Malavika Prabhu, MD

Ashbrook M, et al. Management of complicated appendicitis during pregnancy in the US. JAMA Network Open. 2022;5:e227555. doi:10.1001/jamanetworkopen.2022.7555.

Expert Commentary

Over the last decade, the management of acute appendicitis in the nonpregnant adult has evolved such that some authorities favor first-line nonoperative therapy in the appropriate candidate, including some individuals with complicated appendicitis. While the conventional teaching regarding appendicitis in pregnancy has always been immediate surgery, favorable outcomes from nonoperative management in the nonpregnant population have led to an increasing application of conservative therapy in pregnancy, particularly among patients with uncomplicated appendicitis. However, optimal management of complicated appendicitis in pregnancy is unclear, as the risks of both operative and nonoperative management can be significant.

Details about the study

This retrospective cohort study using data from the National Inpatient Sample (NIS) focuses on outcomes of various management options among pregnant women with complicated appendicitis from January 2003 to September 2015. Complicated appendicitis refers to individuals with appendiceal perforation with peritonitis (a free perforation) or phlegmon/abscess (a walled-off perforation). Women included in the study were identified using ICD-9 codes for both pregnancy and complicated appendicitis; they were categorized into 3 groups: immediate operative management, successful nonoperative management, and failed nonoperative management (defined as surgical intervention >1 day after admission). The clinical and other outcomes of interest included maternal death, preterm labor/delivery or pregnancy loss, amniotic infection, sepsis, pneumonia, antenatal hemorrhage, and premature rupture of membranes. Outcomes included are those that occurred during the hospitalization for appendicitis; outcomes that may have occurred between discharge from the appendicitis hospitalization to the delivery hospitalization are not included in this study.

A total of 8,087 pregnant women with complicated appendicitis were included in this study, of whom 954 (11.8%) had successful nonoperative management, 2,646 (32.7%) had failed nonoperative management, and 4,487 (55.5%) had immediate operative management. First, when comparing successful nonoperative management to immediate operative management, there were no differences in preterm labor/delivery or pregnancy loss, or antenatal hemorrhage; however, successful nonoperative management was also associated with higher risks of maternal infectious complications, including risks of amniotic infection, pneumonia, and sepsis. When comparing failed nonoperative management (women who required surgical intervention during the index hospitalization) to immediate operative management, failed conservative management was associated with higher risks of preterm labor/delivery or pregnancy loss, antenatal hemorrhage, amniotic infection, pneumonia, and sepsis. For every 1 day that surgery was delayed in the group of women who failed nonoperative management, the odds of preterm labor/delivery or pregnancy loss, antenatal hemorrhage, sepsis, amniotic infection, and pneumonia increased.

Study strengths and weaknesses

Database studies have inherent limitations that are overcome with strength in numbers. In this study, our understanding of outcomes associated with management of complicated appendicitis assumes that women were correctly identified as both being pregnant and having complicated appendicitis (as opposed to uncomplicated appendicitis but miscoded). Clinical data that may have led to selection of one management strategy over another, or specific clinical management decisions, are not possible to extract from the NIS. For instance, did nonoperative management systematically include percutaneous guided drainage if an abscess was noted, and appropriately targeted antibiotic therapy? If delayed operative intervention with IV antibiotics to allow for “cooling off” of the abdomen prior to surgery was planned, this strategy would have been included in the failed nonoperative management group, when in fact nonoperative management was never the plan. Whether gestational age (which is not known in this study), or any other clinical data contributed to the initially chosen management strategy is not known.

The treating clinicians, obstetricians and surgeons alike, would like to know the pregnancy outcome when considering the various management strategies for complicated appendicitis. However, this study only provides insight into the outcomes for the hospitalization for appendicitis. Whether or not women categorized as successful nonoperative management go on to require surgery or have preterm labor in the future, or whether women with successful immediate surgical management might be readmitted with complications, is not known. This is a significant limitation of the database, which does not allow for linking of individual hospitalizations, and rather can provide only a snapshot in time.

This study includes a fairly long timespan–2003 to 2015–during which the management of complicated appendicitis was actively evolving. Early in this time frame, nonoperative management outside of pregnancy was uncommon, and nonoperative management may have been even rarer and perhaps reserved for the most ill of pregnant women on presentation (for whom surgery may have been considered too risky without a short time with IV antibiotics to “cool off” the abdomen). As time progressed over the study span, nonoperative management was likely offered with greater frequency and among women with lesser degrees of illness. However, the year of presentation was not controlled for in this study.

Finally, given the differences noted in management strategy by race/ethnicity and type of hospital, it is not clear how this bias influences the findings from this study. ●

Ashbrook M, et al. Management of complicated appendicitis during pregnancy in the US. JAMA Network Open. 2022;5:e227555. doi:10.1001/jamanetworkopen.2022.7555.

Expert Commentary

Over the last decade, the management of acute appendicitis in the nonpregnant adult has evolved such that some authorities favor first-line nonoperative therapy in the appropriate candidate, including some individuals with complicated appendicitis. While the conventional teaching regarding appendicitis in pregnancy has always been immediate surgery, favorable outcomes from nonoperative management in the nonpregnant population have led to an increasing application of conservative therapy in pregnancy, particularly among patients with uncomplicated appendicitis. However, optimal management of complicated appendicitis in pregnancy is unclear, as the risks of both operative and nonoperative management can be significant.

Details about the study

This retrospective cohort study using data from the National Inpatient Sample (NIS) focuses on outcomes of various management options among pregnant women with complicated appendicitis from January 2003 to September 2015. Complicated appendicitis refers to individuals with appendiceal perforation with peritonitis (a free perforation) or phlegmon/abscess (a walled-off perforation). Women included in the study were identified using ICD-9 codes for both pregnancy and complicated appendicitis; they were categorized into 3 groups: immediate operative management, successful nonoperative management, and failed nonoperative management (defined as surgical intervention >1 day after admission). The clinical and other outcomes of interest included maternal death, preterm labor/delivery or pregnancy loss, amniotic infection, sepsis, pneumonia, antenatal hemorrhage, and premature rupture of membranes. Outcomes included are those that occurred during the hospitalization for appendicitis; outcomes that may have occurred between discharge from the appendicitis hospitalization to the delivery hospitalization are not included in this study.

A total of 8,087 pregnant women with complicated appendicitis were included in this study, of whom 954 (11.8%) had successful nonoperative management, 2,646 (32.7%) had failed nonoperative management, and 4,487 (55.5%) had immediate operative management. First, when comparing successful nonoperative management to immediate operative management, there were no differences in preterm labor/delivery or pregnancy loss, or antenatal hemorrhage; however, successful nonoperative management was also associated with higher risks of maternal infectious complications, including risks of amniotic infection, pneumonia, and sepsis. When comparing failed nonoperative management (women who required surgical intervention during the index hospitalization) to immediate operative management, failed conservative management was associated with higher risks of preterm labor/delivery or pregnancy loss, antenatal hemorrhage, amniotic infection, pneumonia, and sepsis. For every 1 day that surgery was delayed in the group of women who failed nonoperative management, the odds of preterm labor/delivery or pregnancy loss, antenatal hemorrhage, sepsis, amniotic infection, and pneumonia increased.

Study strengths and weaknesses

Database studies have inherent limitations that are overcome with strength in numbers. In this study, our understanding of outcomes associated with management of complicated appendicitis assumes that women were correctly identified as both being pregnant and having complicated appendicitis (as opposed to uncomplicated appendicitis but miscoded). Clinical data that may have led to selection of one management strategy over another, or specific clinical management decisions, are not possible to extract from the NIS. For instance, did nonoperative management systematically include percutaneous guided drainage if an abscess was noted, and appropriately targeted antibiotic therapy? If delayed operative intervention with IV antibiotics to allow for “cooling off” of the abdomen prior to surgery was planned, this strategy would have been included in the failed nonoperative management group, when in fact nonoperative management was never the plan. Whether gestational age (which is not known in this study), or any other clinical data contributed to the initially chosen management strategy is not known.

The treating clinicians, obstetricians and surgeons alike, would like to know the pregnancy outcome when considering the various management strategies for complicated appendicitis. However, this study only provides insight into the outcomes for the hospitalization for appendicitis. Whether or not women categorized as successful nonoperative management go on to require surgery or have preterm labor in the future, or whether women with successful immediate surgical management might be readmitted with complications, is not known. This is a significant limitation of the database, which does not allow for linking of individual hospitalizations, and rather can provide only a snapshot in time.

This study includes a fairly long timespan–2003 to 2015–during which the management of complicated appendicitis was actively evolving. Early in this time frame, nonoperative management outside of pregnancy was uncommon, and nonoperative management may have been even rarer and perhaps reserved for the most ill of pregnant women on presentation (for whom surgery may have been considered too risky without a short time with IV antibiotics to “cool off” the abdomen). As time progressed over the study span, nonoperative management was likely offered with greater frequency and among women with lesser degrees of illness. However, the year of presentation was not controlled for in this study.

Finally, given the differences noted in management strategy by race/ethnicity and type of hospital, it is not clear how this bias influences the findings from this study. ●

Ashbrook M, et al. Management of complicated appendicitis during pregnancy in the US. JAMA Network Open. 2022;5:e227555. doi:10.1001/jamanetworkopen.2022.7555.

Expert Commentary

Over the last decade, the management of acute appendicitis in the nonpregnant adult has evolved such that some authorities favor first-line nonoperative therapy in the appropriate candidate, including some individuals with complicated appendicitis. While the conventional teaching regarding appendicitis in pregnancy has always been immediate surgery, favorable outcomes from nonoperative management in the nonpregnant population have led to an increasing application of conservative therapy in pregnancy, particularly among patients with uncomplicated appendicitis. However, optimal management of complicated appendicitis in pregnancy is unclear, as the risks of both operative and nonoperative management can be significant.

Details about the study

This retrospective cohort study using data from the National Inpatient Sample (NIS) focuses on outcomes of various management options among pregnant women with complicated appendicitis from January 2003 to September 2015. Complicated appendicitis refers to individuals with appendiceal perforation with peritonitis (a free perforation) or phlegmon/abscess (a walled-off perforation). Women included in the study were identified using ICD-9 codes for both pregnancy and complicated appendicitis; they were categorized into 3 groups: immediate operative management, successful nonoperative management, and failed nonoperative management (defined as surgical intervention >1 day after admission). The clinical and other outcomes of interest included maternal death, preterm labor/delivery or pregnancy loss, amniotic infection, sepsis, pneumonia, antenatal hemorrhage, and premature rupture of membranes. Outcomes included are those that occurred during the hospitalization for appendicitis; outcomes that may have occurred between discharge from the appendicitis hospitalization to the delivery hospitalization are not included in this study.

A total of 8,087 pregnant women with complicated appendicitis were included in this study, of whom 954 (11.8%) had successful nonoperative management, 2,646 (32.7%) had failed nonoperative management, and 4,487 (55.5%) had immediate operative management. First, when comparing successful nonoperative management to immediate operative management, there were no differences in preterm labor/delivery or pregnancy loss, or antenatal hemorrhage; however, successful nonoperative management was also associated with higher risks of maternal infectious complications, including risks of amniotic infection, pneumonia, and sepsis. When comparing failed nonoperative management (women who required surgical intervention during the index hospitalization) to immediate operative management, failed conservative management was associated with higher risks of preterm labor/delivery or pregnancy loss, antenatal hemorrhage, amniotic infection, pneumonia, and sepsis. For every 1 day that surgery was delayed in the group of women who failed nonoperative management, the odds of preterm labor/delivery or pregnancy loss, antenatal hemorrhage, sepsis, amniotic infection, and pneumonia increased.

Study strengths and weaknesses

Database studies have inherent limitations that are overcome with strength in numbers. In this study, our understanding of outcomes associated with management of complicated appendicitis assumes that women were correctly identified as both being pregnant and having complicated appendicitis (as opposed to uncomplicated appendicitis but miscoded). Clinical data that may have led to selection of one management strategy over another, or specific clinical management decisions, are not possible to extract from the NIS. For instance, did nonoperative management systematically include percutaneous guided drainage if an abscess was noted, and appropriately targeted antibiotic therapy? If delayed operative intervention with IV antibiotics to allow for “cooling off” of the abdomen prior to surgery was planned, this strategy would have been included in the failed nonoperative management group, when in fact nonoperative management was never the plan. Whether gestational age (which is not known in this study), or any other clinical data contributed to the initially chosen management strategy is not known.

The treating clinicians, obstetricians and surgeons alike, would like to know the pregnancy outcome when considering the various management strategies for complicated appendicitis. However, this study only provides insight into the outcomes for the hospitalization for appendicitis. Whether or not women categorized as successful nonoperative management go on to require surgery or have preterm labor in the future, or whether women with successful immediate surgical management might be readmitted with complications, is not known. This is a significant limitation of the database, which does not allow for linking of individual hospitalizations, and rather can provide only a snapshot in time.

This study includes a fairly long timespan–2003 to 2015–during which the management of complicated appendicitis was actively evolving. Early in this time frame, nonoperative management outside of pregnancy was uncommon, and nonoperative management may have been even rarer and perhaps reserved for the most ill of pregnant women on presentation (for whom surgery may have been considered too risky without a short time with IV antibiotics to “cool off” the abdomen). As time progressed over the study span, nonoperative management was likely offered with greater frequency and among women with lesser degrees of illness. However, the year of presentation was not controlled for in this study.

Finally, given the differences noted in management strategy by race/ethnicity and type of hospital, it is not clear how this bias influences the findings from this study. ●

Ferrara A, Hedderson MM, Zhu Y, et al. Perinatal complications in individuals in California with or without SARS-CoV-2 infection during pregnancy. JAMA Intern Med. 2022;182:503-512. doi:10.1001/jamainternmed.2022.0330

Expert Commentary

SARS-CoV-2 infection is associated with several adverse outcomes, with the magnitude of specific risks varying by population studied and study design used. Early Centers for Disease Control and Prevention (CDC) data demonstrated that pregnant women were at increased risk for severe illness, including risks of intensive care unit (ICU) admission, invasive ventilation, and extracorporeal membrane oxygenation, compared with non–pregnant women.¹ Since then, other groups have confirmed the increased risks of severe COVID-19, and also identified pregnancy-specific risks, such as preeclampsia, cesarean delivery (CD), prematurity, venous thromboembolic (VTE) disease, and stillbirth.^2-6

The recent study by Ferrara and colleagues adds more granular data to help refine understanding of COVID-19 in pregnancy and counsel patients.

Details of the study

The authors conducted a retrospective cohort study between March 1, 2020, and March 16, 2021, using the electronic health records (EHRs) from Kaiser Permanente Northern California, an integrated managed care organization that serves 4.5 million patients annually. Universal testing for SARS-CoV-2 upon admission for delivery began December 1, 2020; prior to this date, asymptomatic pregnant women were tested only for certain criteria (such as being a health care worker or having high-risk medical conditions).

Pregnant women were identified with SARS-CoV-2 based on 1) a positive polymerase chain reaction test result between 30 days prior to the last menstrual period up to 7 days after delivery or 2) an ICD-10 diagnosis of SARS-CoV-2 infection. Pregnant women not meeting these criteria were classified as SARS-CoV-2 negative. Women were followed through pregnancy to understand if they experienced preterm birth (spontaneous and medically indicated), gestational hypertension, preeclampsia/eclampsia, VTE disease, gestational diabetes, severe maternal morbidity (as defined by the CDC), hospitalization, and livebirth (or stillbirth), in order to consider the timing of SARS-CoV-2 infection relative to each of these outcomes (and ascertain whether SARS-CoV-2 infection preceded any of these outcomes more commonly than not). Management of pregnancies with COVID-19 across this large organization and multiple hospitals was not specified.

Identified perinatal risks

Among 43,886 pregnant women included in the cohort, 1,332 (3.0%) were diagnosed with SARS-CoV-2, with the vast majority of positive tests in the third trimester. Significant sociodemographic differences were noted between those with and without SARS-CoV-2, including differences in age, self-reported race/ethnicity, neighborhood deprivation index, and pre-pregnancy body mass index; no differences were noted for other pre-existing comorbidities, gestational week at delivery, or smoking in pregnancy.

In multivariable models, SARS-CoV-2 infection in pregnancy was associated with severe maternal morbidity, preterm birth, and VTE disease. It was not associated with stillbirth, any hypertensive disorder of pregnancy, CD, or any neonatal complication.

The prevalence of SARS-CoV-2 was 1.3% prior to and 8.0% after implementation of universal testing in pregnancy for SARS-CoV-2. No differences were noted in the risks of severe maternal morbidity or preterm birth relative to the implementation of universal testing, with risks remaining comparably high even after universal testing.

A total of 307 of the 1,332 pregant women with SARS-CoV-2 were admitted to the hospital for symptomatic infection; 3 required noninvasive positive-pressure ventilation, and 1 required mechanical ventilation.

Continue to: Study strengths and weaknesses...

Study strengths and weaknesses

Strengths include the large, EHR-based dataset from a single organization, allowing for granular analysis on patient comorbidities and outcomes (rather than only based on diagnosis codes, as is true of many other large databases), as well as focus on relevant perinatal outcomes and thoughtful statistical modeling. However, a significant challenge with this, and many other studies, is ascertainment of SARS-CoV-2 infections throughout pregnancy. Asymptomatic and mildly symptomatic women, who may not be as likely to have adverse pregnancy outcomes, can often be counted in the unaffected population, biasing study results toward increased risks of SARS-CoV-2. Although the findings stratified by implementation of universal testing (which captures a greater fraction of asymptomatic patients at admission for delivery), do not suggest risk mitigation with asymptomatic status, this analysis did not capture asymptomatic infections earlier in pregnancy, many of which might not be associated with perinatal risk.

Another challenge with such a dataset is that one cannot determine the severity of illness of each patient without manual review of each chart; however, other data that are easily abstracted from the EHR may serve as a proxy. For instance, of the 307 women with symptomatic COVID-19, 4 required respiratory support above nasal cannula. This suggests a low rate of severely ill women, and may explain some of the findings in the study, such as no differences in the rate of CD, hypertensive disorders of pregnancy, or stillbirth, but does not explain the increased risk of both medically indicated and spontaneous preterm birth, or the rates of acute respiratory distress syndrome and sepsis that drive the increased risk of severe maternal morbidity.

The CDC has published data on the risks of stillbirth from a large hospital-based administrative database for COVID-19 from Premier Healthcare.² In a cohort of over 1.2 million women admitted for delivery, including the timeframe of Ferrara et al’s study, COVID-19 was associated with a 2-fold increased risk of stillbirth, with higher risks noted with the delta variant. A rare outcome, stillbirth occurs in 6/1,000 births,⁷ which was the rate seen in Ferrara’s publication for both women with and without SARS-CoV-2 infection. The rare nature of the outcome may explain why a signal was not noted in the article of interest.

Translating data to patient counseling

Ferrara and colleagues’ study clearly confirms that COVID-19 infection has risks. Although many women with a COVID-19 infection in pregnancy may have an uncomplicated course, a favorable outcome is hard to predict with certainty. Risks of prematurity, VTE, organ dysfunction, and stillbirth from COVID-19 are rare but devastating complications. However, vaccinated women tend to incur far fewer adverse outcomes of COVID-19 in pregnancy, namely a 90% risk reduction in severe or critical COVID-19, with lower rates of ICU admissions and stillbirths.⁸ While these data strongly favor vaccination, we remain ill-advised on management strategies specifically to mitigate risk for the pregnancy once affected by COVID-19 infection. Thus, prevention with vaccination, mask wearing, and physical distancing remains a cornerstone of prenatal care in the current day. ●

Ferrara A, Hedderson MM, Zhu Y, et al. Perinatal complications in individuals in California with or without SARS-CoV-2 infection during pregnancy. JAMA Intern Med. 2022;182:503-512. doi:10.1001/jamainternmed.2022.0330

Expert Commentary

SARS-CoV-2 infection is associated with several adverse outcomes, with the magnitude of specific risks varying by population studied and study design used. Early Centers for Disease Control and Prevention (CDC) data demonstrated that pregnant women were at increased risk for severe illness, including risks of intensive care unit (ICU) admission, invasive ventilation, and extracorporeal membrane oxygenation, compared with non–pregnant women.¹ Since then, other groups have confirmed the increased risks of severe COVID-19, and also identified pregnancy-specific risks, such as preeclampsia, cesarean delivery (CD), prematurity, venous thromboembolic (VTE) disease, and stillbirth.^2-6

The recent study by Ferrara and colleagues adds more granular data to help refine understanding of COVID-19 in pregnancy and counsel patients.

Details of the study

The authors conducted a retrospective cohort study between March 1, 2020, and March 16, 2021, using the electronic health records (EHRs) from Kaiser Permanente Northern California, an integrated managed care organization that serves 4.5 million patients annually. Universal testing for SARS-CoV-2 upon admission for delivery began December 1, 2020; prior to this date, asymptomatic pregnant women were tested only for certain criteria (such as being a health care worker or having high-risk medical conditions).

Pregnant women were identified with SARS-CoV-2 based on 1) a positive polymerase chain reaction test result between 30 days prior to the last menstrual period up to 7 days after delivery or 2) an ICD-10 diagnosis of SARS-CoV-2 infection. Pregnant women not meeting these criteria were classified as SARS-CoV-2 negative. Women were followed through pregnancy to understand if they experienced preterm birth (spontaneous and medically indicated), gestational hypertension, preeclampsia/eclampsia, VTE disease, gestational diabetes, severe maternal morbidity (as defined by the CDC), hospitalization, and livebirth (or stillbirth), in order to consider the timing of SARS-CoV-2 infection relative to each of these outcomes (and ascertain whether SARS-CoV-2 infection preceded any of these outcomes more commonly than not). Management of pregnancies with COVID-19 across this large organization and multiple hospitals was not specified.

Identified perinatal risks

Among 43,886 pregnant women included in the cohort, 1,332 (3.0%) were diagnosed with SARS-CoV-2, with the vast majority of positive tests in the third trimester. Significant sociodemographic differences were noted between those with and without SARS-CoV-2, including differences in age, self-reported race/ethnicity, neighborhood deprivation index, and pre-pregnancy body mass index; no differences were noted for other pre-existing comorbidities, gestational week at delivery, or smoking in pregnancy.

In multivariable models, SARS-CoV-2 infection in pregnancy was associated with severe maternal morbidity, preterm birth, and VTE disease. It was not associated with stillbirth, any hypertensive disorder of pregnancy, CD, or any neonatal complication.

The prevalence of SARS-CoV-2 was 1.3% prior to and 8.0% after implementation of universal testing in pregnancy for SARS-CoV-2. No differences were noted in the risks of severe maternal morbidity or preterm birth relative to the implementation of universal testing, with risks remaining comparably high even after universal testing.

A total of 307 of the 1,332 pregant women with SARS-CoV-2 were admitted to the hospital for symptomatic infection; 3 required noninvasive positive-pressure ventilation, and 1 required mechanical ventilation.

Continue to: Study strengths and weaknesses...

Study strengths and weaknesses

Strengths include the large, EHR-based dataset from a single organization, allowing for granular analysis on patient comorbidities and outcomes (rather than only based on diagnosis codes, as is true of many other large databases), as well as focus on relevant perinatal outcomes and thoughtful statistical modeling. However, a significant challenge with this, and many other studies, is ascertainment of SARS-CoV-2 infections throughout pregnancy. Asymptomatic and mildly symptomatic women, who may not be as likely to have adverse pregnancy outcomes, can often be counted in the unaffected population, biasing study results toward increased risks of SARS-CoV-2. Although the findings stratified by implementation of universal testing (which captures a greater fraction of asymptomatic patients at admission for delivery), do not suggest risk mitigation with asymptomatic status, this analysis did not capture asymptomatic infections earlier in pregnancy, many of which might not be associated with perinatal risk.

Another challenge with such a dataset is that one cannot determine the severity of illness of each patient without manual review of each chart; however, other data that are easily abstracted from the EHR may serve as a proxy. For instance, of the 307 women with symptomatic COVID-19, 4 required respiratory support above nasal cannula. This suggests a low rate of severely ill women, and may explain some of the findings in the study, such as no differences in the rate of CD, hypertensive disorders of pregnancy, or stillbirth, but does not explain the increased risk of both medically indicated and spontaneous preterm birth, or the rates of acute respiratory distress syndrome and sepsis that drive the increased risk of severe maternal morbidity.

The CDC has published data on the risks of stillbirth from a large hospital-based administrative database for COVID-19 from Premier Healthcare.² In a cohort of over 1.2 million women admitted for delivery, including the timeframe of Ferrara et al’s study, COVID-19 was associated with a 2-fold increased risk of stillbirth, with higher risks noted with the delta variant. A rare outcome, stillbirth occurs in 6/1,000 births,⁷ which was the rate seen in Ferrara’s publication for both women with and without SARS-CoV-2 infection. The rare nature of the outcome may explain why a signal was not noted in the article of interest.

Translating data to patient counseling

Ferrara and colleagues’ study clearly confirms that COVID-19 infection has risks. Although many women with a COVID-19 infection in pregnancy may have an uncomplicated course, a favorable outcome is hard to predict with certainty. Risks of prematurity, VTE, organ dysfunction, and stillbirth from COVID-19 are rare but devastating complications. However, vaccinated women tend to incur far fewer adverse outcomes of COVID-19 in pregnancy, namely a 90% risk reduction in severe or critical COVID-19, with lower rates of ICU admissions and stillbirths.⁸ While these data strongly favor vaccination, we remain ill-advised on management strategies specifically to mitigate risk for the pregnancy once affected by COVID-19 infection. Thus, prevention with vaccination, mask wearing, and physical distancing remains a cornerstone of prenatal care in the current day. ●

Ferrara A, Hedderson MM, Zhu Y, et al. Perinatal complications in individuals in California with or without SARS-CoV-2 infection during pregnancy. JAMA Intern Med. 2022;182:503-512. doi:10.1001/jamainternmed.2022.0330

Expert Commentary

SARS-CoV-2 infection is associated with several adverse outcomes, with the magnitude of specific risks varying by population studied and study design used. Early Centers for Disease Control and Prevention (CDC) data demonstrated that pregnant women were at increased risk for severe illness, including risks of intensive care unit (ICU) admission, invasive ventilation, and extracorporeal membrane oxygenation, compared with non–pregnant women.¹ Since then, other groups have confirmed the increased risks of severe COVID-19, and also identified pregnancy-specific risks, such as preeclampsia, cesarean delivery (CD), prematurity, venous thromboembolic (VTE) disease, and stillbirth.^2-6

The recent study by Ferrara and colleagues adds more granular data to help refine understanding of COVID-19 in pregnancy and counsel patients.

Details of the study

The authors conducted a retrospective cohort study between March 1, 2020, and March 16, 2021, using the electronic health records (EHRs) from Kaiser Permanente Northern California, an integrated managed care organization that serves 4.5 million patients annually. Universal testing for SARS-CoV-2 upon admission for delivery began December 1, 2020; prior to this date, asymptomatic pregnant women were tested only for certain criteria (such as being a health care worker or having high-risk medical conditions).

Pregnant women were identified with SARS-CoV-2 based on 1) a positive polymerase chain reaction test result between 30 days prior to the last menstrual period up to 7 days after delivery or 2) an ICD-10 diagnosis of SARS-CoV-2 infection. Pregnant women not meeting these criteria were classified as SARS-CoV-2 negative. Women were followed through pregnancy to understand if they experienced preterm birth (spontaneous and medically indicated), gestational hypertension, preeclampsia/eclampsia, VTE disease, gestational diabetes, severe maternal morbidity (as defined by the CDC), hospitalization, and livebirth (or stillbirth), in order to consider the timing of SARS-CoV-2 infection relative to each of these outcomes (and ascertain whether SARS-CoV-2 infection preceded any of these outcomes more commonly than not). Management of pregnancies with COVID-19 across this large organization and multiple hospitals was not specified.

Identified perinatal risks

Among 43,886 pregnant women included in the cohort, 1,332 (3.0%) were diagnosed with SARS-CoV-2, with the vast majority of positive tests in the third trimester. Significant sociodemographic differences were noted between those with and without SARS-CoV-2, including differences in age, self-reported race/ethnicity, neighborhood deprivation index, and pre-pregnancy body mass index; no differences were noted for other pre-existing comorbidities, gestational week at delivery, or smoking in pregnancy.

In multivariable models, SARS-CoV-2 infection in pregnancy was associated with severe maternal morbidity, preterm birth, and VTE disease. It was not associated with stillbirth, any hypertensive disorder of pregnancy, CD, or any neonatal complication.

The prevalence of SARS-CoV-2 was 1.3% prior to and 8.0% after implementation of universal testing in pregnancy for SARS-CoV-2. No differences were noted in the risks of severe maternal morbidity or preterm birth relative to the implementation of universal testing, with risks remaining comparably high even after universal testing.

A total of 307 of the 1,332 pregant women with SARS-CoV-2 were admitted to the hospital for symptomatic infection; 3 required noninvasive positive-pressure ventilation, and 1 required mechanical ventilation.

Continue to: Study strengths and weaknesses...

Study strengths and weaknesses

Strengths include the large, EHR-based dataset from a single organization, allowing for granular analysis on patient comorbidities and outcomes (rather than only based on diagnosis codes, as is true of many other large databases), as well as focus on relevant perinatal outcomes and thoughtful statistical modeling. However, a significant challenge with this, and many other studies, is ascertainment of SARS-CoV-2 infections throughout pregnancy. Asymptomatic and mildly symptomatic women, who may not be as likely to have adverse pregnancy outcomes, can often be counted in the unaffected population, biasing study results toward increased risks of SARS-CoV-2. Although the findings stratified by implementation of universal testing (which captures a greater fraction of asymptomatic patients at admission for delivery), do not suggest risk mitigation with asymptomatic status, this analysis did not capture asymptomatic infections earlier in pregnancy, many of which might not be associated with perinatal risk.

Another challenge with such a dataset is that one cannot determine the severity of illness of each patient without manual review of each chart; however, other data that are easily abstracted from the EHR may serve as a proxy. For instance, of the 307 women with symptomatic COVID-19, 4 required respiratory support above nasal cannula. This suggests a low rate of severely ill women, and may explain some of the findings in the study, such as no differences in the rate of CD, hypertensive disorders of pregnancy, or stillbirth, but does not explain the increased risk of both medically indicated and spontaneous preterm birth, or the rates of acute respiratory distress syndrome and sepsis that drive the increased risk of severe maternal morbidity.

The CDC has published data on the risks of stillbirth from a large hospital-based administrative database for COVID-19 from Premier Healthcare.² In a cohort of over 1.2 million women admitted for delivery, including the timeframe of Ferrara et al’s study, COVID-19 was associated with a 2-fold increased risk of stillbirth, with higher risks noted with the delta variant. A rare outcome, stillbirth occurs in 6/1,000 births,⁷ which was the rate seen in Ferrara’s publication for both women with and without SARS-CoV-2 infection. The rare nature of the outcome may explain why a signal was not noted in the article of interest.

Translating data to patient counseling

Ferrara and colleagues’ study clearly confirms that COVID-19 infection has risks. Although many women with a COVID-19 infection in pregnancy may have an uncomplicated course, a favorable outcome is hard to predict with certainty. Risks of prematurity, VTE, organ dysfunction, and stillbirth from COVID-19 are rare but devastating complications. However, vaccinated women tend to incur far fewer adverse outcomes of COVID-19 in pregnancy, namely a 90% risk reduction in severe or critical COVID-19, with lower rates of ICU admissions and stillbirths.⁸ While these data strongly favor vaccination, we remain ill-advised on management strategies specifically to mitigate risk for the pregnancy once affected by COVID-19 infection. Thus, prevention with vaccination, mask wearing, and physical distancing remains a cornerstone of prenatal care in the current day. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Pregnant women, or women considering pregnancy, want to know—is pregnancy safe in the midst of the coronavirus disease 2019 (COVID-19) pandemic? In this article, I tackle common questions facing reproductive-aged or pregnant women and their providers.

1. What are the risks of COVID-19 in pregnancy?

A large, national prospective cohort study of outpatient pregnant and recently postpartum women with the diagnosis of suspected or confirmed COVID-19 demonstrated that many affected women have mild illnesses, with typical symptoms including cough, sore throat, body aches, fever, and headache.¹ Although symptoms were most common within the first 3 weeks of presentation, approximately 25% of women had a protracted course of symptoms (8 or more weeks). As this cohort disproportionately enrolled outpatients, it is important to note that many women had mild illnesses, which is the most likely course of infection in otherwise healthy, young women.

Data on the impact of COVID-19 on rates of miscarriage and birth defects are limited, yet the published reports are reassuring, with no increased risks of miscarriage, and no clear signal for birth defects.²

In a prospective cohort study across 3 New York City institutions when universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing was recommended upon admission for delivery, approximately 80% of women who were positive were asymptomatic.³ Maternal outcomes generally were reassuring, with no patients experiencing severe or critical illness. There were no differences in preterm delivery rates by SARS-CoV-2 status, but the rate of cesarean delivery was higher among women with COVID-19, for unclear reasons. Most notably, the rate of postpartum complications was 13% among women with COVID-19, versus 2.5% among women without COVID-19. These complications included readmission for worsening COVID-19, postpartum hypoxia, and postpartum fever.

A recent prospective cohort study from 1 institution in Texas similarly demonstrated favorable maternal outcomes with COVID-19, with 95% of women with asymptomatic or mild illness, and no differences in adverse pregnancy outcomes between COVID-19–positive and COVID-19–negative women, including cesarean delivery rate.⁴

Finally, certain characteristics increase the risk of COVID-19 among pregnant women and nonpregnant individuals alike. In a nationwide prospective cohort from the United Kingdom, medical comorbidities including obesity, diabetes (gestational or pregestational), hypertension, as well as Black or other minority ethnicities are associated with COVID-19.⁵ This is particularly notable given universal health insurance in the United Kingdom. Other data have also confirmed that women with comorbidities, women of Black or Hispanic ethnicity, and women with lower socioeconomic status, are at increased risk of COVID-19.^3,6,7

2. Is COVID-19 worse in pregnancy?

Given the well-documented risks of COVID-19 outside of pregnancy, is COVID-19 worse in a pregnant woman than in a nonpregnant woman? The most recent guidance from the Centers for Disease Control and Prevention (CDC) from November 2020 suggests that pregnant women are at increased risk for severe illness.⁸ However, it is important to understand the design of this study in order to appreciate its implications. Laboratory confirmed SARS-CoV-2 in the United States is systematically reported to the CDC. Among women aged 15–44 years with such confirmation, data on pregnancy status were available for 35.5%, almost 90% of whom were symptomatic. Within this cohort of largely symptomatic pregnant women, risks of intensive care unit (ICU) admission, invasive ventilation, and use of extracorporeal membrane oxygenation (ECMO) were approximately 2 to 3 times higher for pregnant women than for nonpregnant women. The absolute risks, however, were low. The risk of ICU admission for symptomatic pregnant women was approximately 1%; the risk of invasive ventilation, 0.3%; and the risk of ECMO, 0.1%.

Moreover, the lack of uniform data capture on pregnancy status for all women ages 15–44 years may skew the population with known pregnancy status to be sicker and, thus, may bias the results toward increased risks. Nevertheless, there is consistency in several publications with different data sources, all of which suggest pregnancy is an independent risk factor for increased severity of COVID-19.^9-11 Additionally, women with medical comorbidities (such as pregestational or gestational diabetes or obesity) are more likely to have severe COVID-19.

Continue to: 3. What are newborn outcomes if COVID-19 is diagnosed during pregnancy?...

Two large cohorts of newborns, disproportionately term infants, from the first wave of the pandemic in New York City, have reassuring news. In one cohort of 101 infants born at 2 New York City institutions to SARS-CoV-2–positive mothers, 2 neonates were diagnosed with SARS-CoV-2 during the immediate postnatal period.¹² Neither infant demonstrated clinical COVID-19. In another cohort of 120 infants born at 3 other New York City institutions to SARS-CoV-2–positive mothers and tested systematically within 24 hours of life, 5–7 days of life, and 14 days of life, there were no neonates who tested positive for SARS-CoV-2 at the initial time point. Among the 79 infants who had testing at 5–7 days of life and the 72 tested at 14 days of life, there were no infants positive for SARS-CoV-2.¹³ It is important to note that case reports and small case series have demonstrated some convincing evidence of vertical transmission. However, the overwhelming evidence suggests this risk is very low.

4. What is a reasonable outpatient setting–approach to managing COVID-19 in a pregnant woman?

Women should be counseled to quarantine for 10 to 14 days from symptom onset or, if asymptomatic, from positive polymerase chain reaction (PCR) test. Warning signs of worsening COVID-19 disease should be reviewed. Serial telemedicine follow-up for 10 to 14 days is recommended to ensure clinical stability and continued management as an outpatient. A home pulse oximeter is also recommended. Women should be advised to check their oxygen saturation daily and to call if oxygen saturation becomes less than 93%. Supportive care is recommended.

If delay in obstetric care may result in adverse pregnancy outcomes (for instance, postponing indicated fetal surveillance), obstetric care should be delivered, with appropriate personal protective equipment for health care workers and minimization of exposure of other pregnant women to the infected patient. Appointments should be scheduled at the end of the day.

During influenza season, women should receive empiric oseltamivir treatment (75 mg twice a day) per CDC guidelines for symptoms that may also be consistent with influenza, regardless of testing.

Prophylactic anticoagulation is not indicated for pregnant antepartum women who do not require inpatient care.

If inpatient care is required, management is individualized.

The approach to prenatal care after resolution of COVID-19 is not evidence-based. At my institution, all patients have a detailed mid-trimester anatomic evaluation, but if this is not routine, a detailed anatomic ultrasound (Current Procedural Terminology code 76811) may be considered. Additionally, for women with COVID-19 we perform one third-trimester growth ultrasound to screen for fetal growth restriction, on the basis of several placental studies demonstrating clots on the fetal or maternal side of the placenta.^3,14 Routine antenatal testing in the absence of growth restriction, or other comorbid conditions for which testing occurs, is not recommended.

Continue to: 5. What if asymptomatic or mild COVID-19 is diagnosed at the time of delivery?...

5. What if asymptomatic or mild COVID-19 is diagnosed at the time of delivery? What is reasonable management?

Asymptomatic or mildly symptomatic COVID-19 should not alter obstetric management, beyond appropriate use of personal protective equipment. Delayed cord clamping is also reasonable, if there are no other contraindications, as there is no documented harm associated with this practice among women with COVID-19.

Women with COVID-19 may be at higher risk for venous thromboembolic events in the postpartum period. At my institution, prophylactic postpartum anticoagulation is recommended for 2 weeks after vaginal delivery, and 6 weeks after cesarean delivery.

During the postpartum hospitalization, given reassuring data about vertical transmission and postnatal horizontal transmission risks, babies may room in with mothers in a single private room, if rooming-in is the current standard of care—as long as the mother and newborn do not require higher levels of care. Mothers should wear a mask and use hand hygiene when in contact with the baby. Skin-to-skin and breastfeeding or infant feeding of breast milk are appropriate practices to continue. There is no evidence to suggest that transmission of COVID-19 can occur via breastmilk; however, given the close contact inherent in breastfeeding, transmission through direct contact or maternal respiratory droplets is possible, and thus maternal use of masks and hand hygiene is recommended. When not feeding, the infant should be 6 feet away, and if possible, in an isolette.

6. When can individuals with COVID-19 discontinue transmission precautions or “home quarantine”?

For women with mildly symptomatic COVID-19 and without immunocompromise, home quarantine can be discontinued 10 days after onset of symptoms as long as there has been symptom improvement and no fever for at least 24 hours without the use of antipyretics. For immunocompetent women with incidentally diagnosed asymptomatic COVID-19, home quarantine can be discontinued 10 days after the positive test was obtained. Pregnancy in and of itself is not an immunocompromising condition.^15,16

For women with severe or critical COVID-19, who were hospitalized due to their clinical status, home quarantine can be discontinued when at least 10 days, and up to 20 days, after onset of symptoms and with symptom improvement and with no fever for at least 24 hours, without the use of antipyretics. Local hospital infection control experts may be able to guide the recommended practice for your site better, based on local information.^15,16

Repeating a PCR test to discontinue home quarantine is not recommended in most circumstances, as individuals may have prolonged shedding of noninfectious particles in their nasopharynx. Immunocompromise may be one exception to this general guidance, but consultation with local hospital infection control experts will help guide management.^15,16

7. Should women get pregnant during the COVID-19 pandemic?

Every pandemic has its own set of implications for the health of the mother, fetus, or both, and COVID-19 is no exception. While there are risks, described above, to mother and fetus, these risks are not so catastrophic as to strongly and directively recommend a patient not become pregnant.¹⁷ Moreover, the last several months of the pandemic have demonstrated that consistent mask usage, social distancing, and hand hygiene, are effective methods of preventing the acquisition of COVID-19. All of these risk-reducing strategies are available to pregnant women. Finally, accessing care during a pandemic in a hospital setting does not also pose a risk for acquisition of SARS-CoV-2.¹⁸

Continue to: 8. Is the COVID-19 vaccine safe for pregnant or postpartum/lactating women?...

8. Is the COVID-19 vaccine safe for pregnant or postpartum/lactating women?

On December 11, 2020, the US Food and Drug Administration (FDA) issued emergency use authorization (EUA) for the Pfizer-BioNtech mRNA vaccine (BNT 162b2) against COVID-19, for individuals aged 16 and older as a 2-dose series given 21 days apart. Among the more than 40,000 individuals in the trial that led to this EUA, vaccine efficacy was 95%.¹⁹ Adverse effects included fatigue and headache most commonly, with 16% of vaccine recipients experiencing fever after the second dose. Follow-up regarding safety is planned for 2 years by the manufacturer, in addition to safety monitoring by pre-existing national systems.

On December 18, 2020, the FDA announced EUA for Moderna’s mRNA-based vaccine, mRNA-1273, in men and women aged 18 and older. This is a 2-dose series given 28 days apart. The vaccine efficacy has been reported at 94.5%, with the most common adverse effects being injection site pain, tiredness, headache, muscle pain, chills, joint pain, swollen lymph nodes in the same arm as the injection, nausea and vomiting, and fever.^20,21 The phase 3 trial is ongoing.

Despite the speed with which these effective vaccines were developed, it is important to note that all regulatory and safety steps mandated for the development of any vaccine were met for these two, as well as for other COVID-19 vaccinations that will similarly receive EUA from the FDA.

In the EUA for BNT 162b2, the specific language regarding pregnant and lactating women recommends that patients and providers have an individualized conversation about vaccination. In the data presented to the FDA for the Pfizer-BioNtech mRNA vaccine, a limited number of pregnant women received either the vaccine (12 women) or placebo (11 women), with no long-term follow-up data available to characterize either maternal or fetal benefits and risks. The mechanism of action of an mRNA vaccine is to induce the cytoplasmic machinery within cells to create the coronavirus spike protein, which then allows the body’s immune system to create antibodies against this protein and confer protection accordingly. While the above mechanism is not theorized to result in different outcomes or different efficacy, the safety for the pregnant woman and fetus are unknown. It is not believed that vaccination during lactation would cause any adverse outcomes to a neonate, and lactating women do not need to interrupt or discontinue breast milk production in order to receive the vaccine.

The American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory on December 13, 2020, regarding their recommendations.²² ACOG recommends that vaccines against COVID-19 not be withheld from pregnant or lactating women, if they might otherwise meet criteria for and have access to vaccination. Currently, the CDC’s Advisory Committee on Immunization Practices (ACIP) stated that health care workers and long-term care facility residents represent priority groups to vaccinate in the initial phases of vaccination, given limitations in supply.²³ This recommendation is likely to be updated frequently as additional vaccines become available. Shared decision-making between patient and provider may help the patient to make the best decision for herself, but provider input is not required prior to a pregnant woman being vaccinated.

Additional animal data evaluating adverse effects on the reproductive system from developmental and reproductive toxicity (DART) studies for both mRNA vaccines should be available in the coming weeks, which may aid in the counseling of reproductive-aged women.

Vaccine trials to specifically enroll pregnant women are set to begin in early 2021, and more data will certainly inform the conversation between patient and provider regarding risks and benefits.

Conclusions

While the absolute risks of COVID-19 to mothers, fetuses, and neonates is low, pregnancy is a risk factor for severe disease. Many pregnant women with COVID-19 can be safely followed as outpatients via telemedicine, and supportive care is recommended. Inpatient care should be individualized. Pregnancy during the COVID-19 pandemic should be not be absolutely discouraged; instead, a conversation about risk mitigation should be undertaken. The COVID-19 vaccine is available to pregnant and lactating women, and the decision to choose vaccination in pregnancy is in the purview of the patient, in consultation with her physician. ●

Pregnant women, or women considering pregnancy, want to know—is pregnancy safe in the midst of the coronavirus disease 2019 (COVID-19) pandemic? In this article, I tackle common questions facing reproductive-aged or pregnant women and their providers.

1. What are the risks of COVID-19 in pregnancy?

A large, national prospective cohort study of outpatient pregnant and recently postpartum women with the diagnosis of suspected or confirmed COVID-19 demonstrated that many affected women have mild illnesses, with typical symptoms including cough, sore throat, body aches, fever, and headache.¹ Although symptoms were most common within the first 3 weeks of presentation, approximately 25% of women had a protracted course of symptoms (8 or more weeks). As this cohort disproportionately enrolled outpatients, it is important to note that many women had mild illnesses, which is the most likely course of infection in otherwise healthy, young women.

Data on the impact of COVID-19 on rates of miscarriage and birth defects are limited, yet the published reports are reassuring, with no increased risks of miscarriage, and no clear signal for birth defects.²

In a prospective cohort study across 3 New York City institutions when universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing was recommended upon admission for delivery, approximately 80% of women who were positive were asymptomatic.³ Maternal outcomes generally were reassuring, with no patients experiencing severe or critical illness. There were no differences in preterm delivery rates by SARS-CoV-2 status, but the rate of cesarean delivery was higher among women with COVID-19, for unclear reasons. Most notably, the rate of postpartum complications was 13% among women with COVID-19, versus 2.5% among women without COVID-19. These complications included readmission for worsening COVID-19, postpartum hypoxia, and postpartum fever.

A recent prospective cohort study from 1 institution in Texas similarly demonstrated favorable maternal outcomes with COVID-19, with 95% of women with asymptomatic or mild illness, and no differences in adverse pregnancy outcomes between COVID-19–positive and COVID-19–negative women, including cesarean delivery rate.⁴

Finally, certain characteristics increase the risk of COVID-19 among pregnant women and nonpregnant individuals alike. In a nationwide prospective cohort from the United Kingdom, medical comorbidities including obesity, diabetes (gestational or pregestational), hypertension, as well as Black or other minority ethnicities are associated with COVID-19.⁵ This is particularly notable given universal health insurance in the United Kingdom. Other data have also confirmed that women with comorbidities, women of Black or Hispanic ethnicity, and women with lower socioeconomic status, are at increased risk of COVID-19.^3,6,7

2. Is COVID-19 worse in pregnancy?

Given the well-documented risks of COVID-19 outside of pregnancy, is COVID-19 worse in a pregnant woman than in a nonpregnant woman? The most recent guidance from the Centers for Disease Control and Prevention (CDC) from November 2020 suggests that pregnant women are at increased risk for severe illness.⁸ However, it is important to understand the design of this study in order to appreciate its implications. Laboratory confirmed SARS-CoV-2 in the United States is systematically reported to the CDC. Among women aged 15–44 years with such confirmation, data on pregnancy status were available for 35.5%, almost 90% of whom were symptomatic. Within this cohort of largely symptomatic pregnant women, risks of intensive care unit (ICU) admission, invasive ventilation, and use of extracorporeal membrane oxygenation (ECMO) were approximately 2 to 3 times higher for pregnant women than for nonpregnant women. The absolute risks, however, were low. The risk of ICU admission for symptomatic pregnant women was approximately 1%; the risk of invasive ventilation, 0.3%; and the risk of ECMO, 0.1%.

Moreover, the lack of uniform data capture on pregnancy status for all women ages 15–44 years may skew the population with known pregnancy status to be sicker and, thus, may bias the results toward increased risks. Nevertheless, there is consistency in several publications with different data sources, all of which suggest pregnancy is an independent risk factor for increased severity of COVID-19.^9-11 Additionally, women with medical comorbidities (such as pregestational or gestational diabetes or obesity) are more likely to have severe COVID-19.

Continue to: 3. What are newborn outcomes if COVID-19 is diagnosed during pregnancy?...

Two large cohorts of newborns, disproportionately term infants, from the first wave of the pandemic in New York City, have reassuring news. In one cohort of 101 infants born at 2 New York City institutions to SARS-CoV-2–positive mothers, 2 neonates were diagnosed with SARS-CoV-2 during the immediate postnatal period.¹² Neither infant demonstrated clinical COVID-19. In another cohort of 120 infants born at 3 other New York City institutions to SARS-CoV-2–positive mothers and tested systematically within 24 hours of life, 5–7 days of life, and 14 days of life, there were no neonates who tested positive for SARS-CoV-2 at the initial time point. Among the 79 infants who had testing at 5–7 days of life and the 72 tested at 14 days of life, there were no infants positive for SARS-CoV-2.¹³ It is important to note that case reports and small case series have demonstrated some convincing evidence of vertical transmission. However, the overwhelming evidence suggests this risk is very low.

4. What is a reasonable outpatient setting–approach to managing COVID-19 in a pregnant woman?

Women should be counseled to quarantine for 10 to 14 days from symptom onset or, if asymptomatic, from positive polymerase chain reaction (PCR) test. Warning signs of worsening COVID-19 disease should be reviewed. Serial telemedicine follow-up for 10 to 14 days is recommended to ensure clinical stability and continued management as an outpatient. A home pulse oximeter is also recommended. Women should be advised to check their oxygen saturation daily and to call if oxygen saturation becomes less than 93%. Supportive care is recommended.

If delay in obstetric care may result in adverse pregnancy outcomes (for instance, postponing indicated fetal surveillance), obstetric care should be delivered, with appropriate personal protective equipment for health care workers and minimization of exposure of other pregnant women to the infected patient. Appointments should be scheduled at the end of the day.

During influenza season, women should receive empiric oseltamivir treatment (75 mg twice a day) per CDC guidelines for symptoms that may also be consistent with influenza, regardless of testing.

Prophylactic anticoagulation is not indicated for pregnant antepartum women who do not require inpatient care.

If inpatient care is required, management is individualized.

The approach to prenatal care after resolution of COVID-19 is not evidence-based. At my institution, all patients have a detailed mid-trimester anatomic evaluation, but if this is not routine, a detailed anatomic ultrasound (Current Procedural Terminology code 76811) may be considered. Additionally, for women with COVID-19 we perform one third-trimester growth ultrasound to screen for fetal growth restriction, on the basis of several placental studies demonstrating clots on the fetal or maternal side of the placenta.^3,14 Routine antenatal testing in the absence of growth restriction, or other comorbid conditions for which testing occurs, is not recommended.

Continue to: 5. What if asymptomatic or mild COVID-19 is diagnosed at the time of delivery?...

5. What if asymptomatic or mild COVID-19 is diagnosed at the time of delivery? What is reasonable management?

Asymptomatic or mildly symptomatic COVID-19 should not alter obstetric management, beyond appropriate use of personal protective equipment. Delayed cord clamping is also reasonable, if there are no other contraindications, as there is no documented harm associated with this practice among women with COVID-19.

Women with COVID-19 may be at higher risk for venous thromboembolic events in the postpartum period. At my institution, prophylactic postpartum anticoagulation is recommended for 2 weeks after vaginal delivery, and 6 weeks after cesarean delivery.

During the postpartum hospitalization, given reassuring data about vertical transmission and postnatal horizontal transmission risks, babies may room in with mothers in a single private room, if rooming-in is the current standard of care—as long as the mother and newborn do not require higher levels of care. Mothers should wear a mask and use hand hygiene when in contact with the baby. Skin-to-skin and breastfeeding or infant feeding of breast milk are appropriate practices to continue. There is no evidence to suggest that transmission of COVID-19 can occur via breastmilk; however, given the close contact inherent in breastfeeding, transmission through direct contact or maternal respiratory droplets is possible, and thus maternal use of masks and hand hygiene is recommended. When not feeding, the infant should be 6 feet away, and if possible, in an isolette.

6. When can individuals with COVID-19 discontinue transmission precautions or “home quarantine”?

For women with mildly symptomatic COVID-19 and without immunocompromise, home quarantine can be discontinued 10 days after onset of symptoms as long as there has been symptom improvement and no fever for at least 24 hours without the use of antipyretics. For immunocompetent women with incidentally diagnosed asymptomatic COVID-19, home quarantine can be discontinued 10 days after the positive test was obtained. Pregnancy in and of itself is not an immunocompromising condition.^15,16

For women with severe or critical COVID-19, who were hospitalized due to their clinical status, home quarantine can be discontinued when at least 10 days, and up to 20 days, after onset of symptoms and with symptom improvement and with no fever for at least 24 hours, without the use of antipyretics. Local hospital infection control experts may be able to guide the recommended practice for your site better, based on local information.^15,16

Repeating a PCR test to discontinue home quarantine is not recommended in most circumstances, as individuals may have prolonged shedding of noninfectious particles in their nasopharynx. Immunocompromise may be one exception to this general guidance, but consultation with local hospital infection control experts will help guide management.^15,16

7. Should women get pregnant during the COVID-19 pandemic?

Every pandemic has its own set of implications for the health of the mother, fetus, or both, and COVID-19 is no exception. While there are risks, described above, to mother and fetus, these risks are not so catastrophic as to strongly and directively recommend a patient not become pregnant.¹⁷ Moreover, the last several months of the pandemic have demonstrated that consistent mask usage, social distancing, and hand hygiene, are effective methods of preventing the acquisition of COVID-19. All of these risk-reducing strategies are available to pregnant women. Finally, accessing care during a pandemic in a hospital setting does not also pose a risk for acquisition of SARS-CoV-2.¹⁸

Continue to: 8. Is the COVID-19 vaccine safe for pregnant or postpartum/lactating women?...

8. Is the COVID-19 vaccine safe for pregnant or postpartum/lactating women?

On December 11, 2020, the US Food and Drug Administration (FDA) issued emergency use authorization (EUA) for the Pfizer-BioNtech mRNA vaccine (BNT 162b2) against COVID-19, for individuals aged 16 and older as a 2-dose series given 21 days apart. Among the more than 40,000 individuals in the trial that led to this EUA, vaccine efficacy was 95%.¹⁹ Adverse effects included fatigue and headache most commonly, with 16% of vaccine recipients experiencing fever after the second dose. Follow-up regarding safety is planned for 2 years by the manufacturer, in addition to safety monitoring by pre-existing national systems.

On December 18, 2020, the FDA announced EUA for Moderna’s mRNA-based vaccine, mRNA-1273, in men and women aged 18 and older. This is a 2-dose series given 28 days apart. The vaccine efficacy has been reported at 94.5%, with the most common adverse effects being injection site pain, tiredness, headache, muscle pain, chills, joint pain, swollen lymph nodes in the same arm as the injection, nausea and vomiting, and fever.^20,21 The phase 3 trial is ongoing.

Despite the speed with which these effective vaccines were developed, it is important to note that all regulatory and safety steps mandated for the development of any vaccine were met for these two, as well as for other COVID-19 vaccinations that will similarly receive EUA from the FDA.

In the EUA for BNT 162b2, the specific language regarding pregnant and lactating women recommends that patients and providers have an individualized conversation about vaccination. In the data presented to the FDA for the Pfizer-BioNtech mRNA vaccine, a limited number of pregnant women received either the vaccine (12 women) or placebo (11 women), with no long-term follow-up data available to characterize either maternal or fetal benefits and risks. The mechanism of action of an mRNA vaccine is to induce the cytoplasmic machinery within cells to create the coronavirus spike protein, which then allows the body’s immune system to create antibodies against this protein and confer protection accordingly. While the above mechanism is not theorized to result in different outcomes or different efficacy, the safety for the pregnant woman and fetus are unknown. It is not believed that vaccination during lactation would cause any adverse outcomes to a neonate, and lactating women do not need to interrupt or discontinue breast milk production in order to receive the vaccine.

The American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory on December 13, 2020, regarding their recommendations.²² ACOG recommends that vaccines against COVID-19 not be withheld from pregnant or lactating women, if they might otherwise meet criteria for and have access to vaccination. Currently, the CDC’s Advisory Committee on Immunization Practices (ACIP) stated that health care workers and long-term care facility residents represent priority groups to vaccinate in the initial phases of vaccination, given limitations in supply.²³ This recommendation is likely to be updated frequently as additional vaccines become available. Shared decision-making between patient and provider may help the patient to make the best decision for herself, but provider input is not required prior to a pregnant woman being vaccinated.

Additional animal data evaluating adverse effects on the reproductive system from developmental and reproductive toxicity (DART) studies for both mRNA vaccines should be available in the coming weeks, which may aid in the counseling of reproductive-aged women.

Vaccine trials to specifically enroll pregnant women are set to begin in early 2021, and more data will certainly inform the conversation between patient and provider regarding risks and benefits.

Conclusions

While the absolute risks of COVID-19 to mothers, fetuses, and neonates is low, pregnancy is a risk factor for severe disease. Many pregnant women with COVID-19 can be safely followed as outpatients via telemedicine, and supportive care is recommended. Inpatient care should be individualized. Pregnancy during the COVID-19 pandemic should be not be absolutely discouraged; instead, a conversation about risk mitigation should be undertaken. The COVID-19 vaccine is available to pregnant and lactating women, and the decision to choose vaccination in pregnancy is in the purview of the patient, in consultation with her physician. ●

Pregnant women, or women considering pregnancy, want to know—is pregnancy safe in the midst of the coronavirus disease 2019 (COVID-19) pandemic? In this article, I tackle common questions facing reproductive-aged or pregnant women and their providers.

1. What are the risks of COVID-19 in pregnancy?

A large, national prospective cohort study of outpatient pregnant and recently postpartum women with the diagnosis of suspected or confirmed COVID-19 demonstrated that many affected women have mild illnesses, with typical symptoms including cough, sore throat, body aches, fever, and headache.¹ Although symptoms were most common within the first 3 weeks of presentation, approximately 25% of women had a protracted course of symptoms (8 or more weeks). As this cohort disproportionately enrolled outpatients, it is important to note that many women had mild illnesses, which is the most likely course of infection in otherwise healthy, young women.

Data on the impact of COVID-19 on rates of miscarriage and birth defects are limited, yet the published reports are reassuring, with no increased risks of miscarriage, and no clear signal for birth defects.²

In a prospective cohort study across 3 New York City institutions when universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing was recommended upon admission for delivery, approximately 80% of women who were positive were asymptomatic.³ Maternal outcomes generally were reassuring, with no patients experiencing severe or critical illness. There were no differences in preterm delivery rates by SARS-CoV-2 status, but the rate of cesarean delivery was higher among women with COVID-19, for unclear reasons. Most notably, the rate of postpartum complications was 13% among women with COVID-19, versus 2.5% among women without COVID-19. These complications included readmission for worsening COVID-19, postpartum hypoxia, and postpartum fever.

A recent prospective cohort study from 1 institution in Texas similarly demonstrated favorable maternal outcomes with COVID-19, with 95% of women with asymptomatic or mild illness, and no differences in adverse pregnancy outcomes between COVID-19–positive and COVID-19–negative women, including cesarean delivery rate.⁴

Finally, certain characteristics increase the risk of COVID-19 among pregnant women and nonpregnant individuals alike. In a nationwide prospective cohort from the United Kingdom, medical comorbidities including obesity, diabetes (gestational or pregestational), hypertension, as well as Black or other minority ethnicities are associated with COVID-19.⁵ This is particularly notable given universal health insurance in the United Kingdom. Other data have also confirmed that women with comorbidities, women of Black or Hispanic ethnicity, and women with lower socioeconomic status, are at increased risk of COVID-19.^3,6,7

2. Is COVID-19 worse in pregnancy?

Given the well-documented risks of COVID-19 outside of pregnancy, is COVID-19 worse in a pregnant woman than in a nonpregnant woman? The most recent guidance from the Centers for Disease Control and Prevention (CDC) from November 2020 suggests that pregnant women are at increased risk for severe illness.⁸ However, it is important to understand the design of this study in order to appreciate its implications. Laboratory confirmed SARS-CoV-2 in the United States is systematically reported to the CDC. Among women aged 15–44 years with such confirmation, data on pregnancy status were available for 35.5%, almost 90% of whom were symptomatic. Within this cohort of largely symptomatic pregnant women, risks of intensive care unit (ICU) admission, invasive ventilation, and use of extracorporeal membrane oxygenation (ECMO) were approximately 2 to 3 times higher for pregnant women than for nonpregnant women. The absolute risks, however, were low. The risk of ICU admission for symptomatic pregnant women was approximately 1%; the risk of invasive ventilation, 0.3%; and the risk of ECMO, 0.1%.

Moreover, the lack of uniform data capture on pregnancy status for all women ages 15–44 years may skew the population with known pregnancy status to be sicker and, thus, may bias the results toward increased risks. Nevertheless, there is consistency in several publications with different data sources, all of which suggest pregnancy is an independent risk factor for increased severity of COVID-19.^9-11 Additionally, women with medical comorbidities (such as pregestational or gestational diabetes or obesity) are more likely to have severe COVID-19.

Continue to: 3. What are newborn outcomes if COVID-19 is diagnosed during pregnancy?...

Two large cohorts of newborns, disproportionately term infants, from the first wave of the pandemic in New York City, have reassuring news. In one cohort of 101 infants born at 2 New York City institutions to SARS-CoV-2–positive mothers, 2 neonates were diagnosed with SARS-CoV-2 during the immediate postnatal period.¹² Neither infant demonstrated clinical COVID-19. In another cohort of 120 infants born at 3 other New York City institutions to SARS-CoV-2–positive mothers and tested systematically within 24 hours of life, 5–7 days of life, and 14 days of life, there were no neonates who tested positive for SARS-CoV-2 at the initial time point. Among the 79 infants who had testing at 5–7 days of life and the 72 tested at 14 days of life, there were no infants positive for SARS-CoV-2.¹³ It is important to note that case reports and small case series have demonstrated some convincing evidence of vertical transmission. However, the overwhelming evidence suggests this risk is very low.

4. What is a reasonable outpatient setting–approach to managing COVID-19 in a pregnant woman?

Women should be counseled to quarantine for 10 to 14 days from symptom onset or, if asymptomatic, from positive polymerase chain reaction (PCR) test. Warning signs of worsening COVID-19 disease should be reviewed. Serial telemedicine follow-up for 10 to 14 days is recommended to ensure clinical stability and continued management as an outpatient. A home pulse oximeter is also recommended. Women should be advised to check their oxygen saturation daily and to call if oxygen saturation becomes less than 93%. Supportive care is recommended.

If delay in obstetric care may result in adverse pregnancy outcomes (for instance, postponing indicated fetal surveillance), obstetric care should be delivered, with appropriate personal protective equipment for health care workers and minimization of exposure of other pregnant women to the infected patient. Appointments should be scheduled at the end of the day.

During influenza season, women should receive empiric oseltamivir treatment (75 mg twice a day) per CDC guidelines for symptoms that may also be consistent with influenza, regardless of testing.

Prophylactic anticoagulation is not indicated for pregnant antepartum women who do not require inpatient care.

If inpatient care is required, management is individualized.

The approach to prenatal care after resolution of COVID-19 is not evidence-based. At my institution, all patients have a detailed mid-trimester anatomic evaluation, but if this is not routine, a detailed anatomic ultrasound (Current Procedural Terminology code 76811) may be considered. Additionally, for women with COVID-19 we perform one third-trimester growth ultrasound to screen for fetal growth restriction, on the basis of several placental studies demonstrating clots on the fetal or maternal side of the placenta.^3,14 Routine antenatal testing in the absence of growth restriction, or other comorbid conditions for which testing occurs, is not recommended.

Continue to: 5. What if asymptomatic or mild COVID-19 is diagnosed at the time of delivery?...

5. What if asymptomatic or mild COVID-19 is diagnosed at the time of delivery? What is reasonable management?

Asymptomatic or mildly symptomatic COVID-19 should not alter obstetric management, beyond appropriate use of personal protective equipment. Delayed cord clamping is also reasonable, if there are no other contraindications, as there is no documented harm associated with this practice among women with COVID-19.

Women with COVID-19 may be at higher risk for venous thromboembolic events in the postpartum period. At my institution, prophylactic postpartum anticoagulation is recommended for 2 weeks after vaginal delivery, and 6 weeks after cesarean delivery.

During the postpartum hospitalization, given reassuring data about vertical transmission and postnatal horizontal transmission risks, babies may room in with mothers in a single private room, if rooming-in is the current standard of care—as long as the mother and newborn do not require higher levels of care. Mothers should wear a mask and use hand hygiene when in contact with the baby. Skin-to-skin and breastfeeding or infant feeding of breast milk are appropriate practices to continue. There is no evidence to suggest that transmission of COVID-19 can occur via breastmilk; however, given the close contact inherent in breastfeeding, transmission through direct contact or maternal respiratory droplets is possible, and thus maternal use of masks and hand hygiene is recommended. When not feeding, the infant should be 6 feet away, and if possible, in an isolette.

6. When can individuals with COVID-19 discontinue transmission precautions or “home quarantine”?

For women with mildly symptomatic COVID-19 and without immunocompromise, home quarantine can be discontinued 10 days after onset of symptoms as long as there has been symptom improvement and no fever for at least 24 hours without the use of antipyretics. For immunocompetent women with incidentally diagnosed asymptomatic COVID-19, home quarantine can be discontinued 10 days after the positive test was obtained. Pregnancy in and of itself is not an immunocompromising condition.^15,16

For women with severe or critical COVID-19, who were hospitalized due to their clinical status, home quarantine can be discontinued when at least 10 days, and up to 20 days, after onset of symptoms and with symptom improvement and with no fever for at least 24 hours, without the use of antipyretics. Local hospital infection control experts may be able to guide the recommended practice for your site better, based on local information.^15,16

Repeating a PCR test to discontinue home quarantine is not recommended in most circumstances, as individuals may have prolonged shedding of noninfectious particles in their nasopharynx. Immunocompromise may be one exception to this general guidance, but consultation with local hospital infection control experts will help guide management.^15,16

7. Should women get pregnant during the COVID-19 pandemic?

Every pandemic has its own set of implications for the health of the mother, fetus, or both, and COVID-19 is no exception. While there are risks, described above, to mother and fetus, these risks are not so catastrophic as to strongly and directively recommend a patient not become pregnant.¹⁷ Moreover, the last several months of the pandemic have demonstrated that consistent mask usage, social distancing, and hand hygiene, are effective methods of preventing the acquisition of COVID-19. All of these risk-reducing strategies are available to pregnant women. Finally, accessing care during a pandemic in a hospital setting does not also pose a risk for acquisition of SARS-CoV-2.¹⁸

Continue to: 8. Is the COVID-19 vaccine safe for pregnant or postpartum/lactating women?...

8. Is the COVID-19 vaccine safe for pregnant or postpartum/lactating women?

On December 11, 2020, the US Food and Drug Administration (FDA) issued emergency use authorization (EUA) for the Pfizer-BioNtech mRNA vaccine (BNT 162b2) against COVID-19, for individuals aged 16 and older as a 2-dose series given 21 days apart. Among the more than 40,000 individuals in the trial that led to this EUA, vaccine efficacy was 95%.¹⁹ Adverse effects included fatigue and headache most commonly, with 16% of vaccine recipients experiencing fever after the second dose. Follow-up regarding safety is planned for 2 years by the manufacturer, in addition to safety monitoring by pre-existing national systems.

On December 18, 2020, the FDA announced EUA for Moderna’s mRNA-based vaccine, mRNA-1273, in men and women aged 18 and older. This is a 2-dose series given 28 days apart. The vaccine efficacy has been reported at 94.5%, with the most common adverse effects being injection site pain, tiredness, headache, muscle pain, chills, joint pain, swollen lymph nodes in the same arm as the injection, nausea and vomiting, and fever.^20,21 The phase 3 trial is ongoing.

Despite the speed with which these effective vaccines were developed, it is important to note that all regulatory and safety steps mandated for the development of any vaccine were met for these two, as well as for other COVID-19 vaccinations that will similarly receive EUA from the FDA.

In the EUA for BNT 162b2, the specific language regarding pregnant and lactating women recommends that patients and providers have an individualized conversation about vaccination. In the data presented to the FDA for the Pfizer-BioNtech mRNA vaccine, a limited number of pregnant women received either the vaccine (12 women) or placebo (11 women), with no long-term follow-up data available to characterize either maternal or fetal benefits and risks. The mechanism of action of an mRNA vaccine is to induce the cytoplasmic machinery within cells to create the coronavirus spike protein, which then allows the body’s immune system to create antibodies against this protein and confer protection accordingly. While the above mechanism is not theorized to result in different outcomes or different efficacy, the safety for the pregnant woman and fetus are unknown. It is not believed that vaccination during lactation would cause any adverse outcomes to a neonate, and lactating women do not need to interrupt or discontinue breast milk production in order to receive the vaccine.

The American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory on December 13, 2020, regarding their recommendations.²² ACOG recommends that vaccines against COVID-19 not be withheld from pregnant or lactating women, if they might otherwise meet criteria for and have access to vaccination. Currently, the CDC’s Advisory Committee on Immunization Practices (ACIP) stated that health care workers and long-term care facility residents represent priority groups to vaccinate in the initial phases of vaccination, given limitations in supply.²³ This recommendation is likely to be updated frequently as additional vaccines become available. Shared decision-making between patient and provider may help the patient to make the best decision for herself, but provider input is not required prior to a pregnant woman being vaccinated.

Additional animal data evaluating adverse effects on the reproductive system from developmental and reproductive toxicity (DART) studies for both mRNA vaccines should be available in the coming weeks, which may aid in the counseling of reproductive-aged women.

Vaccine trials to specifically enroll pregnant women are set to begin in early 2021, and more data will certainly inform the conversation between patient and provider regarding risks and benefits.

Conclusions

While the absolute risks of COVID-19 to mothers, fetuses, and neonates is low, pregnancy is a risk factor for severe disease. Many pregnant women with COVID-19 can be safely followed as outpatients via telemedicine, and supportive care is recommended. Inpatient care should be individualized. Pregnancy during the COVID-19 pandemic should be not be absolutely discouraged; instead, a conversation about risk mitigation should be undertaken. The COVID-19 vaccine is available to pregnant and lactating women, and the decision to choose vaccination in pregnancy is in the purview of the patient, in consultation with her physician. ●