, respectively, in the first and third trimesters and below 10.5 g/dL and 32%, respectively, in the second trimester.¹ The prevalence of anemia in the first, second, and third trimesters is approximately 3%, 2%, and 11%, respectively.² At a hemoglobin concentration <11 g/dL, severe maternal morbidity rises significantly.³ The laboratory evaluation of pregnant women with anemia may require assessment of iron stores, measurement of folate and cobalamin (vitamin B12), and hemoglobin electrophoresis, if indicated.

Diagnosis of iron deficiency

Iron deficiency anemia is diagnosed by a ferritin level below 30 ng/mL.^4,5 Normal iron stores and iron insufficiency are indicated by ferritin levels 45 to 150 ng/mL and 30 to 44 ng/mL, respectively.^4,5 Ferritin is an acute phase reactant, and patients with inflammation or chronic illnesses may have iron deficiency and a normal ferritin level. For these patients, a transferrin saturation (TSAT) <16% would support a diagnosis of iron deficiency.⁶ TSAT is calculated from measurement of serum iron and total iron binding capacity. TSAT saturation may be elevated by iron supplements, which increase serum iron. If measurement of TSAT is necessary, interference with the measurement accuracy can be minimized by not taking an iron supplement on the day of testing.

Iron deficiency is present in approximately 50% of pregnant women.^7,8 The greatest prevalence of iron deficiency in pregnancy is observed in non-Hispanic Black females, followed by Hispanic females. Non-Hispanic White females had the lowest prevalence of iron deficiency.²

Fetal needs for iron often cause the depletion of maternal iron stores. Many pregnant women who have a normal ferritin level in the first trimester will develop iron deficiency in the third trimester, even with the usual recommended daily oral iron supplementation. We recommend measuring ferritin and hemoglobin at the first prenatal visit and again between 24 and 28 weeks’ gestation.

Impact of maternal anemia on maternal and newborn health

Iron plays a critical role in maternal health and fetal development independent of its role in red blood cell formation. Many proteins critical to maternal health and fetal development contain iron, including hemoglobin, myoglobin, cytochromes, ribonucleotide reductase, peroxidases, lipoxygenases, and cyclooxygenases. In the fetus, iron plays an important role in myelination of nerves, dendrite arborization, and synthesis of monoamine neurotransmitters.⁹

Many studies report that maternal anemia is associated with severe maternal morbidity and adverse newborn outcomes. The current literature must be interpreted with caution because socioeconomic factors influence iron stores. Iron deficiency and anemia is more common among economically and socially disadvantaged populations.^10-12 It is possible that repleting iron stores, alone, without addressing social determinants of health, including food and housing insecurity, may be insufficient to improve maternal and newborn health.

Maternal anemia is a risk factor for severe maternal morbidity and adverse newborn outcomes.^3,13-18 In a study of 515,270 live births in British Columbia between 2004 and 2016, maternal anemia was diagnosed in 12.8% of mothers.¹⁵ Maternal morbidity at birth was increased among patients with mild anemia (hemoglobin concentration of 9 to 10.9 g/dL), including higher rates of intrapartum transfusion (adjusted odds ratio [OR], 2.45; 95% confidence interval [CI], 1.74-3.45), cesarean birth (aOR, 1.17; 95% CI, 1.14-1.19), and chorioamnionitis (aOR, 1.35; 95% CI, 1.27-1.44). Newborn morbidity was also increased among newborns of mothers with mild anemia (hemoglobin concentrations of 9 to 10.9 g/dL), including birth before 37 weeks’ gestation (aOR, 1.09; 95% CI, 1.05-1.12), birth before 32 weeks’ gestation (aOR, 1.30; 95% CI, 1.21-1.39), admission to the intensive care unit (aOR, 1.21; 95% CI, 1.17-1.25), and respiratory distress syndrome (aOR, 1.35; 95% CI, 1.24-1.46).¹⁵ Adverse maternal and newborn outcomes were more prevalent among mothers with moderate (hemoglobin concentrations of 7 to 8.9 g/dL) or severe anemia (hemoglobin concentrations of <7 g/dL), compared with mild anemia. For example, compared with mothers with no anemia, mothers with moderate anemia had an increased risk of birth <37 weeks (aOR, 2.26) and birth <32 weeks (aOR, 3.95).¹⁵

In a study of 166,566 US pregnant patients, 6.1% were diagnosed with anemia.¹⁸ Patients with anemia were more likely to have antepartum thrombosis, preeclampsia, eclampsia, a cesarean birth, postpartum hemorrhage, a blood transfusion, and postpartum thrombosis.¹⁸ In this study, the newborns of mothers with anemia were more likely to have a diagnosis of antenatal or intrapartum fetal distress, a 5-minute Apgar score <7, and an admission to the neonatal intensive care unit.

Continue to: Maternal anemia and neurodevelopmental disorders in children...

Some experts, but not all, believe that iron deficiency during pregnancy may adversely impact fetal neurodevelopment and result in childhood behavior issues. All experts agree that more research is needed to understand if maternal anemia causes mental health issues in newborns. In one meta-analysis, among 20 studies of the association of maternal iron deficiency and newborn neurodevelopment, approximately half the studies reported that low maternal ferritin levels were associated with lower childhood performance on standardized tests of cognitive, motor, verbal, and memory function.¹⁹ Another systematic review concluded that the evidence linking maternal iron deficiency and child neurodevelopment is equivocal.²⁰

In a study of 532,232 nonadoptive children born in Sweden from 1987 to 2010, maternal anemia was associated with an increased risk of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID).²¹ In Sweden maternal hemoglobin concentration is measured at 10, 25, and 37 weeks of gestation, permitting comparisons of anemia diagnosed early and late in pregnancy with neurodevelopmental outcomes. The association between anemia and neurodevelopmental disorders was greatest if anemia was diagnosed within the first 30 weeks of pregnancy. Compared with mothers without anemia, maternal anemia diagnosed within the first 30 weeks of pregnancy was associated with higher childhood rates of ASD (4.9% vs 3.5%), ADHD (9.3% vs 7.1%), and ID (3.1% vs 1.3%).²¹ The differences persisted in analyses that controlled for socioeconomic, maternal, and pregnancy-related factors. In a matched sibling comparison, the diagnosis of maternal anemia within the first 30 weeks of gestation was associated with an increased risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) but not ADHD.²¹ Other studies have also reported a relationship between maternal anemia and intellectual disability.^22,23

Measurement of hemoglobin will identify anemia, but hemoglobin measurement is not sufficiently sensitive to identify most cases of iron deficiency. Measuring ferritin can help to identify cases of iron deficiency before the onset of anemia, permitting early treatment of the nutrient deficiency. In pregnancy, iron deficiency is the prelude to developing anemia. Waiting until anemia occurs to diagnose and treat iron deficiency is suboptimal and may miss a critical window of fetal development that is dependent on maternal iron stores. During pregnancy, ferritin levels decrease as much as 80% between the first and third trimesters, as the fetus utilizes maternal iron stores for its growth.²⁴ We recommend the measurement of ferritin and hemoglobin at the first prenatal visit and again at 24 to 28 weeks’ gestation to optimize early detection and treatment of iron deficiency and reduce the frequency of anemia prior to birth. ●

During pregnancy, anemia and iron deficiency are prevalent because the fetus depletes maternal iron stores. Iron deficiency and iron deficiency anemia are not synonymous. Effective screening for iron deficiency in the first trimester of pregnancy requires the measurement of a sensitive and specific biomarker of iron deficiency, such as ferritin. Limiting the measurement of ferritin to the subset of patients with anemia will result in missing many cases of iron deficiency. By the time iron deficiency causes anemia, a severe deficiency is present. Detecting iron deficiency in pregnancy and promptly treating the deficiency will reduce the number of women with anemia in the third trimester and at birth.

Diagnosis of anemia

Anemia in pregnancy is diagnosed by a hemoglobin level and hematocrit concentration below 11 g/dL and 33%, respectively, in the first and third trimesters and below 10.5 g/dL and 32%, respectively, in the second trimester.¹ The prevalence of anemia in the first, second, and third trimesters is approximately 3%, 2%, and 11%, respectively.² At a hemoglobin concentration <11 g/dL, severe maternal morbidity rises significantly.³ The laboratory evaluation of pregnant women with anemia may require assessment of iron stores, measurement of folate and cobalamin (vitamin B12), and hemoglobin electrophoresis, if indicated.

Diagnosis of iron deficiency

Iron deficiency anemia is diagnosed by a ferritin level below 30 ng/mL.^4,5 Normal iron stores and iron insufficiency are indicated by ferritin levels 45 to 150 ng/mL and 30 to 44 ng/mL, respectively.^4,5 Ferritin is an acute phase reactant, and patients with inflammation or chronic illnesses may have iron deficiency and a normal ferritin level. For these patients, a transferrin saturation (TSAT) <16% would support a diagnosis of iron deficiency.⁶ TSAT is calculated from measurement of serum iron and total iron binding capacity. TSAT saturation may be elevated by iron supplements, which increase serum iron. If measurement of TSAT is necessary, interference with the measurement accuracy can be minimized by not taking an iron supplement on the day of testing.

Iron deficiency is present in approximately 50% of pregnant women.^7,8 The greatest prevalence of iron deficiency in pregnancy is observed in non-Hispanic Black females, followed by Hispanic females. Non-Hispanic White females had the lowest prevalence of iron deficiency.²

Fetal needs for iron often cause the depletion of maternal iron stores. Many pregnant women who have a normal ferritin level in the first trimester will develop iron deficiency in the third trimester, even with the usual recommended daily oral iron supplementation. We recommend measuring ferritin and hemoglobin at the first prenatal visit and again between 24 and 28 weeks’ gestation.

Impact of maternal anemia on maternal and newborn health

Iron plays a critical role in maternal health and fetal development independent of its role in red blood cell formation. Many proteins critical to maternal health and fetal development contain iron, including hemoglobin, myoglobin, cytochromes, ribonucleotide reductase, peroxidases, lipoxygenases, and cyclooxygenases. In the fetus, iron plays an important role in myelination of nerves, dendrite arborization, and synthesis of monoamine neurotransmitters.⁹

Many studies report that maternal anemia is associated with severe maternal morbidity and adverse newborn outcomes. The current literature must be interpreted with caution because socioeconomic factors influence iron stores. Iron deficiency and anemia is more common among economically and socially disadvantaged populations.^10-12 It is possible that repleting iron stores, alone, without addressing social determinants of health, including food and housing insecurity, may be insufficient to improve maternal and newborn health.

Maternal anemia is a risk factor for severe maternal morbidity and adverse newborn outcomes.^3,13-18 In a study of 515,270 live births in British Columbia between 2004 and 2016, maternal anemia was diagnosed in 12.8% of mothers.¹⁵ Maternal morbidity at birth was increased among patients with mild anemia (hemoglobin concentration of 9 to 10.9 g/dL), including higher rates of intrapartum transfusion (adjusted odds ratio [OR], 2.45; 95% confidence interval [CI], 1.74-3.45), cesarean birth (aOR, 1.17; 95% CI, 1.14-1.19), and chorioamnionitis (aOR, 1.35; 95% CI, 1.27-1.44). Newborn morbidity was also increased among newborns of mothers with mild anemia (hemoglobin concentrations of 9 to 10.9 g/dL), including birth before 37 weeks’ gestation (aOR, 1.09; 95% CI, 1.05-1.12), birth before 32 weeks’ gestation (aOR, 1.30; 95% CI, 1.21-1.39), admission to the intensive care unit (aOR, 1.21; 95% CI, 1.17-1.25), and respiratory distress syndrome (aOR, 1.35; 95% CI, 1.24-1.46).¹⁵ Adverse maternal and newborn outcomes were more prevalent among mothers with moderate (hemoglobin concentrations of 7 to 8.9 g/dL) or severe anemia (hemoglobin concentrations of <7 g/dL), compared with mild anemia. For example, compared with mothers with no anemia, mothers with moderate anemia had an increased risk of birth <37 weeks (aOR, 2.26) and birth <32 weeks (aOR, 3.95).¹⁵

In a study of 166,566 US pregnant patients, 6.1% were diagnosed with anemia.¹⁸ Patients with anemia were more likely to have antepartum thrombosis, preeclampsia, eclampsia, a cesarean birth, postpartum hemorrhage, a blood transfusion, and postpartum thrombosis.¹⁸ In this study, the newborns of mothers with anemia were more likely to have a diagnosis of antenatal or intrapartum fetal distress, a 5-minute Apgar score <7, and an admission to the neonatal intensive care unit.

Continue to: Maternal anemia and neurodevelopmental disorders in children...

Some experts, but not all, believe that iron deficiency during pregnancy may adversely impact fetal neurodevelopment and result in childhood behavior issues. All experts agree that more research is needed to understand if maternal anemia causes mental health issues in newborns. In one meta-analysis, among 20 studies of the association of maternal iron deficiency and newborn neurodevelopment, approximately half the studies reported that low maternal ferritin levels were associated with lower childhood performance on standardized tests of cognitive, motor, verbal, and memory function.¹⁹ Another systematic review concluded that the evidence linking maternal iron deficiency and child neurodevelopment is equivocal.²⁰

In a study of 532,232 nonadoptive children born in Sweden from 1987 to 2010, maternal anemia was associated with an increased risk of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID).²¹ In Sweden maternal hemoglobin concentration is measured at 10, 25, and 37 weeks of gestation, permitting comparisons of anemia diagnosed early and late in pregnancy with neurodevelopmental outcomes. The association between anemia and neurodevelopmental disorders was greatest if anemia was diagnosed within the first 30 weeks of pregnancy. Compared with mothers without anemia, maternal anemia diagnosed within the first 30 weeks of pregnancy was associated with higher childhood rates of ASD (4.9% vs 3.5%), ADHD (9.3% vs 7.1%), and ID (3.1% vs 1.3%).²¹ The differences persisted in analyses that controlled for socioeconomic, maternal, and pregnancy-related factors. In a matched sibling comparison, the diagnosis of maternal anemia within the first 30 weeks of gestation was associated with an increased risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) but not ADHD.²¹ Other studies have also reported a relationship between maternal anemia and intellectual disability.^22,23

Measurement of hemoglobin will identify anemia, but hemoglobin measurement is not sufficiently sensitive to identify most cases of iron deficiency. Measuring ferritin can help to identify cases of iron deficiency before the onset of anemia, permitting early treatment of the nutrient deficiency. In pregnancy, iron deficiency is the prelude to developing anemia. Waiting until anemia occurs to diagnose and treat iron deficiency is suboptimal and may miss a critical window of fetal development that is dependent on maternal iron stores. During pregnancy, ferritin levels decrease as much as 80% between the first and third trimesters, as the fetus utilizes maternal iron stores for its growth.²⁴ We recommend the measurement of ferritin and hemoglobin at the first prenatal visit and again at 24 to 28 weeks’ gestation to optimize early detection and treatment of iron deficiency and reduce the frequency of anemia prior to birth. ●

During pregnancy, anemia and iron deficiency are prevalent because the fetus depletes maternal iron stores. Iron deficiency and iron deficiency anemia are not synonymous. Effective screening for iron deficiency in the first trimester of pregnancy requires the measurement of a sensitive and specific biomarker of iron deficiency, such as ferritin. Limiting the measurement of ferritin to the subset of patients with anemia will result in missing many cases of iron deficiency. By the time iron deficiency causes anemia, a severe deficiency is present. Detecting iron deficiency in pregnancy and promptly treating the deficiency will reduce the number of women with anemia in the third trimester and at birth.

Diagnosis of anemia

Anemia in pregnancy is diagnosed by a hemoglobin level and hematocrit concentration below 11 g/dL and 33%, respectively, in the first and third trimesters and below 10.5 g/dL and 32%, respectively, in the second trimester.¹ The prevalence of anemia in the first, second, and third trimesters is approximately 3%, 2%, and 11%, respectively.² At a hemoglobin concentration <11 g/dL, severe maternal morbidity rises significantly.³ The laboratory evaluation of pregnant women with anemia may require assessment of iron stores, measurement of folate and cobalamin (vitamin B12), and hemoglobin electrophoresis, if indicated.

Diagnosis of iron deficiency

Iron deficiency anemia is diagnosed by a ferritin level below 30 ng/mL.^4,5 Normal iron stores and iron insufficiency are indicated by ferritin levels 45 to 150 ng/mL and 30 to 44 ng/mL, respectively.^4,5 Ferritin is an acute phase reactant, and patients with inflammation or chronic illnesses may have iron deficiency and a normal ferritin level. For these patients, a transferrin saturation (TSAT) <16% would support a diagnosis of iron deficiency.⁶ TSAT is calculated from measurement of serum iron and total iron binding capacity. TSAT saturation may be elevated by iron supplements, which increase serum iron. If measurement of TSAT is necessary, interference with the measurement accuracy can be minimized by not taking an iron supplement on the day of testing.

Iron deficiency is present in approximately 50% of pregnant women.^7,8 The greatest prevalence of iron deficiency in pregnancy is observed in non-Hispanic Black females, followed by Hispanic females. Non-Hispanic White females had the lowest prevalence of iron deficiency.²

Fetal needs for iron often cause the depletion of maternal iron stores. Many pregnant women who have a normal ferritin level in the first trimester will develop iron deficiency in the third trimester, even with the usual recommended daily oral iron supplementation. We recommend measuring ferritin and hemoglobin at the first prenatal visit and again between 24 and 28 weeks’ gestation.

Impact of maternal anemia on maternal and newborn health

Iron plays a critical role in maternal health and fetal development independent of its role in red blood cell formation. Many proteins critical to maternal health and fetal development contain iron, including hemoglobin, myoglobin, cytochromes, ribonucleotide reductase, peroxidases, lipoxygenases, and cyclooxygenases. In the fetus, iron plays an important role in myelination of nerves, dendrite arborization, and synthesis of monoamine neurotransmitters.⁹

Many studies report that maternal anemia is associated with severe maternal morbidity and adverse newborn outcomes. The current literature must be interpreted with caution because socioeconomic factors influence iron stores. Iron deficiency and anemia is more common among economically and socially disadvantaged populations.^10-12 It is possible that repleting iron stores, alone, without addressing social determinants of health, including food and housing insecurity, may be insufficient to improve maternal and newborn health.

Maternal anemia is a risk factor for severe maternal morbidity and adverse newborn outcomes.^3,13-18 In a study of 515,270 live births in British Columbia between 2004 and 2016, maternal anemia was diagnosed in 12.8% of mothers.¹⁵ Maternal morbidity at birth was increased among patients with mild anemia (hemoglobin concentration of 9 to 10.9 g/dL), including higher rates of intrapartum transfusion (adjusted odds ratio [OR], 2.45; 95% confidence interval [CI], 1.74-3.45), cesarean birth (aOR, 1.17; 95% CI, 1.14-1.19), and chorioamnionitis (aOR, 1.35; 95% CI, 1.27-1.44). Newborn morbidity was also increased among newborns of mothers with mild anemia (hemoglobin concentrations of 9 to 10.9 g/dL), including birth before 37 weeks’ gestation (aOR, 1.09; 95% CI, 1.05-1.12), birth before 32 weeks’ gestation (aOR, 1.30; 95% CI, 1.21-1.39), admission to the intensive care unit (aOR, 1.21; 95% CI, 1.17-1.25), and respiratory distress syndrome (aOR, 1.35; 95% CI, 1.24-1.46).¹⁵ Adverse maternal and newborn outcomes were more prevalent among mothers with moderate (hemoglobin concentrations of 7 to 8.9 g/dL) or severe anemia (hemoglobin concentrations of <7 g/dL), compared with mild anemia. For example, compared with mothers with no anemia, mothers with moderate anemia had an increased risk of birth <37 weeks (aOR, 2.26) and birth <32 weeks (aOR, 3.95).¹⁵

In a study of 166,566 US pregnant patients, 6.1% were diagnosed with anemia.¹⁸ Patients with anemia were more likely to have antepartum thrombosis, preeclampsia, eclampsia, a cesarean birth, postpartum hemorrhage, a blood transfusion, and postpartum thrombosis.¹⁸ In this study, the newborns of mothers with anemia were more likely to have a diagnosis of antenatal or intrapartum fetal distress, a 5-minute Apgar score <7, and an admission to the neonatal intensive care unit.

Continue to: Maternal anemia and neurodevelopmental disorders in children...

Some experts, but not all, believe that iron deficiency during pregnancy may adversely impact fetal neurodevelopment and result in childhood behavior issues. All experts agree that more research is needed to understand if maternal anemia causes mental health issues in newborns. In one meta-analysis, among 20 studies of the association of maternal iron deficiency and newborn neurodevelopment, approximately half the studies reported that low maternal ferritin levels were associated with lower childhood performance on standardized tests of cognitive, motor, verbal, and memory function.¹⁹ Another systematic review concluded that the evidence linking maternal iron deficiency and child neurodevelopment is equivocal.²⁰

In a study of 532,232 nonadoptive children born in Sweden from 1987 to 2010, maternal anemia was associated with an increased risk of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID).²¹ In Sweden maternal hemoglobin concentration is measured at 10, 25, and 37 weeks of gestation, permitting comparisons of anemia diagnosed early and late in pregnancy with neurodevelopmental outcomes. The association between anemia and neurodevelopmental disorders was greatest if anemia was diagnosed within the first 30 weeks of pregnancy. Compared with mothers without anemia, maternal anemia diagnosed within the first 30 weeks of pregnancy was associated with higher childhood rates of ASD (4.9% vs 3.5%), ADHD (9.3% vs 7.1%), and ID (3.1% vs 1.3%).²¹ The differences persisted in analyses that controlled for socioeconomic, maternal, and pregnancy-related factors. In a matched sibling comparison, the diagnosis of maternal anemia within the first 30 weeks of gestation was associated with an increased risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) but not ADHD.²¹ Other studies have also reported a relationship between maternal anemia and intellectual disability.^22,23

Measurement of hemoglobin will identify anemia, but hemoglobin measurement is not sufficiently sensitive to identify most cases of iron deficiency. Measuring ferritin can help to identify cases of iron deficiency before the onset of anemia, permitting early treatment of the nutrient deficiency. In pregnancy, iron deficiency is the prelude to developing anemia. Waiting until anemia occurs to diagnose and treat iron deficiency is suboptimal and may miss a critical window of fetal development that is dependent on maternal iron stores. During pregnancy, ferritin levels decrease as much as 80% between the first and third trimesters, as the fetus utilizes maternal iron stores for its growth.²⁴ We recommend the measurement of ferritin and hemoglobin at the first prenatal visit and again at 24 to 28 weeks’ gestation to optimize early detection and treatment of iron deficiency and reduce the frequency of anemia prior to birth. ●