Errol R. Norwitz, MD, PhD

Obstetric care providers have two patients: the mother and the fetus. Although it is relatively easy to tell when the mother is unwell, determining the well-being of the fetus is far more difficult.

Several tests have been developed to confirm fetal well-being during labor. The most widely used is electronic fetal heart rate monitoring (EFM), also referred to as fetal cardiotocography. EFM was introduced by Hon and Lee in the 1960s, and is now the most common obstetric procedure in the United States.^1,2 It is noninvasive, simple to perform, inexpensive, and readily available in almost all obstetric units. However, despite our best efforts, we have little objective evidence that EFM has improved perinatal outcomes.

A 2006 Cochrane review of 12 randomized, controlled trials (RCTs) involving more than 37,000 women concluded that, compared with intermittent auscultation—the only acceptable control because randomization to no intrapartum monitoring would be unethical—the only benefit of intrapartum EFM was a reduction in the incidence of seizures in the early neonatal period (the number needed to treat to prevent one event was 661). However, this finding did not translate into a diminished risk of seizures after the first week of life. There was otherwise no significant difference in perinatal outcomes, including no difference in the rates of cerebral palsy or death, although EFM was associated with an increased risk of obstetric intervention and operative delivery.³

It is this contradiction between the almost routine use of intrapartum EFM in the United States and the lack of evidence supporting its use that the authors hoped to address in their analysis.

What did Chen et al find?

In the lead-up to their analysis, the authors make a compelling argument that the existing data—including the 12 RCTs summarized in the Cochrane review³—are flawed. They raise specific concerns about such issues as “low-quality” study design, insufficient data in low-risk populations, and the use of pathologic antecedents (such as newborn encephalopathy) instead of cerebral palsy as a clinical endpoint. These are all reasonable and valid critiques.

So how did Chen and colleagues proceed? Did they design and execute a high-quality prospective study to address these issues? Did they reanalyze the existing RCTs using more sophisticated statistical methodology in an effort to correct for these deficiencies?

They did neither. They simply carried out another retrospective study using a large but poorly validated data set. In doing so, they transgressed and indeed aggravated all of the concerns they themselves raised about the existing literature. Specifically:

• Their retrospective analysis is a far inferior study design, compared with the RCTs they criticized
• Their efforts to distinguish between high-risk and low-risk pregnancies were rudimentary at best and relied on reported birth/death certificate data, which—as the authors themselves and the accompanying editorial concede⁴—is a notoriously unreliable source
• They made no effort to look at any medium- or long-term measures of neurologic injury.

The observation that EFM was associated with a decreased risk of neonatal seizures and 5-minute Apgar scores below 4 is not novel. Neither is the observation that EFM is associated with an increased risk of operative delivery—both cesarean and operative vaginal delivery. The only novel observation in this study is that, in a cohort of 1.7 million singleton pregnancies, EFM appeared to be associated with a decrease in the risk of early neonatal death (defined as death within the first 6 days of life), although no such association was noted for deaths in the late neonatal (7–27 days) or postneonatal (28–364 days) periods.

Limitations of the study design

RCTs remain the gold standard for clinical trials, and for good reason. The absence of randomization in the current study poses significant limitations. It prevents us from understanding why some women received intrapartum EFM while others did not. This makes it impossible to determine if we are comparing two equal groups, a limitation that cannot be overcome even with the most elegant of statistical analyses.

More concerning, however, is the lack of an adequate control group. The authors conclude that “the use of electronic fetal heart rate monitoring was associated with a substantial decrease in early neonatal mortality and morbidity.” This begs the question: compared with what? In the numerous RCTs on this topic, intrapartum EFM was compared head-to-head with a standardized protocol of intermittent auscultation, whereas the comparison group in the current study was women who did not receive EFM.³ Stated differently, the absence of EFM is not equivalent to intermittent auscultation. An alternative and, in my opinion, far more likely explanation for the observed difference in mortality is that the current study compares women who received intrapartum EFM with those who simply had inadequate fetal monitoring in labor. And I am not aware of any report or, for that matter, any obstetric care provider who believes that it is unnecessary to monitor fetal well-being in labor.

The conclusion of this study should have been that adequate monitoring of the fetus in labor can prevent early neonatal death, not that adequate monitoring of the fetus in labor with EFM can prevent early neonatal death. Moreover, the authors’ attempt to deflect this issue by referring to the current study as an example of “reality-based medicine” as opposed to “evidence-based medicine” undermines the very foundation of scientific investigation.

More questions than answers

The major conclusion of this study is that EFM protects against early neonatal death. So why is there no information about cause of death? These data should be readily available from a linked birth/death certificate data set. Such information might help to determine whether the excess early neonatal deaths were related to EFM or, more likely, to other variables surrounding or related to the delivery, such as the inability to perform an emergency cesarean, if indicated, or the lack of providers skilled in neonatal resuscitation.

We want to hear from you!  Tell us what you think.

Obstetric care providers have two patients: the mother and the fetus. Although it is relatively easy to tell when the mother is unwell, determining the well-being of the fetus is far more difficult.

Several tests have been developed to confirm fetal well-being during labor. The most widely used is electronic fetal heart rate monitoring (EFM), also referred to as fetal cardiotocography. EFM was introduced by Hon and Lee in the 1960s, and is now the most common obstetric procedure in the United States.^1,2 It is noninvasive, simple to perform, inexpensive, and readily available in almost all obstetric units. However, despite our best efforts, we have little objective evidence that EFM has improved perinatal outcomes.

A 2006 Cochrane review of 12 randomized, controlled trials (RCTs) involving more than 37,000 women concluded that, compared with intermittent auscultation—the only acceptable control because randomization to no intrapartum monitoring would be unethical—the only benefit of intrapartum EFM was a reduction in the incidence of seizures in the early neonatal period (the number needed to treat to prevent one event was 661). However, this finding did not translate into a diminished risk of seizures after the first week of life. There was otherwise no significant difference in perinatal outcomes, including no difference in the rates of cerebral palsy or death, although EFM was associated with an increased risk of obstetric intervention and operative delivery.³

It is this contradiction between the almost routine use of intrapartum EFM in the United States and the lack of evidence supporting its use that the authors hoped to address in their analysis.

What did Chen et al find?

In the lead-up to their analysis, the authors make a compelling argument that the existing data—including the 12 RCTs summarized in the Cochrane review³—are flawed. They raise specific concerns about such issues as “low-quality” study design, insufficient data in low-risk populations, and the use of pathologic antecedents (such as newborn encephalopathy) instead of cerebral palsy as a clinical endpoint. These are all reasonable and valid critiques.

So how did Chen and colleagues proceed? Did they design and execute a high-quality prospective study to address these issues? Did they reanalyze the existing RCTs using more sophisticated statistical methodology in an effort to correct for these deficiencies?

They did neither. They simply carried out another retrospective study using a large but poorly validated data set. In doing so, they transgressed and indeed aggravated all of the concerns they themselves raised about the existing literature. Specifically:

• Their retrospective analysis is a far inferior study design, compared with the RCTs they criticized
• Their efforts to distinguish between high-risk and low-risk pregnancies were rudimentary at best and relied on reported birth/death certificate data, which—as the authors themselves and the accompanying editorial concede⁴—is a notoriously unreliable source
• They made no effort to look at any medium- or long-term measures of neurologic injury.

The observation that EFM was associated with a decreased risk of neonatal seizures and 5-minute Apgar scores below 4 is not novel. Neither is the observation that EFM is associated with an increased risk of operative delivery—both cesarean and operative vaginal delivery. The only novel observation in this study is that, in a cohort of 1.7 million singleton pregnancies, EFM appeared to be associated with a decrease in the risk of early neonatal death (defined as death within the first 6 days of life), although no such association was noted for deaths in the late neonatal (7–27 days) or postneonatal (28–364 days) periods.

Limitations of the study design

RCTs remain the gold standard for clinical trials, and for good reason. The absence of randomization in the current study poses significant limitations. It prevents us from understanding why some women received intrapartum EFM while others did not. This makes it impossible to determine if we are comparing two equal groups, a limitation that cannot be overcome even with the most elegant of statistical analyses.

More concerning, however, is the lack of an adequate control group. The authors conclude that “the use of electronic fetal heart rate monitoring was associated with a substantial decrease in early neonatal mortality and morbidity.” This begs the question: compared with what? In the numerous RCTs on this topic, intrapartum EFM was compared head-to-head with a standardized protocol of intermittent auscultation, whereas the comparison group in the current study was women who did not receive EFM.³ Stated differently, the absence of EFM is not equivalent to intermittent auscultation. An alternative and, in my opinion, far more likely explanation for the observed difference in mortality is that the current study compares women who received intrapartum EFM with those who simply had inadequate fetal monitoring in labor. And I am not aware of any report or, for that matter, any obstetric care provider who believes that it is unnecessary to monitor fetal well-being in labor.

The conclusion of this study should have been that adequate monitoring of the fetus in labor can prevent early neonatal death, not that adequate monitoring of the fetus in labor with EFM can prevent early neonatal death. Moreover, the authors’ attempt to deflect this issue by referring to the current study as an example of “reality-based medicine” as opposed to “evidence-based medicine” undermines the very foundation of scientific investigation.

More questions than answers

The major conclusion of this study is that EFM protects against early neonatal death. So why is there no information about cause of death? These data should be readily available from a linked birth/death certificate data set. Such information might help to determine whether the excess early neonatal deaths were related to EFM or, more likely, to other variables surrounding or related to the delivery, such as the inability to perform an emergency cesarean, if indicated, or the lack of providers skilled in neonatal resuscitation.

We want to hear from you!  Tell us what you think.

Obstetric care providers have two patients: the mother and the fetus. Although it is relatively easy to tell when the mother is unwell, determining the well-being of the fetus is far more difficult.

Several tests have been developed to confirm fetal well-being during labor. The most widely used is electronic fetal heart rate monitoring (EFM), also referred to as fetal cardiotocography. EFM was introduced by Hon and Lee in the 1960s, and is now the most common obstetric procedure in the United States.^1,2 It is noninvasive, simple to perform, inexpensive, and readily available in almost all obstetric units. However, despite our best efforts, we have little objective evidence that EFM has improved perinatal outcomes.

A 2006 Cochrane review of 12 randomized, controlled trials (RCTs) involving more than 37,000 women concluded that, compared with intermittent auscultation—the only acceptable control because randomization to no intrapartum monitoring would be unethical—the only benefit of intrapartum EFM was a reduction in the incidence of seizures in the early neonatal period (the number needed to treat to prevent one event was 661). However, this finding did not translate into a diminished risk of seizures after the first week of life. There was otherwise no significant difference in perinatal outcomes, including no difference in the rates of cerebral palsy or death, although EFM was associated with an increased risk of obstetric intervention and operative delivery.³

It is this contradiction between the almost routine use of intrapartum EFM in the United States and the lack of evidence supporting its use that the authors hoped to address in their analysis.

What did Chen et al find?

In the lead-up to their analysis, the authors make a compelling argument that the existing data—including the 12 RCTs summarized in the Cochrane review³—are flawed. They raise specific concerns about such issues as “low-quality” study design, insufficient data in low-risk populations, and the use of pathologic antecedents (such as newborn encephalopathy) instead of cerebral palsy as a clinical endpoint. These are all reasonable and valid critiques.

So how did Chen and colleagues proceed? Did they design and execute a high-quality prospective study to address these issues? Did they reanalyze the existing RCTs using more sophisticated statistical methodology in an effort to correct for these deficiencies?

They did neither. They simply carried out another retrospective study using a large but poorly validated data set. In doing so, they transgressed and indeed aggravated all of the concerns they themselves raised about the existing literature. Specifically:

• Their retrospective analysis is a far inferior study design, compared with the RCTs they criticized
• Their efforts to distinguish between high-risk and low-risk pregnancies were rudimentary at best and relied on reported birth/death certificate data, which—as the authors themselves and the accompanying editorial concede⁴—is a notoriously unreliable source
• They made no effort to look at any medium- or long-term measures of neurologic injury.

The observation that EFM was associated with a decreased risk of neonatal seizures and 5-minute Apgar scores below 4 is not novel. Neither is the observation that EFM is associated with an increased risk of operative delivery—both cesarean and operative vaginal delivery. The only novel observation in this study is that, in a cohort of 1.7 million singleton pregnancies, EFM appeared to be associated with a decrease in the risk of early neonatal death (defined as death within the first 6 days of life), although no such association was noted for deaths in the late neonatal (7–27 days) or postneonatal (28–364 days) periods.

Limitations of the study design

RCTs remain the gold standard for clinical trials, and for good reason. The absence of randomization in the current study poses significant limitations. It prevents us from understanding why some women received intrapartum EFM while others did not. This makes it impossible to determine if we are comparing two equal groups, a limitation that cannot be overcome even with the most elegant of statistical analyses.

More concerning, however, is the lack of an adequate control group. The authors conclude that “the use of electronic fetal heart rate monitoring was associated with a substantial decrease in early neonatal mortality and morbidity.” This begs the question: compared with what? In the numerous RCTs on this topic, intrapartum EFM was compared head-to-head with a standardized protocol of intermittent auscultation, whereas the comparison group in the current study was women who did not receive EFM.³ Stated differently, the absence of EFM is not equivalent to intermittent auscultation. An alternative and, in my opinion, far more likely explanation for the observed difference in mortality is that the current study compares women who received intrapartum EFM with those who simply had inadequate fetal monitoring in labor. And I am not aware of any report or, for that matter, any obstetric care provider who believes that it is unnecessary to monitor fetal well-being in labor.

The conclusion of this study should have been that adequate monitoring of the fetus in labor can prevent early neonatal death, not that adequate monitoring of the fetus in labor with EFM can prevent early neonatal death. Moreover, the authors’ attempt to deflect this issue by referring to the current study as an example of “reality-based medicine” as opposed to “evidence-based medicine” undermines the very foundation of scientific investigation.

More questions than answers

The major conclusion of this study is that EFM protects against early neonatal death. So why is there no information about cause of death? These data should be readily available from a linked birth/death certificate data set. Such information might help to determine whether the excess early neonatal deaths were related to EFM or, more likely, to other variables surrounding or related to the delivery, such as the inability to perform an emergency cesarean, if indicated, or the lack of providers skilled in neonatal resuscitation.

We want to hear from you!  Tell us what you think.

CP is heterogeneous in both its clinical manifestations and its causation. It is now clear that no more than 10% of all cases result from intrapartum injury.^1-3 The vast majority of cases (>90%) arise from circumstances unrelated to labor. Among the variables associated with CP are antepartum entities such as developmental abnormality, metabolic derangement, genetic disorders, infection or inflammation, antepartum hemorrhage (with or without a recognized coagulation disorder), and autoimmune disease. Even postnatal events within the first few years of life may be implicated, including complications of prematurity or postmaturity, trauma, and infection.

It has long been known from case series, case-control studies, cohort studies, and at least two earlier meta-analyses^4,5 that a diagnosis of intrauterine infection (chorioamnionitis) during pregnancy—whether made by clinical examination, histologic examination of the placenta, or amniotic fluid culture—is associated with an increased risk of CP. (These data are reviewed in a joint statement by ACOG and the American Academy of Pediatrics on the pathogenesis of neonatal encephalopathy and CP.²)

This new meta-analysis by Shatrov and colleagues confirms the association between chorioamnionitis and CP. Other than that, it adds little to the existing literature and provides no additional information for clinicians on how to manage high-risk patients.

Inflammation may be the real culprit

The association between intrauterine infection and neurologic injury in offspring (including CP) is almost certainly causal. Using a rabbit model, Yoon and coworkers demonstrated that intrauterine infection leads to white matter lesions in the fetal brain that closely resemble the lesions of infection-associated CP seen in the human infant.⁶ Similar observations have been made in mice and pigs.

The mechanisms underlying these end-organ injuries are not well understood, but the weight of evidence suggests that they are an indirect result of the pro-inflammatory cascade triggered to subdue the infection, rather than a direct effect of the infectious organisms themselves.^7,8 Therefore, it may be more accurate to refer to an association between CP and intra-amniotic inflammation rather than intra-amniotic infection.

Increasing evidence suggests that it is low-grade chronic inflammation that leads to neurologic injury rather than acute infection.^9,10 Clinicians should find this evidence reassuring because it suggests that we are doing our patients no harm when we recommend, for example, expectant management for ruptured membranes remote from term or induction of labor rather than urgent cesarean in the setting of confirmed intraamniotic infection.

Can CP be prevented?

A number of interventions have been proposed in an effort to prevent CP, with variable results. They include selective administration of antenatal corticosteroids or magnesium sulfate, elective cesarean delivery, and neonatal hypothermia therapy. Broad-spectrum antibiotics are routinely administered to women who have intra-amniotic infection, primarily to prevent the spread of infection beyond the uterus. If intrauterine infection is causally related to brain injury, can such antibiotic therapy prevent CP?

There is no evidence that antibiotics can protect against neurologic injury. In fact, antibiotics can be detrimental, according to a recent 7-year follow-up of the ORACLE-II randomized clinical trial, which was designed to investigate the effect of broad-spectrum antibiotics on perinatal outcome in women who have preterm labor and intact membranes.¹¹ In this study, fetuses exposed to broad-spectrum antibiotics had a significantly higher risk of CP at age 7 years, with an adjusted odds ratio (OR) of 1.93 for erythromycin (95% CI, 1.21–3.09) and 1.69 for co-amoxiclav (95% CI, 1.07–2.67). Fetuses randomized to receive both antibiotics had an even higher risk of CP. The incidence of CP was 4.55% among these fetuses, compared with 1.97% among those receiving co-amoxiclav alone, 2.29% for those receiving erythromycin alone, and 1.63% for those randomized to the placebo group.

The mechanism of injury is not clear, but it may be that antibiotics may suppress infection and delay delivery, thereby prolonging the fetus’s sojourn in a hostile, pro-inflammatory intrauterine milieu.

If neurologic injury is indeed the result of inflammation rather than infection, then anti-inflammatory agents, such as corticosteroids, cyclooxygenase inhibitors, and N-acetylcysteine—alone or in combination with antibiotics—may prevent neurologic injury in the setting of intrauterine infection. Studies into this possibility are under way, and the results are eagerly awaited.

We want to hear from you! Tell us what you think.

CP is heterogeneous in both its clinical manifestations and its causation. It is now clear that no more than 10% of all cases result from intrapartum injury.^1-3 The vast majority of cases (>90%) arise from circumstances unrelated to labor. Among the variables associated with CP are antepartum entities such as developmental abnormality, metabolic derangement, genetic disorders, infection or inflammation, antepartum hemorrhage (with or without a recognized coagulation disorder), and autoimmune disease. Even postnatal events within the first few years of life may be implicated, including complications of prematurity or postmaturity, trauma, and infection.

It has long been known from case series, case-control studies, cohort studies, and at least two earlier meta-analyses^4,5 that a diagnosis of intrauterine infection (chorioamnionitis) during pregnancy—whether made by clinical examination, histologic examination of the placenta, or amniotic fluid culture—is associated with an increased risk of CP. (These data are reviewed in a joint statement by ACOG and the American Academy of Pediatrics on the pathogenesis of neonatal encephalopathy and CP.²)

This new meta-analysis by Shatrov and colleagues confirms the association between chorioamnionitis and CP. Other than that, it adds little to the existing literature and provides no additional information for clinicians on how to manage high-risk patients.

Inflammation may be the real culprit

The association between intrauterine infection and neurologic injury in offspring (including CP) is almost certainly causal. Using a rabbit model, Yoon and coworkers demonstrated that intrauterine infection leads to white matter lesions in the fetal brain that closely resemble the lesions of infection-associated CP seen in the human infant.⁶ Similar observations have been made in mice and pigs.

The mechanisms underlying these end-organ injuries are not well understood, but the weight of evidence suggests that they are an indirect result of the pro-inflammatory cascade triggered to subdue the infection, rather than a direct effect of the infectious organisms themselves.^7,8 Therefore, it may be more accurate to refer to an association between CP and intra-amniotic inflammation rather than intra-amniotic infection.

Increasing evidence suggests that it is low-grade chronic inflammation that leads to neurologic injury rather than acute infection.^9,10 Clinicians should find this evidence reassuring because it suggests that we are doing our patients no harm when we recommend, for example, expectant management for ruptured membranes remote from term or induction of labor rather than urgent cesarean in the setting of confirmed intraamniotic infection.

Can CP be prevented?

A number of interventions have been proposed in an effort to prevent CP, with variable results. They include selective administration of antenatal corticosteroids or magnesium sulfate, elective cesarean delivery, and neonatal hypothermia therapy. Broad-spectrum antibiotics are routinely administered to women who have intra-amniotic infection, primarily to prevent the spread of infection beyond the uterus. If intrauterine infection is causally related to brain injury, can such antibiotic therapy prevent CP?

There is no evidence that antibiotics can protect against neurologic injury. In fact, antibiotics can be detrimental, according to a recent 7-year follow-up of the ORACLE-II randomized clinical trial, which was designed to investigate the effect of broad-spectrum antibiotics on perinatal outcome in women who have preterm labor and intact membranes.¹¹ In this study, fetuses exposed to broad-spectrum antibiotics had a significantly higher risk of CP at age 7 years, with an adjusted odds ratio (OR) of 1.93 for erythromycin (95% CI, 1.21–3.09) and 1.69 for co-amoxiclav (95% CI, 1.07–2.67). Fetuses randomized to receive both antibiotics had an even higher risk of CP. The incidence of CP was 4.55% among these fetuses, compared with 1.97% among those receiving co-amoxiclav alone, 2.29% for those receiving erythromycin alone, and 1.63% for those randomized to the placebo group.

The mechanism of injury is not clear, but it may be that antibiotics may suppress infection and delay delivery, thereby prolonging the fetus’s sojourn in a hostile, pro-inflammatory intrauterine milieu.

If neurologic injury is indeed the result of inflammation rather than infection, then anti-inflammatory agents, such as corticosteroids, cyclooxygenase inhibitors, and N-acetylcysteine—alone or in combination with antibiotics—may prevent neurologic injury in the setting of intrauterine infection. Studies into this possibility are under way, and the results are eagerly awaited.

We want to hear from you! Tell us what you think.

CP is heterogeneous in both its clinical manifestations and its causation. It is now clear that no more than 10% of all cases result from intrapartum injury.^1-3 The vast majority of cases (>90%) arise from circumstances unrelated to labor. Among the variables associated with CP are antepartum entities such as developmental abnormality, metabolic derangement, genetic disorders, infection or inflammation, antepartum hemorrhage (with or without a recognized coagulation disorder), and autoimmune disease. Even postnatal events within the first few years of life may be implicated, including complications of prematurity or postmaturity, trauma, and infection.

It has long been known from case series, case-control studies, cohort studies, and at least two earlier meta-analyses^4,5 that a diagnosis of intrauterine infection (chorioamnionitis) during pregnancy—whether made by clinical examination, histologic examination of the placenta, or amniotic fluid culture—is associated with an increased risk of CP. (These data are reviewed in a joint statement by ACOG and the American Academy of Pediatrics on the pathogenesis of neonatal encephalopathy and CP.²)

This new meta-analysis by Shatrov and colleagues confirms the association between chorioamnionitis and CP. Other than that, it adds little to the existing literature and provides no additional information for clinicians on how to manage high-risk patients.

Inflammation may be the real culprit

The association between intrauterine infection and neurologic injury in offspring (including CP) is almost certainly causal. Using a rabbit model, Yoon and coworkers demonstrated that intrauterine infection leads to white matter lesions in the fetal brain that closely resemble the lesions of infection-associated CP seen in the human infant.⁶ Similar observations have been made in mice and pigs.

The mechanisms underlying these end-organ injuries are not well understood, but the weight of evidence suggests that they are an indirect result of the pro-inflammatory cascade triggered to subdue the infection, rather than a direct effect of the infectious organisms themselves.^7,8 Therefore, it may be more accurate to refer to an association between CP and intra-amniotic inflammation rather than intra-amniotic infection.

Increasing evidence suggests that it is low-grade chronic inflammation that leads to neurologic injury rather than acute infection.^9,10 Clinicians should find this evidence reassuring because it suggests that we are doing our patients no harm when we recommend, for example, expectant management for ruptured membranes remote from term or induction of labor rather than urgent cesarean in the setting of confirmed intraamniotic infection.

Can CP be prevented?

A number of interventions have been proposed in an effort to prevent CP, with variable results. They include selective administration of antenatal corticosteroids or magnesium sulfate, elective cesarean delivery, and neonatal hypothermia therapy. Broad-spectrum antibiotics are routinely administered to women who have intra-amniotic infection, primarily to prevent the spread of infection beyond the uterus. If intrauterine infection is causally related to brain injury, can such antibiotic therapy prevent CP?

There is no evidence that antibiotics can protect against neurologic injury. In fact, antibiotics can be detrimental, according to a recent 7-year follow-up of the ORACLE-II randomized clinical trial, which was designed to investigate the effect of broad-spectrum antibiotics on perinatal outcome in women who have preterm labor and intact membranes.¹¹ In this study, fetuses exposed to broad-spectrum antibiotics had a significantly higher risk of CP at age 7 years, with an adjusted odds ratio (OR) of 1.93 for erythromycin (95% CI, 1.21–3.09) and 1.69 for co-amoxiclav (95% CI, 1.07–2.67). Fetuses randomized to receive both antibiotics had an even higher risk of CP. The incidence of CP was 4.55% among these fetuses, compared with 1.97% among those receiving co-amoxiclav alone, 2.29% for those receiving erythromycin alone, and 1.63% for those randomized to the placebo group.

The mechanism of injury is not clear, but it may be that antibiotics may suppress infection and delay delivery, thereby prolonging the fetus’s sojourn in a hostile, pro-inflammatory intrauterine milieu.

If neurologic injury is indeed the result of inflammation rather than infection, then anti-inflammatory agents, such as corticosteroids, cyclooxygenase inhibitors, and N-acetylcysteine—alone or in combination with antibiotics—may prevent neurologic injury in the setting of intrauterine infection. Studies into this possibility are under way, and the results are eagerly awaited.

We want to hear from you! Tell us what you think.

Objective

To determine whether weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) reduce the risk of preterm delivery in women with a documented history of spontaneous preterm delivery.

Methods And Results

In this double-blind, placebo-controlled trial, researchers randomly assigned 463 patients at high risk for preterm delivery to receive weekly intramuscular injections of 17P (250 mg) or placebo from 16 to 20 weeks of gestation through 36 weeks. Outcome data were available for 459 women (99.1%).

Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks’ gestation: Incidence was 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk, 0.66; 95% confidence interval, 0.54 to 0.81). It also reduced the risk of delivery at less than 35 weeks and less than 32 weeks. Infants of women treated with the compound had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. There was no significant difference in miscarriage or stillbirth rates.

Who May Be Affected By These Findings?

Gravidas at high risk for preterm delivery.

Expert Commentary

Although we have improved our ability to identify women at risk, we have not been successful at preventing preterm birth—indeed, its incidence is actually rising, due primarily to increased use of assisted reproductive technology. Preterm birth complicates approximately 12% of deliveries, but accounts for more than 85% of perinatal morbidity and mortality.^1,2

The study by Meis and colleagues is a well-designed and well-executed randomized, double-blind, placebo-controlled, multicenter trial. Compliance with designated therapy was reported as 91.5%. The preterm delivery rate of 54.9% in the control group confirms that this cohort is indeed at high risk of preterm birth (see “Why progesterone?”).

I have only 1 minor criticism: The authors chose to deliver the drug via weekly intramuscular injections, which may not be a desirable route of administration for many women. Half of the women (231 of 463) reported at least 1 adverse effect, though most of these were minor local reactions at the injection site.

The authors found no evidence of teratogenicity—of note, no virilization of female offspring, which was a theoretic concern.

Findings apply only to high-risk gravidas. More study is required to determine whether progesterone supplementation can reduce preterm birth in low-risk women. This is important because most preterm births occur in patients with no identifiable risk factors.

The results of this study are consistent with prior publications.^8,9 In a similar recent trial carried out in Brazil, 142 women at high risk for preterm birth were randomized to receive daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.⁹ The preterm delivery rate was significantly lower in the progesterone group, as was the rate of delivery before 34 weeks. By monitoring patients with an external tocodynamometer once a week for 60 minutes, researchers also were able to demonstrate a significant difference in spontaneous uterine contractions between the groups, suggesting that progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.

Bottom Line

Progesterone supplementation to prevent preterm birth remains investigational. Further studies are needed to evaluate its effectiveness in decreasing preterm delivery rates in high- and low-risk populations and to better understand its mechanism of action.

Given the absence of proven alternatives, however, it may be appropriate to offer such treatment to patients at highest risk for early preterm birth, such as those with higher-order multifetal pregnancies or a history of recurrent preterm deliveries. Evidence is insufficient to recommend progesterone treatment for women presenting in acute preterm labor.

Objective

To determine whether weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) reduce the risk of preterm delivery in women with a documented history of spontaneous preterm delivery.

Methods And Results

In this double-blind, placebo-controlled trial, researchers randomly assigned 463 patients at high risk for preterm delivery to receive weekly intramuscular injections of 17P (250 mg) or placebo from 16 to 20 weeks of gestation through 36 weeks. Outcome data were available for 459 women (99.1%).

Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks’ gestation: Incidence was 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk, 0.66; 95% confidence interval, 0.54 to 0.81). It also reduced the risk of delivery at less than 35 weeks and less than 32 weeks. Infants of women treated with the compound had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. There was no significant difference in miscarriage or stillbirth rates.

Who May Be Affected By These Findings?

Gravidas at high risk for preterm delivery.

Expert Commentary

Although we have improved our ability to identify women at risk, we have not been successful at preventing preterm birth—indeed, its incidence is actually rising, due primarily to increased use of assisted reproductive technology. Preterm birth complicates approximately 12% of deliveries, but accounts for more than 85% of perinatal morbidity and mortality.^1,2

The study by Meis and colleagues is a well-designed and well-executed randomized, double-blind, placebo-controlled, multicenter trial. Compliance with designated therapy was reported as 91.5%. The preterm delivery rate of 54.9% in the control group confirms that this cohort is indeed at high risk of preterm birth (see “Why progesterone?”).

I have only 1 minor criticism: The authors chose to deliver the drug via weekly intramuscular injections, which may not be a desirable route of administration for many women. Half of the women (231 of 463) reported at least 1 adverse effect, though most of these were minor local reactions at the injection site.

The authors found no evidence of teratogenicity—of note, no virilization of female offspring, which was a theoretic concern.

Findings apply only to high-risk gravidas. More study is required to determine whether progesterone supplementation can reduce preterm birth in low-risk women. This is important because most preterm births occur in patients with no identifiable risk factors.

The results of this study are consistent with prior publications.^8,9 In a similar recent trial carried out in Brazil, 142 women at high risk for preterm birth were randomized to receive daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.⁹ The preterm delivery rate was significantly lower in the progesterone group, as was the rate of delivery before 34 weeks. By monitoring patients with an external tocodynamometer once a week for 60 minutes, researchers also were able to demonstrate a significant difference in spontaneous uterine contractions between the groups, suggesting that progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.

Bottom Line

Progesterone supplementation to prevent preterm birth remains investigational. Further studies are needed to evaluate its effectiveness in decreasing preterm delivery rates in high- and low-risk populations and to better understand its mechanism of action.

Given the absence of proven alternatives, however, it may be appropriate to offer such treatment to patients at highest risk for early preterm birth, such as those with higher-order multifetal pregnancies or a history of recurrent preterm deliveries. Evidence is insufficient to recommend progesterone treatment for women presenting in acute preterm labor.

Objective

To determine whether weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) reduce the risk of preterm delivery in women with a documented history of spontaneous preterm delivery.

Methods And Results

In this double-blind, placebo-controlled trial, researchers randomly assigned 463 patients at high risk for preterm delivery to receive weekly intramuscular injections of 17P (250 mg) or placebo from 16 to 20 weeks of gestation through 36 weeks. Outcome data were available for 459 women (99.1%).

Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks’ gestation: Incidence was 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk, 0.66; 95% confidence interval, 0.54 to 0.81). It also reduced the risk of delivery at less than 35 weeks and less than 32 weeks. Infants of women treated with the compound had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. There was no significant difference in miscarriage or stillbirth rates.

Who May Be Affected By These Findings?

Gravidas at high risk for preterm delivery.

Expert Commentary

Although we have improved our ability to identify women at risk, we have not been successful at preventing preterm birth—indeed, its incidence is actually rising, due primarily to increased use of assisted reproductive technology. Preterm birth complicates approximately 12% of deliveries, but accounts for more than 85% of perinatal morbidity and mortality.^1,2

The study by Meis and colleagues is a well-designed and well-executed randomized, double-blind, placebo-controlled, multicenter trial. Compliance with designated therapy was reported as 91.5%. The preterm delivery rate of 54.9% in the control group confirms that this cohort is indeed at high risk of preterm birth (see “Why progesterone?”).

I have only 1 minor criticism: The authors chose to deliver the drug via weekly intramuscular injections, which may not be a desirable route of administration for many women. Half of the women (231 of 463) reported at least 1 adverse effect, though most of these were minor local reactions at the injection site.

The authors found no evidence of teratogenicity—of note, no virilization of female offspring, which was a theoretic concern.

Findings apply only to high-risk gravidas. More study is required to determine whether progesterone supplementation can reduce preterm birth in low-risk women. This is important because most preterm births occur in patients with no identifiable risk factors.

The results of this study are consistent with prior publications.^8,9 In a similar recent trial carried out in Brazil, 142 women at high risk for preterm birth were randomized to receive daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.⁹ The preterm delivery rate was significantly lower in the progesterone group, as was the rate of delivery before 34 weeks. By monitoring patients with an external tocodynamometer once a week for 60 minutes, researchers also were able to demonstrate a significant difference in spontaneous uterine contractions between the groups, suggesting that progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.

Bottom Line

Progesterone supplementation to prevent preterm birth remains investigational. Further studies are needed to evaluate its effectiveness in decreasing preterm delivery rates in high- and low-risk populations and to better understand its mechanism of action.

Given the absence of proven alternatives, however, it may be appropriate to offer such treatment to patients at highest risk for early preterm birth, such as those with higher-order multifetal pregnancies or a history of recurrent preterm deliveries. Evidence is insufficient to recommend progesterone treatment for women presenting in acute preterm labor.

THE QUESTION:
Is insulin pump therapy safe and effective for maintaining glycemic control in women with gestational diabetes mellitus (GDM) or type 2 diabetes requiring large doses of insulin?

Past studies:

These have shown that insulin pumps have been well tolerated in gravidas with type 1 diabetes. However, there has been no substantial evidence on the use of insulin pumps in patients with GDM or type 2 diabetes. For these gravidas, the current standard of care is to monitor glucose levels 4 times per day and to administer regular insulin injections several times a day, as required.

This study:

Gravidas with GDM or type 2 diabetes were examined over a 4-year period. Parturients on insulin pump therapy were compared to gravidas who did not use an insulin pump. Patients were matched for ethnicity and diabetes type and monitored at a hospital in New Zealand. Of 251 Polynesian, European, and South Asian women, 30 used an insulin pump. None of the patients experienced severe hypoglycemia and 79% had improved glycemic control within 1 to 4 weeks. However, 2 women discontinued pump therapy.

Gravidas using a pump had greater insulin requirements than those not using a pump (median maximum 246 units/day and 130 units/day, respectively) and greater maternal weight gain (10.6 kg and 5.0 kg, respectively). Infants of mothers using insulin pumps were more likely to be admitted to the neonatal care unit, but were neither significantly heavier nor more likely to experience hypoglycemia than control subjects.

Find this study:

December 2001 issue of Diabetes Care; abstract online at www.diabetes.org/diabetescare.

Who may be affected by these findings?

Parturients with GDM or type 2 diabetes.

Expert commentary:

This study addresses an important clinical issue: Although insulin pumps are safe and effective for use in gravidas with type 1 diabetes, it is not clear whether they should be used in women with GDM or type 2 diabetes. Unfortunately, this study does little to clarify this issue. As the authors point out, this was not a clinical trial, but rather a “service audit.” As such, only 2 conclusions can be reasonably extracted from the reported data. First, there were no serious adverse events in gravidas using the insulin pump. Second, an improvement in glycemic control was evident in all 14 women for whom results of self-glucose monitoring was available both before and after initiation of pump therapy. However, it is likely that this improvement was not a result of the pump, but rather of improved overall obstetric care, including more intensive glycemic monitoring and more aggressive insulin dosing.

To consider the use of insulin pumps in gravidas with GDM or type 2 diabetes, researchers must seek to answer the following:

• Are pumps safe in this population?
• Do pumps effectively control blood sugar, decrease the incidence of fetal macrosomia and/or cesarean delivery, and prevent such complications as shoulder dystocia?
• How does pump therapy compare to current regimens of subcutaneous insulin injections?
• Are patients more or less satisfied?

Potential advantages of the insulin pump over subcutaneous insulin include fewer injections, a continuous insulin infusion, and improved patient satisfaction, which could lead to improved compliance. A possible disadvantage of the pump may be infection at the injection site.

Caveats:

This study is marred by several major methodological, statistical, and reporting errors, which include the following:

• The cases and controls were not correctly assigned. One woman was treated with the insulin pump in 2 pregnancies and included in the analysis twice. Controls included women with “preexisting tablet-treated type 2 diabetes,” whereas all cases were treated with insulin. Seven women with type 1 diabetes also were treated with insulin pumps, but it is not clear from the text whether or not these women were included in the analysis.
• Gravidas with GDM or type 2 diabetes were seen monthly until 28 weeks’ gestation, fortnightly until 36 weeks’ gestation, and then weekly until term. By U.S. standards, this represents suboptimal antenatal care for high-risk women.
• There was no power analysis, but it is likely that the study lacked the patient numbers to draw any conclusions about the use of insulin pump therapy in this patient cohort.
• There was a “lack of quality measures of hypoglycemia.” Researchers stated that “problems with precision and reporting were frequently demonstrated by inconsistencies between laboratory and self-glucose monitoring results.”

The bottom line:

Given the difference in pathophysiology between type 1 diabetes (due to an absolute deficiency of insulin) and GDM or type 2 diabetes (characterized by increased peripheral resistance to circulating insulin), extrapolation from gravidas with type 1 diabetes may not be valid. Well-designed, prospective, clinical trials are still needed to assess the value of insulin pump therapy in parturients exclusively suffering from GDM or type 2 diabetes. Future studies will likely demonstrate that insulin pumps are equally—if not more—effective in achieving adequate glycemic control in such women as compared with the current regimen of regular subcutaneous insulin injections. Until such studies are available, parturients with GDM or type 2 diabetes may be managed with intermittent self-administered subcutaneous insulin injections.

THE QUESTION:
Is insulin pump therapy safe and effective for maintaining glycemic control in women with gestational diabetes mellitus (GDM) or type 2 diabetes requiring large doses of insulin?

Past studies:

These have shown that insulin pumps have been well tolerated in gravidas with type 1 diabetes. However, there has been no substantial evidence on the use of insulin pumps in patients with GDM or type 2 diabetes. For these gravidas, the current standard of care is to monitor glucose levels 4 times per day and to administer regular insulin injections several times a day, as required.

This study:

Gravidas with GDM or type 2 diabetes were examined over a 4-year period. Parturients on insulin pump therapy were compared to gravidas who did not use an insulin pump. Patients were matched for ethnicity and diabetes type and monitored at a hospital in New Zealand. Of 251 Polynesian, European, and South Asian women, 30 used an insulin pump. None of the patients experienced severe hypoglycemia and 79% had improved glycemic control within 1 to 4 weeks. However, 2 women discontinued pump therapy.

Gravidas using a pump had greater insulin requirements than those not using a pump (median maximum 246 units/day and 130 units/day, respectively) and greater maternal weight gain (10.6 kg and 5.0 kg, respectively). Infants of mothers using insulin pumps were more likely to be admitted to the neonatal care unit, but were neither significantly heavier nor more likely to experience hypoglycemia than control subjects.

Find this study:

December 2001 issue of Diabetes Care; abstract online at www.diabetes.org/diabetescare.

Who may be affected by these findings?

Parturients with GDM or type 2 diabetes.

Expert commentary:

This study addresses an important clinical issue: Although insulin pumps are safe and effective for use in gravidas with type 1 diabetes, it is not clear whether they should be used in women with GDM or type 2 diabetes. Unfortunately, this study does little to clarify this issue. As the authors point out, this was not a clinical trial, but rather a “service audit.” As such, only 2 conclusions can be reasonably extracted from the reported data. First, there were no serious adverse events in gravidas using the insulin pump. Second, an improvement in glycemic control was evident in all 14 women for whom results of self-glucose monitoring was available both before and after initiation of pump therapy. However, it is likely that this improvement was not a result of the pump, but rather of improved overall obstetric care, including more intensive glycemic monitoring and more aggressive insulin dosing.

To consider the use of insulin pumps in gravidas with GDM or type 2 diabetes, researchers must seek to answer the following:

• Are pumps safe in this population?
• Do pumps effectively control blood sugar, decrease the incidence of fetal macrosomia and/or cesarean delivery, and prevent such complications as shoulder dystocia?
• How does pump therapy compare to current regimens of subcutaneous insulin injections?
• Are patients more or less satisfied?

Potential advantages of the insulin pump over subcutaneous insulin include fewer injections, a continuous insulin infusion, and improved patient satisfaction, which could lead to improved compliance. A possible disadvantage of the pump may be infection at the injection site.

Caveats:

This study is marred by several major methodological, statistical, and reporting errors, which include the following:

• The cases and controls were not correctly assigned. One woman was treated with the insulin pump in 2 pregnancies and included in the analysis twice. Controls included women with “preexisting tablet-treated type 2 diabetes,” whereas all cases were treated with insulin. Seven women with type 1 diabetes also were treated with insulin pumps, but it is not clear from the text whether or not these women were included in the analysis.
• Gravidas with GDM or type 2 diabetes were seen monthly until 28 weeks’ gestation, fortnightly until 36 weeks’ gestation, and then weekly until term. By U.S. standards, this represents suboptimal antenatal care for high-risk women.
• There was no power analysis, but it is likely that the study lacked the patient numbers to draw any conclusions about the use of insulin pump therapy in this patient cohort.
• There was a “lack of quality measures of hypoglycemia.” Researchers stated that “problems with precision and reporting were frequently demonstrated by inconsistencies between laboratory and self-glucose monitoring results.”

The bottom line:

Given the difference in pathophysiology between type 1 diabetes (due to an absolute deficiency of insulin) and GDM or type 2 diabetes (characterized by increased peripheral resistance to circulating insulin), extrapolation from gravidas with type 1 diabetes may not be valid. Well-designed, prospective, clinical trials are still needed to assess the value of insulin pump therapy in parturients exclusively suffering from GDM or type 2 diabetes. Future studies will likely demonstrate that insulin pumps are equally—if not more—effective in achieving adequate glycemic control in such women as compared with the current regimen of regular subcutaneous insulin injections. Until such studies are available, parturients with GDM or type 2 diabetes may be managed with intermittent self-administered subcutaneous insulin injections.

THE QUESTION:
Is insulin pump therapy safe and effective for maintaining glycemic control in women with gestational diabetes mellitus (GDM) or type 2 diabetes requiring large doses of insulin?

Past studies:

These have shown that insulin pumps have been well tolerated in gravidas with type 1 diabetes. However, there has been no substantial evidence on the use of insulin pumps in patients with GDM or type 2 diabetes. For these gravidas, the current standard of care is to monitor glucose levels 4 times per day and to administer regular insulin injections several times a day, as required.

This study:

Gravidas with GDM or type 2 diabetes were examined over a 4-year period. Parturients on insulin pump therapy were compared to gravidas who did not use an insulin pump. Patients were matched for ethnicity and diabetes type and monitored at a hospital in New Zealand. Of 251 Polynesian, European, and South Asian women, 30 used an insulin pump. None of the patients experienced severe hypoglycemia and 79% had improved glycemic control within 1 to 4 weeks. However, 2 women discontinued pump therapy.

Gravidas using a pump had greater insulin requirements than those not using a pump (median maximum 246 units/day and 130 units/day, respectively) and greater maternal weight gain (10.6 kg and 5.0 kg, respectively). Infants of mothers using insulin pumps were more likely to be admitted to the neonatal care unit, but were neither significantly heavier nor more likely to experience hypoglycemia than control subjects.

Find this study:

December 2001 issue of Diabetes Care; abstract online at www.diabetes.org/diabetescare.

Who may be affected by these findings?

Parturients with GDM or type 2 diabetes.

Expert commentary:

This study addresses an important clinical issue: Although insulin pumps are safe and effective for use in gravidas with type 1 diabetes, it is not clear whether they should be used in women with GDM or type 2 diabetes. Unfortunately, this study does little to clarify this issue. As the authors point out, this was not a clinical trial, but rather a “service audit.” As such, only 2 conclusions can be reasonably extracted from the reported data. First, there were no serious adverse events in gravidas using the insulin pump. Second, an improvement in glycemic control was evident in all 14 women for whom results of self-glucose monitoring was available both before and after initiation of pump therapy. However, it is likely that this improvement was not a result of the pump, but rather of improved overall obstetric care, including more intensive glycemic monitoring and more aggressive insulin dosing.

To consider the use of insulin pumps in gravidas with GDM or type 2 diabetes, researchers must seek to answer the following:

• Are pumps safe in this population?
• Do pumps effectively control blood sugar, decrease the incidence of fetal macrosomia and/or cesarean delivery, and prevent such complications as shoulder dystocia?
• How does pump therapy compare to current regimens of subcutaneous insulin injections?
• Are patients more or less satisfied?

Potential advantages of the insulin pump over subcutaneous insulin include fewer injections, a continuous insulin infusion, and improved patient satisfaction, which could lead to improved compliance. A possible disadvantage of the pump may be infection at the injection site.

Caveats:

This study is marred by several major methodological, statistical, and reporting errors, which include the following:

• The cases and controls were not correctly assigned. One woman was treated with the insulin pump in 2 pregnancies and included in the analysis twice. Controls included women with “preexisting tablet-treated type 2 diabetes,” whereas all cases were treated with insulin. Seven women with type 1 diabetes also were treated with insulin pumps, but it is not clear from the text whether or not these women were included in the analysis.
• Gravidas with GDM or type 2 diabetes were seen monthly until 28 weeks’ gestation, fortnightly until 36 weeks’ gestation, and then weekly until term. By U.S. standards, this represents suboptimal antenatal care for high-risk women.
• There was no power analysis, but it is likely that the study lacked the patient numbers to draw any conclusions about the use of insulin pump therapy in this patient cohort.
• There was a “lack of quality measures of hypoglycemia.” Researchers stated that “problems with precision and reporting were frequently demonstrated by inconsistencies between laboratory and self-glucose monitoring results.”

The bottom line:

Given the difference in pathophysiology between type 1 diabetes (due to an absolute deficiency of insulin) and GDM or type 2 diabetes (characterized by increased peripheral resistance to circulating insulin), extrapolation from gravidas with type 1 diabetes may not be valid. Well-designed, prospective, clinical trials are still needed to assess the value of insulin pump therapy in parturients exclusively suffering from GDM or type 2 diabetes. Future studies will likely demonstrate that insulin pumps are equally—if not more—effective in achieving adequate glycemic control in such women as compared with the current regimen of regular subcutaneous insulin injections. Until such studies are available, parturients with GDM or type 2 diabetes may be managed with intermittent self-administered subcutaneous insulin injections.

<huc>Q</huc> OBG Management: In what ways does this bulletin represent an evolution in the specialty’s thinking about preterm labor?

<huc>A</huc> NORWITZ: It represents an attempt by ACOG to synthesize the extensive and rapidly expanding body of literature on risk factors for PTD into a single, succinct, and practical document.² As such, it replaces prior ACOG publications on preterm labor,³ home uterine-activity monitoring (HUAM),⁴ salivary estriol testing,⁵ fetal fibronectin (fFN) testing,⁶ and bacterial vaginosis (BV) screening and treatment.⁷ However, the current Practice Bulletin is a far less ambitious document than the prior review of preterm labor,³ which dealt not only with risk factors for preterm irth, but also with its management.

Nonetheless, it represents an evolution in thinking about preterm birth, as it includes a detailed discussion of fetal fibronectin screening and sonographic assessment of cervical length.

<huc>Q</huc> OBG Management: According to the bulletin, “There are no current data to support the use of salivary estriol, HUAM, or BV screening as strategies to identify or prevent preterm birth.” How widely are each of these modalities being employed by Ob/Gyns? What impact do you see this statement having on their future use?

<huc>A</huc> NORWITZ: HUAM testing had largely fallen by the wayside even before this bulletin was published. Most obstetric-care providers were already aware of the extensive literature showing that HUAM does not prevent preterm birth or improve perinatal outcome.^8-11

As for salivary estriol, the development of a reliable endocrine assay to predict PTD would represent a significant advance in the field. Progesterone withdrawal is not a prerequisite for labor; nor are serum progesterone levels or progesterone/17ß-estradiol ratios predictive of preterm birth.^12,1

Lower-genital-tract BV may be a marker of upper-genital-tract infection, which in turn may be the real cause of preterm birth.

On the other hand, maternal serum estriol levels accurately reflect activation of the fetal hypothalamic-pituitary-adrenal axis, which occurs in all women prior to the onset of labor, both at term and preterm.^13,14 More-over, salivary estriol measurements correlate well with levels of biologically active (unconjugated) estriol in the circulation.¹⁵ The detection of elevated levels of estriol (≥2.1 ng/mL) in maternal saliva is predictive of delivery prior to 37 weeks in a high-risk population, with a sensitivity of 68% to 87% and a specificity of 77%.^16,17 Serial (weekly) measurements have been shown to be more accurate in predicting preterm birth than a single measurement.¹⁷

However, salivary estriol testing to identify women at high risk of PTD has not been widely accepted. The reasons: First, maternal estriol levels show diurnal variation, peaking at night,¹⁸ making it difficult to standardize such testing. Additionally, the false-positive rate of 23% to 35% is considered unacceptably high and may lead to unnecessary intervention.^16,17 Finally, salivary estriol levels may be suppressed by betamethasone administration, making the test unreliable in patients treated with corticosteroids.¹⁹ The statement in the latest ACOG bulletin that “trials with salivary estriol testing to predict preterm birth have failed to establish its usefulness for anything more than investigational purposes at present”² is likely to further limit the use of this test, and may have the unfortunate effect of discouraging future research in the field.

In regard to BV, recent data demonstrate conclusively that screening and treating low-risk asymptomatic pregnant women for BV does not prevent preterm birth.^20-22 However, the data for women at high risk for preterm birth are conflicting. Some studies suggest that the strategy of screening and treating asymptomatic BV in high-risk women may significantly decrease the incidence of preterm birth and low-birthweight infants.^22-24 But the statement by ACOG that “there are insufficient data to suggest screening and treating women at…high risk will reduce the overall rate of preterm birth”² is likely to limit the use of this strategy. The hypothesis that lower-genital-tract BV may be a marker of upper-genital-tract infection, which in turn is the real cause of preterm labor and delivery, is intriguing and deserves further attention.

The preventive strategy of screening and treating BV should not be confused with the management of women with symptomatic BV. These women should be treated with oral metronidazole after the first trimester, as vaginal metronidazole and clindamycin preparations appear to be less effective during pregnancy.²⁵

<huc>Q</huc> OBG Management: The Practice Bulletin also stated that, “Screening for risk of preterm labor by means other than historic risk factors is not beneficial in the general obstetric population.” Please outline this set of historic risk factors.

<huc>A</huc> NORWITZ: Risk factors for preterm birth resulting from spontaneous preterm labor, which excludes indicated (iatrogenic) PTD for severe preeclampsia, a prior high vertical (“classical”) cesarean, or chorioamnionitis, are as follows:

• Demographic characteristics such as African-American race, poor socioeconomic status, low pre-pregnancy weight, extremes of maternal age, and absent or inadequate prenatal care.
• Behavioral factors such as cigarette smoking, substance abuse, and high personal stress or a strenuous work environment.
• Aspects of obstetric history such as prior PTD, multiple gestation, uterine anomalies, anemia, polyhydramnios, vaginal bleeding, cervical incompetence, and BV.

Several scoring systems have been developed to predict a woman’s likelihood of delivering preterm. However, reliance on risk factors alone will fail to identify more than 50% of pregnancies that deliver at less than 37 weeks.^26,27

The most important risk factor is a history of one or more preterm deliveries. If the prior PTD was due to spontaneous preterm labor, a screening strategy comprised of serial cervical examinations and/or fFN testing should be initiated in the mid- to late second trimester.

Sonography has shown a strong correlation between cervical length and PTD.

If the prior PTD is suggestive of cervical incompetence, it may be appropriate to discuss other management options. These include prophylactic cervical cerclage or serial measurements of cervical length using transvaginal sonography and placement of an emergent cerclage, if indicated.²⁸ (The generally accepted definition of cervical incompetence is the inability to support a pregnancy to term due to a structural or functional defect of the cervix. It is characterized by acute, painless dilatation of the cervix, usually in the middle trimester, culminating in prolapse and/or rupture of the membranes, which leads to preterm—and often pre-viable—delivery.) A history of in utero diethylstilbestrol (DES) exposure or multiple gestation in the absence of a history of cervical incompetence is not generally accepted as a sufficient indication for elective cerclage.²⁸

<huc>Q</huc> OBG Management: What about fFN testing and the use of ultrasound to determine cervical length? The ACOG Practice Bulletin recommended that either modality or “a combination of both may be useful in determining high risk for preterm labor,” adding that the clinical utility of both modalities may rest primarily with their negative predictive value. How do you use cervical ultrasound and fFN screening in your practice?

<huc>A</huc>NORWITZ: In women at risk for preterm birth, serial digital evaluation of the cervix starting in the mid- to late second trimester is useful if the examination remains normal. However, an abnormal cervical finding (shortening, dilatation, or both) is associated with PTD in only 4% of low-risk women and in just 12% to 20% of high-risk women.²⁹ Real-time sonographic evaluation of the cervix, on the other hand, has demonstrated a strong and reproducible inverse correlation between cervical length and PTD.^30,31 If the cervical length is lower than the 10th percentile for gestational age, the pregnancy is at a 6-fold increased risk of delivery prior to 35 weeks.³⁰ A cervical length of 15 mm or less at 23 weeks occurs in less than 2% of low-risk women, but is predictive of delivery prior to 28 weeks and 32 weeks in 60% and 90% of cases, respectively.³¹

A cervical length of 2.5 cm or less at 22 to 24 weeks in a pregnancy at high risk for PTD should be considered abnormal and requires further evaluation.

The latest Practice Bulletin concludes that: “Despite the usefulness of cervical length determination by ultrasonography as a predictor of preterm labor, routine use is not recommended because of the lack of proven treatments affecting outcome.”^2,32 Therefore, perinatologists and sonographers should not include cervical-length measurements in routine prenatal ultrasounds. However, in carefully selected women at increased risk for PTD, serial measurements of cervical length may help modify the risk estimate for preterm birth. This is especially true in women with a history suggestive of cervical incompetence in whom cervical cerclage is being considered. That said, it remains unclear whether placement of a cervical cerclage in women with a shortened cervix can prevent preterm birth or improve perinatal outcome.²⁸

Cervical-length measurement as a screening test for preterm birth was accepted relatively quickly in clinical practice. This is likely because of the ready availability of transvaginal ultrasound in most obstetric suites and labor and delivery (L&D) units, and because of a high level of comfort and expertise with its use. The possibility that a shortened cervix may represent cervical incompetence and that placement of a cervical cerclage may serve to avert PTD altogether or at least delay delivery to a more favorable gestational age, also may be a factor in that acceptance.

Obstetric-care providers have been far more skeptical about fFN testing, and its introduction into clinical practice has been more protracted. An elevated level of fFN (≥50 ng/mL) in cervicovaginal secretions, which probably reflects separation of the fetal membranes from the maternal decidua,³³ is associated with premature delivery. However, in a low-risk population, the positive predictive value of a positive fFN test at 22 to 24 weeks for spontaneous PTD prior to 28 weeks and 37 weeks is only 13% and 36%, respectively.³⁴ As such, the value of this test lies primarily in its negative predictive value; 99% of patients with a negative fFN test will not deliver within 7 days.³⁵ ACOG currently recommends the use of this test only in a very specific subgroup of women (particularly, in symptomatic women with intact membranes, cervical dilatation <3 cm, and a gestational age of 24-0/7 to 34-6/7 weeks).^2,6

Cervicovaginal swabs for fFN measurement should be taken prior to bimanual examination. For this reason, the clinician should consider collecting a specimen at the time of initial speculum examination in all women being evaluated for preterm labor, regardless of the initial index of suspicion. There is no charge for discarded specimens.

The ACOG bulletin also states that, in order for the fFN test to be “clinically useful, the results must be available from a laboratory within a time frame that allows for clinical decision-making (ideally within 24 hours).”² The introduction of a rapid fFN test and its approval by the FDA in September 1998 have greatly improved the utility of determining fFN levels in cervicovaginal secretions. The test itself takes 26 minutes to complete, and most laboratories can get a result back to the clinician within 1 to 2 hours.

<huc>Q</huc> OBG Management: What findings on cervical ultrasonography are reassuring for you, and which are nonreassuring?

<huc>A</huc> NORWITZ: The most important measurement on cervical ultrasonography is residual cervical length. Both transvaginal and transperineal sonography are reliable and reproducible ways to assess the length of the cervix,^2,36 although transvaginal sonography is considered by most practitioners to be the gold standard. Mean cervical length changes with gestational age,^30-32 but a cervical length of 2.5 cm or less at 22 to 24 weeks in a pregnancy at high risk for PTD should be considered abnormal and requires further evaluation.

Funneling (or beaking) at the internal os also is concerning as it may indicate an intrinsically weak cervicoisthmic junction suggestive of cervical incompetence, but the data are less consistent. Some studies have found the presence of funneling to be an independent risk factor for preterm birth (independent of cervical length),^37,38 whereas other studies have been unable to confirm this observation.^30,39 It also has been suggested that a “cervical stress test” be performed by applying transfundal pressure and watching for funneling at the internal os, and several studies have shown that a positive test is predictive of PTD.^40,41 Whether such testing should be performed in all women at risk of preterm birth remains unclear.

There are several factors to consider when assessing cervical length and dilatation. These include the orientation of the transducer, the potential distortion of the cervix by the transducer, and the fact that a full bladder may artificially lengthen the cervix and obscure dilatation of the internal os.⁴² Careful attention to maternal position also is essential.⁴³

All cervical abnormalities should be reported to the patient. Deciding whether to repeat the cervical ultrasound in 1 to 2 weeks versus placing a cervical cerclage versus bed rest should be individualized, and will depend on such factors as gestational age, a priori risk of PTD, and patient preference. I typically review in detail the risks and potential benefits of each management option with the patient, and will recommend cervical cerclage if the pregnancy is at high risk of PTD, if the gestational age is less than 24 weeks, and if there is evidence of progressive cervical shortening with a residual length (with or without funneling) of less than 2 cm.

Whether cervical length and fFN are additive in their ability to predict preterm delivery in women at high risk remains controversial.

Although I have chosen 2 cm as a cutoff for recommending cervical cerclage, the optimal cutoff value remains controversial, ranging from 1.5 to 3 cm.³⁸ Whether the cutoff value should differ for women with multiple gestations or women who have had prior cervical surgery is unclear.

<huc>Q</huc> OBG Management: When you use ultrasonography in combination with fFN screening, how do you make decisions based on the combination of results? How do you proceed in the face of discordant findings?

<huc>A</huc> NORWITZ: In my practice, it is unusual for women to be screened with both cervical ultrasound and fFN testing. I use cervical ultrasound more often in the mid- to late second trimester in asymptomatic women with a history of preterm birth suggestive of cervical incompetence, and fFN more often in symptomatic women presenting to the outpatient clinic or L&D unit remote from term. However, there are a few exceptions. These include women with higher-order multiple gestations (triplets and up), in whom the risk of preterm birth remote from term is extremely high, and symptomatic women at 22 to 28 weeks, when the bimanual examination suggests cause for concern and ultrasound confirms substantial cervical shortening.

Whether cervical length and fFN are additive in their ability to predict PTD in women at high risk, or whether they are simply 2 separate methods of assessing the same pathophysiologic process, remains controversial. Recent data suggest that these tests are indeed additive. High-risk women at 22 to 24 weeks with a residual cervical length of less than 2.5 cm and a positive fFN screening test have a 65% risk of delivering at less than 35 weeks, even if they are asymptomatic at presentation.^2,44

A negative fFN test excludes imminent delivery, with less than 1% of such women delivering within 14 days of presentation.

Which of the 2 tests is more reliable in any given patient also is not clear. This becomes important when the testing is discordant. In a woman with an abnormal cervical examination remote from term, a negative fFN test is reassuring because the data suggest that she is highly unlikely to deliver within the next 2 weeks.² How to interpret a positive fFN test in an asymptomatic woman with normal cervical length, however, is not clear. As the bulletin states: “The clinical implications of a positive test have not been evaluated fully.”²

My approach to such patients is to increase antenatal surveillance, but not to modify their care in any other way on the basis of a single positive fFN, i.e., no corticosteroids, no tocolysis, no bed rest. I typically will not repeat the fFN test, although some practitioners would recommend repeating it in 1 to 2 weeks if the patient remains undelivered. Although a subsequent negative fFN test cannot “remove” the implications of the previous positive test, some evidence suggests that 2 negative test results following a positive test reduce the risk of spontaneous preterm birth back to baseline.⁴⁵

<huc>Q</huc> OBG Management: The bulletin stated that fFN may be useful in “avoiding unnecessary intervention” in symptomatic women by virtue of its negative predictive value. What has been your experience in this regard?

<huc>A</huc> NORWITZ: The first question to ask is how best to define a “symptomatic” woman. ACOG says the following symptoms and signs suggestive of preterm labor deserve further evaluation:

• Uterine contractions (with or without pain)
• Intermittent lower abdominal pain, dull backache, pelvic pressure
• Vaginal bleeding during the second or third trimester
• Menstrual-like intestinal cramping (with or without diarrhea)
• Change in vaginal discharge (amount, color, consistency)
• Vague sense of discomfort characterized as “not feeling right”

This question pertains specifically to symptomatic women presenting to the out-patient clinic or to the L&D unit. Of all women at 24-0/7 to 34-6/7 weeks with symptoms or signs suggestive of preterm labor, about 80% will be fFN-negative, i.e., fFN <50 ng/mL in cervicovaginal secretions. A negative fFN test effectively excludes imminent delivery, with less than 1% (1 in 125) of such women delivering within 14 days of presentation.

A positive fFN test, on the other hand, will predict delivery within the next 14 days in only 16% (1 in 6) of symptomatic women. As such, the value of the fFN test lies primarily in its negative predictive value (124 of 125 women with a negative fFN test will not deliver within the next 14 days).^33-35,45 Indeed, a negative fFN test in symptomatic women has been shown to reduce admissions for preterm labor, length of stay, and use of tocolytic agents,⁴⁶ as well as to reduce unnecessary transfers to a tertiary care center.⁴⁷ These benefits translate into substantial cost savings^46,47 and likely minimize adverse events in pregnant women by avoiding unnecessary interventions.

<huc>Q</huc> OBG Management: What is your screening modality of choice for symptomatic women and why?

<huc>A</huc> NORWITZ: Two key elements should be considered when evaluating a woman who presents with 1 or more symptoms or signs suggestive of preterm labor: the gestational age and the best estimate of the patient’s a priori risk of PTD. The latter requires knowledge about the presence or absence of risk factors for preterm birth (especially a history of prior PTD), uterine contractility, cervical examination (including dilatation, effacement, and station), presence or absence of ruptured membranes, and fetal well-being.

If the index of suspicion for PTD is high in a symptomatic woman, admit her for observation to exclude preterm labor.

If the index of suspicion for preterm delivery remote from term is high, the patient should be admitted for observation to exclude preterm labor. Antenatal corticosteroid and tocolytic therapy should be initiated, if indicated. Broad-spectrum antibiotic therapy has not been found to be useful in the setting of preterm labor with intact membranes, although there is a considerable body of evidence demonstrating its efficacy in the setting of ruptured membranes at less than 34 weeks.^48,49 Tocolysis has not been shown to be effective once the fetal membranes are ruptured, and is best avoided in this setting.⁵⁰

If there is no evidence of preterm labor and the index of suspicion for PTD is low, the patient may be discharged home, even if she is symptomatic. Careful follow-up should be arranged within 1 to 2 weeks, and the patient should be counseled to return to the office if the symptoms of preterm labor worsen. In this setting—and depending on the gestational age—it may be appropriate to screen the patient with either fFN or sonographic estimation of cervical length.

The author reports no financial relationship with any companies whose products are mentioned in this article.

<huc>Q</huc> OBG Management: In what ways does this bulletin represent an evolution in the specialty’s thinking about preterm labor?

<huc>A</huc> NORWITZ: It represents an attempt by ACOG to synthesize the extensive and rapidly expanding body of literature on risk factors for PTD into a single, succinct, and practical document.² As such, it replaces prior ACOG publications on preterm labor,³ home uterine-activity monitoring (HUAM),⁴ salivary estriol testing,⁵ fetal fibronectin (fFN) testing,⁶ and bacterial vaginosis (BV) screening and treatment.⁷ However, the current Practice Bulletin is a far less ambitious document than the prior review of preterm labor,³ which dealt not only with risk factors for preterm irth, but also with its management.

Nonetheless, it represents an evolution in thinking about preterm birth, as it includes a detailed discussion of fetal fibronectin screening and sonographic assessment of cervical length.

<huc>Q</huc> OBG Management: According to the bulletin, “There are no current data to support the use of salivary estriol, HUAM, or BV screening as strategies to identify or prevent preterm birth.” How widely are each of these modalities being employed by Ob/Gyns? What impact do you see this statement having on their future use?

<huc>A</huc> NORWITZ: HUAM testing had largely fallen by the wayside even before this bulletin was published. Most obstetric-care providers were already aware of the extensive literature showing that HUAM does not prevent preterm birth or improve perinatal outcome.^8-11

As for salivary estriol, the development of a reliable endocrine assay to predict PTD would represent a significant advance in the field. Progesterone withdrawal is not a prerequisite for labor; nor are serum progesterone levels or progesterone/17ß-estradiol ratios predictive of preterm birth.^12,1

Lower-genital-tract BV may be a marker of upper-genital-tract infection, which in turn may be the real cause of preterm birth.

On the other hand, maternal serum estriol levels accurately reflect activation of the fetal hypothalamic-pituitary-adrenal axis, which occurs in all women prior to the onset of labor, both at term and preterm.^13,14 More-over, salivary estriol measurements correlate well with levels of biologically active (unconjugated) estriol in the circulation.¹⁵ The detection of elevated levels of estriol (≥2.1 ng/mL) in maternal saliva is predictive of delivery prior to 37 weeks in a high-risk population, with a sensitivity of 68% to 87% and a specificity of 77%.^16,17 Serial (weekly) measurements have been shown to be more accurate in predicting preterm birth than a single measurement.¹⁷

However, salivary estriol testing to identify women at high risk of PTD has not been widely accepted. The reasons: First, maternal estriol levels show diurnal variation, peaking at night,¹⁸ making it difficult to standardize such testing. Additionally, the false-positive rate of 23% to 35% is considered unacceptably high and may lead to unnecessary intervention.^16,17 Finally, salivary estriol levels may be suppressed by betamethasone administration, making the test unreliable in patients treated with corticosteroids.¹⁹ The statement in the latest ACOG bulletin that “trials with salivary estriol testing to predict preterm birth have failed to establish its usefulness for anything more than investigational purposes at present”² is likely to further limit the use of this test, and may have the unfortunate effect of discouraging future research in the field.

In regard to BV, recent data demonstrate conclusively that screening and treating low-risk asymptomatic pregnant women for BV does not prevent preterm birth.^20-22 However, the data for women at high risk for preterm birth are conflicting. Some studies suggest that the strategy of screening and treating asymptomatic BV in high-risk women may significantly decrease the incidence of preterm birth and low-birthweight infants.^22-24 But the statement by ACOG that “there are insufficient data to suggest screening and treating women at…high risk will reduce the overall rate of preterm birth”² is likely to limit the use of this strategy. The hypothesis that lower-genital-tract BV may be a marker of upper-genital-tract infection, which in turn is the real cause of preterm labor and delivery, is intriguing and deserves further attention.

The preventive strategy of screening and treating BV should not be confused with the management of women with symptomatic BV. These women should be treated with oral metronidazole after the first trimester, as vaginal metronidazole and clindamycin preparations appear to be less effective during pregnancy.²⁵

<huc>Q</huc> OBG Management: The Practice Bulletin also stated that, “Screening for risk of preterm labor by means other than historic risk factors is not beneficial in the general obstetric population.” Please outline this set of historic risk factors.

<huc>A</huc> NORWITZ: Risk factors for preterm birth resulting from spontaneous preterm labor, which excludes indicated (iatrogenic) PTD for severe preeclampsia, a prior high vertical (“classical”) cesarean, or chorioamnionitis, are as follows:

• Demographic characteristics such as African-American race, poor socioeconomic status, low pre-pregnancy weight, extremes of maternal age, and absent or inadequate prenatal care.
• Behavioral factors such as cigarette smoking, substance abuse, and high personal stress or a strenuous work environment.
• Aspects of obstetric history such as prior PTD, multiple gestation, uterine anomalies, anemia, polyhydramnios, vaginal bleeding, cervical incompetence, and BV.

Several scoring systems have been developed to predict a woman’s likelihood of delivering preterm. However, reliance on risk factors alone will fail to identify more than 50% of pregnancies that deliver at less than 37 weeks.^26,27

The most important risk factor is a history of one or more preterm deliveries. If the prior PTD was due to spontaneous preterm labor, a screening strategy comprised of serial cervical examinations and/or fFN testing should be initiated in the mid- to late second trimester.

Sonography has shown a strong correlation between cervical length and PTD.

If the prior PTD is suggestive of cervical incompetence, it may be appropriate to discuss other management options. These include prophylactic cervical cerclage or serial measurements of cervical length using transvaginal sonography and placement of an emergent cerclage, if indicated.²⁸ (The generally accepted definition of cervical incompetence is the inability to support a pregnancy to term due to a structural or functional defect of the cervix. It is characterized by acute, painless dilatation of the cervix, usually in the middle trimester, culminating in prolapse and/or rupture of the membranes, which leads to preterm—and often pre-viable—delivery.) A history of in utero diethylstilbestrol (DES) exposure or multiple gestation in the absence of a history of cervical incompetence is not generally accepted as a sufficient indication for elective cerclage.²⁸

<huc>Q</huc> OBG Management: What about fFN testing and the use of ultrasound to determine cervical length? The ACOG Practice Bulletin recommended that either modality or “a combination of both may be useful in determining high risk for preterm labor,” adding that the clinical utility of both modalities may rest primarily with their negative predictive value. How do you use cervical ultrasound and fFN screening in your practice?

<huc>A</huc>NORWITZ: In women at risk for preterm birth, serial digital evaluation of the cervix starting in the mid- to late second trimester is useful if the examination remains normal. However, an abnormal cervical finding (shortening, dilatation, or both) is associated with PTD in only 4% of low-risk women and in just 12% to 20% of high-risk women.²⁹ Real-time sonographic evaluation of the cervix, on the other hand, has demonstrated a strong and reproducible inverse correlation between cervical length and PTD.^30,31 If the cervical length is lower than the 10th percentile for gestational age, the pregnancy is at a 6-fold increased risk of delivery prior to 35 weeks.³⁰ A cervical length of 15 mm or less at 23 weeks occurs in less than 2% of low-risk women, but is predictive of delivery prior to 28 weeks and 32 weeks in 60% and 90% of cases, respectively.³¹

A cervical length of 2.5 cm or less at 22 to 24 weeks in a pregnancy at high risk for PTD should be considered abnormal and requires further evaluation.

The latest Practice Bulletin concludes that: “Despite the usefulness of cervical length determination by ultrasonography as a predictor of preterm labor, routine use is not recommended because of the lack of proven treatments affecting outcome.”^2,32 Therefore, perinatologists and sonographers should not include cervical-length measurements in routine prenatal ultrasounds. However, in carefully selected women at increased risk for PTD, serial measurements of cervical length may help modify the risk estimate for preterm birth. This is especially true in women with a history suggestive of cervical incompetence in whom cervical cerclage is being considered. That said, it remains unclear whether placement of a cervical cerclage in women with a shortened cervix can prevent preterm birth or improve perinatal outcome.²⁸

Cervical-length measurement as a screening test for preterm birth was accepted relatively quickly in clinical practice. This is likely because of the ready availability of transvaginal ultrasound in most obstetric suites and labor and delivery (L&D) units, and because of a high level of comfort and expertise with its use. The possibility that a shortened cervix may represent cervical incompetence and that placement of a cervical cerclage may serve to avert PTD altogether or at least delay delivery to a more favorable gestational age, also may be a factor in that acceptance.

Obstetric-care providers have been far more skeptical about fFN testing, and its introduction into clinical practice has been more protracted. An elevated level of fFN (≥50 ng/mL) in cervicovaginal secretions, which probably reflects separation of the fetal membranes from the maternal decidua,³³ is associated with premature delivery. However, in a low-risk population, the positive predictive value of a positive fFN test at 22 to 24 weeks for spontaneous PTD prior to 28 weeks and 37 weeks is only 13% and 36%, respectively.³⁴ As such, the value of this test lies primarily in its negative predictive value; 99% of patients with a negative fFN test will not deliver within 7 days.³⁵ ACOG currently recommends the use of this test only in a very specific subgroup of women (particularly, in symptomatic women with intact membranes, cervical dilatation <3 cm, and a gestational age of 24-0/7 to 34-6/7 weeks).^2,6

Cervicovaginal swabs for fFN measurement should be taken prior to bimanual examination. For this reason, the clinician should consider collecting a specimen at the time of initial speculum examination in all women being evaluated for preterm labor, regardless of the initial index of suspicion. There is no charge for discarded specimens.

The ACOG bulletin also states that, in order for the fFN test to be “clinically useful, the results must be available from a laboratory within a time frame that allows for clinical decision-making (ideally within 24 hours).”² The introduction of a rapid fFN test and its approval by the FDA in September 1998 have greatly improved the utility of determining fFN levels in cervicovaginal secretions. The test itself takes 26 minutes to complete, and most laboratories can get a result back to the clinician within 1 to 2 hours.

<huc>Q</huc> OBG Management: What findings on cervical ultrasonography are reassuring for you, and which are nonreassuring?

<huc>A</huc> NORWITZ: The most important measurement on cervical ultrasonography is residual cervical length. Both transvaginal and transperineal sonography are reliable and reproducible ways to assess the length of the cervix,^2,36 although transvaginal sonography is considered by most practitioners to be the gold standard. Mean cervical length changes with gestational age,^30-32 but a cervical length of 2.5 cm or less at 22 to 24 weeks in a pregnancy at high risk for PTD should be considered abnormal and requires further evaluation.

Funneling (or beaking) at the internal os also is concerning as it may indicate an intrinsically weak cervicoisthmic junction suggestive of cervical incompetence, but the data are less consistent. Some studies have found the presence of funneling to be an independent risk factor for preterm birth (independent of cervical length),^37,38 whereas other studies have been unable to confirm this observation.^30,39 It also has been suggested that a “cervical stress test” be performed by applying transfundal pressure and watching for funneling at the internal os, and several studies have shown that a positive test is predictive of PTD.^40,41 Whether such testing should be performed in all women at risk of preterm birth remains unclear.

There are several factors to consider when assessing cervical length and dilatation. These include the orientation of the transducer, the potential distortion of the cervix by the transducer, and the fact that a full bladder may artificially lengthen the cervix and obscure dilatation of the internal os.⁴² Careful attention to maternal position also is essential.⁴³

All cervical abnormalities should be reported to the patient. Deciding whether to repeat the cervical ultrasound in 1 to 2 weeks versus placing a cervical cerclage versus bed rest should be individualized, and will depend on such factors as gestational age, a priori risk of PTD, and patient preference. I typically review in detail the risks and potential benefits of each management option with the patient, and will recommend cervical cerclage if the pregnancy is at high risk of PTD, if the gestational age is less than 24 weeks, and if there is evidence of progressive cervical shortening with a residual length (with or without funneling) of less than 2 cm.

Whether cervical length and fFN are additive in their ability to predict preterm delivery in women at high risk remains controversial.

Although I have chosen 2 cm as a cutoff for recommending cervical cerclage, the optimal cutoff value remains controversial, ranging from 1.5 to 3 cm.³⁸ Whether the cutoff value should differ for women with multiple gestations or women who have had prior cervical surgery is unclear.

<huc>Q</huc> OBG Management: When you use ultrasonography in combination with fFN screening, how do you make decisions based on the combination of results? How do you proceed in the face of discordant findings?

<huc>A</huc> NORWITZ: In my practice, it is unusual for women to be screened with both cervical ultrasound and fFN testing. I use cervical ultrasound more often in the mid- to late second trimester in asymptomatic women with a history of preterm birth suggestive of cervical incompetence, and fFN more often in symptomatic women presenting to the outpatient clinic or L&D unit remote from term. However, there are a few exceptions. These include women with higher-order multiple gestations (triplets and up), in whom the risk of preterm birth remote from term is extremely high, and symptomatic women at 22 to 28 weeks, when the bimanual examination suggests cause for concern and ultrasound confirms substantial cervical shortening.

Whether cervical length and fFN are additive in their ability to predict PTD in women at high risk, or whether they are simply 2 separate methods of assessing the same pathophysiologic process, remains controversial. Recent data suggest that these tests are indeed additive. High-risk women at 22 to 24 weeks with a residual cervical length of less than 2.5 cm and a positive fFN screening test have a 65% risk of delivering at less than 35 weeks, even if they are asymptomatic at presentation.^2,44

A negative fFN test excludes imminent delivery, with less than 1% of such women delivering within 14 days of presentation.

Which of the 2 tests is more reliable in any given patient also is not clear. This becomes important when the testing is discordant. In a woman with an abnormal cervical examination remote from term, a negative fFN test is reassuring because the data suggest that she is highly unlikely to deliver within the next 2 weeks.² How to interpret a positive fFN test in an asymptomatic woman with normal cervical length, however, is not clear. As the bulletin states: “The clinical implications of a positive test have not been evaluated fully.”²

My approach to such patients is to increase antenatal surveillance, but not to modify their care in any other way on the basis of a single positive fFN, i.e., no corticosteroids, no tocolysis, no bed rest. I typically will not repeat the fFN test, although some practitioners would recommend repeating it in 1 to 2 weeks if the patient remains undelivered. Although a subsequent negative fFN test cannot “remove” the implications of the previous positive test, some evidence suggests that 2 negative test results following a positive test reduce the risk of spontaneous preterm birth back to baseline.⁴⁵

<huc>Q</huc> OBG Management: The bulletin stated that fFN may be useful in “avoiding unnecessary intervention” in symptomatic women by virtue of its negative predictive value. What has been your experience in this regard?

<huc>A</huc> NORWITZ: The first question to ask is how best to define a “symptomatic” woman. ACOG says the following symptoms and signs suggestive of preterm labor deserve further evaluation:

• Uterine contractions (with or without pain)
• Intermittent lower abdominal pain, dull backache, pelvic pressure
• Vaginal bleeding during the second or third trimester
• Menstrual-like intestinal cramping (with or without diarrhea)
• Change in vaginal discharge (amount, color, consistency)
• Vague sense of discomfort characterized as “not feeling right”

This question pertains specifically to symptomatic women presenting to the out-patient clinic or to the L&D unit. Of all women at 24-0/7 to 34-6/7 weeks with symptoms or signs suggestive of preterm labor, about 80% will be fFN-negative, i.e., fFN <50 ng/mL in cervicovaginal secretions. A negative fFN test effectively excludes imminent delivery, with less than 1% (1 in 125) of such women delivering within 14 days of presentation.

A positive fFN test, on the other hand, will predict delivery within the next 14 days in only 16% (1 in 6) of symptomatic women. As such, the value of the fFN test lies primarily in its negative predictive value (124 of 125 women with a negative fFN test will not deliver within the next 14 days).^33-35,45 Indeed, a negative fFN test in symptomatic women has been shown to reduce admissions for preterm labor, length of stay, and use of tocolytic agents,⁴⁶ as well as to reduce unnecessary transfers to a tertiary care center.⁴⁷ These benefits translate into substantial cost savings^46,47 and likely minimize adverse events in pregnant women by avoiding unnecessary interventions.

<huc>Q</huc> OBG Management: What is your screening modality of choice for symptomatic women and why?

<huc>A</huc> NORWITZ: Two key elements should be considered when evaluating a woman who presents with 1 or more symptoms or signs suggestive of preterm labor: the gestational age and the best estimate of the patient’s a priori risk of PTD. The latter requires knowledge about the presence or absence of risk factors for preterm birth (especially a history of prior PTD), uterine contractility, cervical examination (including dilatation, effacement, and station), presence or absence of ruptured membranes, and fetal well-being.

If the index of suspicion for PTD is high in a symptomatic woman, admit her for observation to exclude preterm labor.

If the index of suspicion for preterm delivery remote from term is high, the patient should be admitted for observation to exclude preterm labor. Antenatal corticosteroid and tocolytic therapy should be initiated, if indicated. Broad-spectrum antibiotic therapy has not been found to be useful in the setting of preterm labor with intact membranes, although there is a considerable body of evidence demonstrating its efficacy in the setting of ruptured membranes at less than 34 weeks.^48,49 Tocolysis has not been shown to be effective once the fetal membranes are ruptured, and is best avoided in this setting.⁵⁰

If there is no evidence of preterm labor and the index of suspicion for PTD is low, the patient may be discharged home, even if she is symptomatic. Careful follow-up should be arranged within 1 to 2 weeks, and the patient should be counseled to return to the office if the symptoms of preterm labor worsen. In this setting—and depending on the gestational age—it may be appropriate to screen the patient with either fFN or sonographic estimation of cervical length.

The author reports no financial relationship with any companies whose products are mentioned in this article.

<huc>Q</huc> OBG Management: In what ways does this bulletin represent an evolution in the specialty’s thinking about preterm labor?

<huc>A</huc> NORWITZ: It represents an attempt by ACOG to synthesize the extensive and rapidly expanding body of literature on risk factors for PTD into a single, succinct, and practical document.² As such, it replaces prior ACOG publications on preterm labor,³ home uterine-activity monitoring (HUAM),⁴ salivary estriol testing,⁵ fetal fibronectin (fFN) testing,⁶ and bacterial vaginosis (BV) screening and treatment.⁷ However, the current Practice Bulletin is a far less ambitious document than the prior review of preterm labor,³ which dealt not only with risk factors for preterm irth, but also with its management.

Nonetheless, it represents an evolution in thinking about preterm birth, as it includes a detailed discussion of fetal fibronectin screening and sonographic assessment of cervical length.

<huc>Q</huc> OBG Management: According to the bulletin, “There are no current data to support the use of salivary estriol, HUAM, or BV screening as strategies to identify or prevent preterm birth.” How widely are each of these modalities being employed by Ob/Gyns? What impact do you see this statement having on their future use?

<huc>A</huc> NORWITZ: HUAM testing had largely fallen by the wayside even before this bulletin was published. Most obstetric-care providers were already aware of the extensive literature showing that HUAM does not prevent preterm birth or improve perinatal outcome.^8-11

As for salivary estriol, the development of a reliable endocrine assay to predict PTD would represent a significant advance in the field. Progesterone withdrawal is not a prerequisite for labor; nor are serum progesterone levels or progesterone/17ß-estradiol ratios predictive of preterm birth.^12,1

Lower-genital-tract BV may be a marker of upper-genital-tract infection, which in turn may be the real cause of preterm birth.

On the other hand, maternal serum estriol levels accurately reflect activation of the fetal hypothalamic-pituitary-adrenal axis, which occurs in all women prior to the onset of labor, both at term and preterm.^13,14 More-over, salivary estriol measurements correlate well with levels of biologically active (unconjugated) estriol in the circulation.¹⁵ The detection of elevated levels of estriol (≥2.1 ng/mL) in maternal saliva is predictive of delivery prior to 37 weeks in a high-risk population, with a sensitivity of 68% to 87% and a specificity of 77%.^16,17 Serial (weekly) measurements have been shown to be more accurate in predicting preterm birth than a single measurement.¹⁷

However, salivary estriol testing to identify women at high risk of PTD has not been widely accepted. The reasons: First, maternal estriol levels show diurnal variation, peaking at night,¹⁸ making it difficult to standardize such testing. Additionally, the false-positive rate of 23% to 35% is considered unacceptably high and may lead to unnecessary intervention.^16,17 Finally, salivary estriol levels may be suppressed by betamethasone administration, making the test unreliable in patients treated with corticosteroids.¹⁹ The statement in the latest ACOG bulletin that “trials with salivary estriol testing to predict preterm birth have failed to establish its usefulness for anything more than investigational purposes at present”² is likely to further limit the use of this test, and may have the unfortunate effect of discouraging future research in the field.

In regard to BV, recent data demonstrate conclusively that screening and treating low-risk asymptomatic pregnant women for BV does not prevent preterm birth.^20-22 However, the data for women at high risk for preterm birth are conflicting. Some studies suggest that the strategy of screening and treating asymptomatic BV in high-risk women may significantly decrease the incidence of preterm birth and low-birthweight infants.^22-24 But the statement by ACOG that “there are insufficient data to suggest screening and treating women at…high risk will reduce the overall rate of preterm birth”² is likely to limit the use of this strategy. The hypothesis that lower-genital-tract BV may be a marker of upper-genital-tract infection, which in turn is the real cause of preterm labor and delivery, is intriguing and deserves further attention.

The preventive strategy of screening and treating BV should not be confused with the management of women with symptomatic BV. These women should be treated with oral metronidazole after the first trimester, as vaginal metronidazole and clindamycin preparations appear to be less effective during pregnancy.²⁵

<huc>Q</huc> OBG Management: The Practice Bulletin also stated that, “Screening for risk of preterm labor by means other than historic risk factors is not beneficial in the general obstetric population.” Please outline this set of historic risk factors.

<huc>A</huc> NORWITZ: Risk factors for preterm birth resulting from spontaneous preterm labor, which excludes indicated (iatrogenic) PTD for severe preeclampsia, a prior high vertical (“classical”) cesarean, or chorioamnionitis, are as follows:

• Demographic characteristics such as African-American race, poor socioeconomic status, low pre-pregnancy weight, extremes of maternal age, and absent or inadequate prenatal care.
• Behavioral factors such as cigarette smoking, substance abuse, and high personal stress or a strenuous work environment.
• Aspects of obstetric history such as prior PTD, multiple gestation, uterine anomalies, anemia, polyhydramnios, vaginal bleeding, cervical incompetence, and BV.

Several scoring systems have been developed to predict a woman’s likelihood of delivering preterm. However, reliance on risk factors alone will fail to identify more than 50% of pregnancies that deliver at less than 37 weeks.^26,27

The most important risk factor is a history of one or more preterm deliveries. If the prior PTD was due to spontaneous preterm labor, a screening strategy comprised of serial cervical examinations and/or fFN testing should be initiated in the mid- to late second trimester.

Sonography has shown a strong correlation between cervical length and PTD.

If the prior PTD is suggestive of cervical incompetence, it may be appropriate to discuss other management options. These include prophylactic cervical cerclage or serial measurements of cervical length using transvaginal sonography and placement of an emergent cerclage, if indicated.²⁸ (The generally accepted definition of cervical incompetence is the inability to support a pregnancy to term due to a structural or functional defect of the cervix. It is characterized by acute, painless dilatation of the cervix, usually in the middle trimester, culminating in prolapse and/or rupture of the membranes, which leads to preterm—and often pre-viable—delivery.) A history of in utero diethylstilbestrol (DES) exposure or multiple gestation in the absence of a history of cervical incompetence is not generally accepted as a sufficient indication for elective cerclage.²⁸

<huc>Q</huc> OBG Management: What about fFN testing and the use of ultrasound to determine cervical length? The ACOG Practice Bulletin recommended that either modality or “a combination of both may be useful in determining high risk for preterm labor,” adding that the clinical utility of both modalities may rest primarily with their negative predictive value. How do you use cervical ultrasound and fFN screening in your practice?

<huc>A</huc>NORWITZ: In women at risk for preterm birth, serial digital evaluation of the cervix starting in the mid- to late second trimester is useful if the examination remains normal. However, an abnormal cervical finding (shortening, dilatation, or both) is associated with PTD in only 4% of low-risk women and in just 12% to 20% of high-risk women.²⁹ Real-time sonographic evaluation of the cervix, on the other hand, has demonstrated a strong and reproducible inverse correlation between cervical length and PTD.^30,31 If the cervical length is lower than the 10th percentile for gestational age, the pregnancy is at a 6-fold increased risk of delivery prior to 35 weeks.³⁰ A cervical length of 15 mm or less at 23 weeks occurs in less than 2% of low-risk women, but is predictive of delivery prior to 28 weeks and 32 weeks in 60% and 90% of cases, respectively.³¹

A cervical length of 2.5 cm or less at 22 to 24 weeks in a pregnancy at high risk for PTD should be considered abnormal and requires further evaluation.

The latest Practice Bulletin concludes that: “Despite the usefulness of cervical length determination by ultrasonography as a predictor of preterm labor, routine use is not recommended because of the lack of proven treatments affecting outcome.”^2,32 Therefore, perinatologists and sonographers should not include cervical-length measurements in routine prenatal ultrasounds. However, in carefully selected women at increased risk for PTD, serial measurements of cervical length may help modify the risk estimate for preterm birth. This is especially true in women with a history suggestive of cervical incompetence in whom cervical cerclage is being considered. That said, it remains unclear whether placement of a cervical cerclage in women with a shortened cervix can prevent preterm birth or improve perinatal outcome.²⁸

Cervical-length measurement as a screening test for preterm birth was accepted relatively quickly in clinical practice. This is likely because of the ready availability of transvaginal ultrasound in most obstetric suites and labor and delivery (L&D) units, and because of a high level of comfort and expertise with its use. The possibility that a shortened cervix may represent cervical incompetence and that placement of a cervical cerclage may serve to avert PTD altogether or at least delay delivery to a more favorable gestational age, also may be a factor in that acceptance.

Obstetric-care providers have been far more skeptical about fFN testing, and its introduction into clinical practice has been more protracted. An elevated level of fFN (≥50 ng/mL) in cervicovaginal secretions, which probably reflects separation of the fetal membranes from the maternal decidua,³³ is associated with premature delivery. However, in a low-risk population, the positive predictive value of a positive fFN test at 22 to 24 weeks for spontaneous PTD prior to 28 weeks and 37 weeks is only 13% and 36%, respectively.³⁴ As such, the value of this test lies primarily in its negative predictive value; 99% of patients with a negative fFN test will not deliver within 7 days.³⁵ ACOG currently recommends the use of this test only in a very specific subgroup of women (particularly, in symptomatic women with intact membranes, cervical dilatation <3 cm, and a gestational age of 24-0/7 to 34-6/7 weeks).^2,6

Cervicovaginal swabs for fFN measurement should be taken prior to bimanual examination. For this reason, the clinician should consider collecting a specimen at the time of initial speculum examination in all women being evaluated for preterm labor, regardless of the initial index of suspicion. There is no charge for discarded specimens.

The ACOG bulletin also states that, in order for the fFN test to be “clinically useful, the results must be available from a laboratory within a time frame that allows for clinical decision-making (ideally within 24 hours).”² The introduction of a rapid fFN test and its approval by the FDA in September 1998 have greatly improved the utility of determining fFN levels in cervicovaginal secretions. The test itself takes 26 minutes to complete, and most laboratories can get a result back to the clinician within 1 to 2 hours.

<huc>Q</huc> OBG Management: What findings on cervical ultrasonography are reassuring for you, and which are nonreassuring?

<huc>A</huc> NORWITZ: The most important measurement on cervical ultrasonography is residual cervical length. Both transvaginal and transperineal sonography are reliable and reproducible ways to assess the length of the cervix,^2,36 although transvaginal sonography is considered by most practitioners to be the gold standard. Mean cervical length changes with gestational age,^30-32 but a cervical length of 2.5 cm or less at 22 to 24 weeks in a pregnancy at high risk for PTD should be considered abnormal and requires further evaluation.

Funneling (or beaking) at the internal os also is concerning as it may indicate an intrinsically weak cervicoisthmic junction suggestive of cervical incompetence, but the data are less consistent. Some studies have found the presence of funneling to be an independent risk factor for preterm birth (independent of cervical length),^37,38 whereas other studies have been unable to confirm this observation.^30,39 It also has been suggested that a “cervical stress test” be performed by applying transfundal pressure and watching for funneling at the internal os, and several studies have shown that a positive test is predictive of PTD.^40,41 Whether such testing should be performed in all women at risk of preterm birth remains unclear.

There are several factors to consider when assessing cervical length and dilatation. These include the orientation of the transducer, the potential distortion of the cervix by the transducer, and the fact that a full bladder may artificially lengthen the cervix and obscure dilatation of the internal os.⁴² Careful attention to maternal position also is essential.⁴³

All cervical abnormalities should be reported to the patient. Deciding whether to repeat the cervical ultrasound in 1 to 2 weeks versus placing a cervical cerclage versus bed rest should be individualized, and will depend on such factors as gestational age, a priori risk of PTD, and patient preference. I typically review in detail the risks and potential benefits of each management option with the patient, and will recommend cervical cerclage if the pregnancy is at high risk of PTD, if the gestational age is less than 24 weeks, and if there is evidence of progressive cervical shortening with a residual length (with or without funneling) of less than 2 cm.

Whether cervical length and fFN are additive in their ability to predict preterm delivery in women at high risk remains controversial.

Although I have chosen 2 cm as a cutoff for recommending cervical cerclage, the optimal cutoff value remains controversial, ranging from 1.5 to 3 cm.³⁸ Whether the cutoff value should differ for women with multiple gestations or women who have had prior cervical surgery is unclear.

<huc>Q</huc> OBG Management: When you use ultrasonography in combination with fFN screening, how do you make decisions based on the combination of results? How do you proceed in the face of discordant findings?

<huc>A</huc> NORWITZ: In my practice, it is unusual for women to be screened with both cervical ultrasound and fFN testing. I use cervical ultrasound more often in the mid- to late second trimester in asymptomatic women with a history of preterm birth suggestive of cervical incompetence, and fFN more often in symptomatic women presenting to the outpatient clinic or L&D unit remote from term. However, there are a few exceptions. These include women with higher-order multiple gestations (triplets and up), in whom the risk of preterm birth remote from term is extremely high, and symptomatic women at 22 to 28 weeks, when the bimanual examination suggests cause for concern and ultrasound confirms substantial cervical shortening.

Whether cervical length and fFN are additive in their ability to predict PTD in women at high risk, or whether they are simply 2 separate methods of assessing the same pathophysiologic process, remains controversial. Recent data suggest that these tests are indeed additive. High-risk women at 22 to 24 weeks with a residual cervical length of less than 2.5 cm and a positive fFN screening test have a 65% risk of delivering at less than 35 weeks, even if they are asymptomatic at presentation.^2,44

A negative fFN test excludes imminent delivery, with less than 1% of such women delivering within 14 days of presentation.

Which of the 2 tests is more reliable in any given patient also is not clear. This becomes important when the testing is discordant. In a woman with an abnormal cervical examination remote from term, a negative fFN test is reassuring because the data suggest that she is highly unlikely to deliver within the next 2 weeks.² How to interpret a positive fFN test in an asymptomatic woman with normal cervical length, however, is not clear. As the bulletin states: “The clinical implications of a positive test have not been evaluated fully.”²

My approach to such patients is to increase antenatal surveillance, but not to modify their care in any other way on the basis of a single positive fFN, i.e., no corticosteroids, no tocolysis, no bed rest. I typically will not repeat the fFN test, although some practitioners would recommend repeating it in 1 to 2 weeks if the patient remains undelivered. Although a subsequent negative fFN test cannot “remove” the implications of the previous positive test, some evidence suggests that 2 negative test results following a positive test reduce the risk of spontaneous preterm birth back to baseline.⁴⁵

<huc>Q</huc> OBG Management: The bulletin stated that fFN may be useful in “avoiding unnecessary intervention” in symptomatic women by virtue of its negative predictive value. What has been your experience in this regard?

<huc>A</huc> NORWITZ: The first question to ask is how best to define a “symptomatic” woman. ACOG says the following symptoms and signs suggestive of preterm labor deserve further evaluation:

• Uterine contractions (with or without pain)
• Intermittent lower abdominal pain, dull backache, pelvic pressure
• Vaginal bleeding during the second or third trimester
• Menstrual-like intestinal cramping (with or without diarrhea)
• Change in vaginal discharge (amount, color, consistency)
• Vague sense of discomfort characterized as “not feeling right”

This question pertains specifically to symptomatic women presenting to the out-patient clinic or to the L&D unit. Of all women at 24-0/7 to 34-6/7 weeks with symptoms or signs suggestive of preterm labor, about 80% will be fFN-negative, i.e., fFN <50 ng/mL in cervicovaginal secretions. A negative fFN test effectively excludes imminent delivery, with less than 1% (1 in 125) of such women delivering within 14 days of presentation.

A positive fFN test, on the other hand, will predict delivery within the next 14 days in only 16% (1 in 6) of symptomatic women. As such, the value of the fFN test lies primarily in its negative predictive value (124 of 125 women with a negative fFN test will not deliver within the next 14 days).^33-35,45 Indeed, a negative fFN test in symptomatic women has been shown to reduce admissions for preterm labor, length of stay, and use of tocolytic agents,⁴⁶ as well as to reduce unnecessary transfers to a tertiary care center.⁴⁷ These benefits translate into substantial cost savings^46,47 and likely minimize adverse events in pregnant women by avoiding unnecessary interventions.

<huc>Q</huc> OBG Management: What is your screening modality of choice for symptomatic women and why?

<huc>A</huc> NORWITZ: Two key elements should be considered when evaluating a woman who presents with 1 or more symptoms or signs suggestive of preterm labor: the gestational age and the best estimate of the patient’s a priori risk of PTD. The latter requires knowledge about the presence or absence of risk factors for preterm birth (especially a history of prior PTD), uterine contractility, cervical examination (including dilatation, effacement, and station), presence or absence of ruptured membranes, and fetal well-being.

If the index of suspicion for PTD is high in a symptomatic woman, admit her for observation to exclude preterm labor.

If the index of suspicion for preterm delivery remote from term is high, the patient should be admitted for observation to exclude preterm labor. Antenatal corticosteroid and tocolytic therapy should be initiated, if indicated. Broad-spectrum antibiotic therapy has not been found to be useful in the setting of preterm labor with intact membranes, although there is a considerable body of evidence demonstrating its efficacy in the setting of ruptured membranes at less than 34 weeks.^48,49 Tocolysis has not been shown to be effective once the fetal membranes are ruptured, and is best avoided in this setting.⁵⁰

If there is no evidence of preterm labor and the index of suspicion for PTD is low, the patient may be discharged home, even if she is symptomatic. Careful follow-up should be arranged within 1 to 2 weeks, and the patient should be counseled to return to the office if the symptoms of preterm labor worsen. In this setting—and depending on the gestational age—it may be appropriate to screen the patient with either fFN or sonographic estimation of cervical length.

The author reports no financial relationship with any companies whose products are mentioned in this article.