Obstetrics

While low-dose aspirin has been shown for decades to decrease the risk of preterm preeclampsia, yet to be established are the optimal dose and time of day to administer aspirin; how preeclampsia risk is best assessed; and at what gestational week it is best to start aspirin.

New findings from a randomized, double-blind, placebo-controlled trial show that a daily 150-mg dose of aspirin, taken at night, significantly reduced incidence of preterm preeclampsia in women identified as being at high risk in the first trimester (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1704559).

copyright Darren Hester/Fotolia.com

copyright Sohel_Parvez_Haque/Thinkstock

While low-dose aspirin has been shown for decades to decrease the risk of preterm preeclampsia, yet to be established are the optimal dose and time of day to administer aspirin; how preeclampsia risk is best assessed; and at what gestational week it is best to start aspirin.

New findings from a randomized, double-blind, placebo-controlled trial show that a daily 150-mg dose of aspirin, taken at night, significantly reduced incidence of preterm preeclampsia in women identified as being at high risk in the first trimester (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1704559).

copyright Darren Hester/Fotolia.com

copyright Sohel_Parvez_Haque/Thinkstock

While low-dose aspirin has been shown for decades to decrease the risk of preterm preeclampsia, yet to be established are the optimal dose and time of day to administer aspirin; how preeclampsia risk is best assessed; and at what gestational week it is best to start aspirin.

New findings from a randomized, double-blind, placebo-controlled trial show that a daily 150-mg dose of aspirin, taken at night, significantly reduced incidence of preterm preeclampsia in women identified as being at high risk in the first trimester (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1704559).

copyright Darren Hester/Fotolia.com

copyright Sohel_Parvez_Haque/Thinkstock

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

With more than 1,000 diseases for which genetic testing is available, and with the completion of the Human Genome Project, more patients are requesting genetic testing and more clinicians are utilizing such testing; it has become mainstream.¹ This increased utilization has resulted in increased cost as well, say Ruzzo and colleagues, who presented research on genetic testing costs and compliance with clinical best practices at the 2017 Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists (ACOG).² But, according to previous research say Ruzzo and colleagues, these costs can be quelled by involving genetic counselors in the test-ordering process.

Just how much cost savings can be achieved? In their quality improvement project, the investigators found that 38.6% of 44 genetic tests reviewed were inappropriately ordered—either they were not indicated (21%), misordered for false reassurance (7%), or inadequately ordered (10.5%). If the tests were ordered as appropriately recommended, a cost savings of $20,912.58 would have been realized, according to the researchers.

Ruzzo and colleagues reviewed 114 charts over a 3-month period for adherence with published clinical practice guidelines. All of the charts were associated with a genetic test billing code for common tests ordered through LabCorp (for cystic fibrosis, BRCA mutation, factor V Leiden, prothrombin, alpha-thalassemia, hemochromatosis, and cell-free DNA).

The researchers concluded that genetic counselor review or involvement in genetic test ordering can decrease inappropriate spending and improve patient care. They pointed out that the 114 charts reviewed represent a fraction of genetic tests ordered at their institution, and further study should broaden the research scope to determine the full extent of the problem.

Ruzzo and colleagues were awarded first prize for their research as presented at ACOG.
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

With more than 1,000 diseases for which genetic testing is available, and with the completion of the Human Genome Project, more patients are requesting genetic testing and more clinicians are utilizing such testing; it has become mainstream.¹ This increased utilization has resulted in increased cost as well, say Ruzzo and colleagues, who presented research on genetic testing costs and compliance with clinical best practices at the 2017 Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists (ACOG).² But, according to previous research say Ruzzo and colleagues, these costs can be quelled by involving genetic counselors in the test-ordering process.

Just how much cost savings can be achieved? In their quality improvement project, the investigators found that 38.6% of 44 genetic tests reviewed were inappropriately ordered—either they were not indicated (21%), misordered for false reassurance (7%), or inadequately ordered (10.5%). If the tests were ordered as appropriately recommended, a cost savings of $20,912.58 would have been realized, according to the researchers.

Ruzzo and colleagues reviewed 114 charts over a 3-month period for adherence with published clinical practice guidelines. All of the charts were associated with a genetic test billing code for common tests ordered through LabCorp (for cystic fibrosis, BRCA mutation, factor V Leiden, prothrombin, alpha-thalassemia, hemochromatosis, and cell-free DNA).

The researchers concluded that genetic counselor review or involvement in genetic test ordering can decrease inappropriate spending and improve patient care. They pointed out that the 114 charts reviewed represent a fraction of genetic tests ordered at their institution, and further study should broaden the research scope to determine the full extent of the problem.

Ruzzo and colleagues were awarded first prize for their research as presented at ACOG.
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

With more than 1,000 diseases for which genetic testing is available, and with the completion of the Human Genome Project, more patients are requesting genetic testing and more clinicians are utilizing such testing; it has become mainstream.¹ This increased utilization has resulted in increased cost as well, say Ruzzo and colleagues, who presented research on genetic testing costs and compliance with clinical best practices at the 2017 Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists (ACOG).² But, according to previous research say Ruzzo and colleagues, these costs can be quelled by involving genetic counselors in the test-ordering process.

Just how much cost savings can be achieved? In their quality improvement project, the investigators found that 38.6% of 44 genetic tests reviewed were inappropriately ordered—either they were not indicated (21%), misordered for false reassurance (7%), or inadequately ordered (10.5%). If the tests were ordered as appropriately recommended, a cost savings of $20,912.58 would have been realized, according to the researchers.

Ruzzo and colleagues reviewed 114 charts over a 3-month period for adherence with published clinical practice guidelines. All of the charts were associated with a genetic test billing code for common tests ordered through LabCorp (for cystic fibrosis, BRCA mutation, factor V Leiden, prothrombin, alpha-thalassemia, hemochromatosis, and cell-free DNA).

The researchers concluded that genetic counselor review or involvement in genetic test ordering can decrease inappropriate spending and improve patient care. They pointed out that the 114 charts reviewed represent a fraction of genetic tests ordered at their institution, and further study should broaden the research scope to determine the full extent of the problem.

Ruzzo and colleagues were awarded first prize for their research as presented at ACOG.
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Labor and delivery mismanaged, child has CP: $30.5M award

Two days later, the mother reported decreased fetal movement; she was admitted to the hospital for continuous fetal heart-rate (FHR) monitoring, and a maternal-fetal medicine (MFM) specialist was consulted. The mother was not placed on FHR monitoring until 2 hours after admission. Three hours after admission, the MFM, by phone, recommended further testing and later, cesarean delivery.

The child was found to have spastic quadriplegic cerebral palsy, profound developmental delays, a seizure disorder, and cortical blindness.

PARENTS' CLAIM:

The child's injuries were due to mismanagement of labor and delivery. The MFM prescribed ultrasonographic biophysical profiles, but they were not performed until 2 hours after ordered. There were 3 ultrasonography (US) technicians at the hospital when the mother was admitted: 1 was on break, another was performing other tests, and the third was not notified because the hospital's computer system was down. When test results were unfavorable, the MFM recommended emergency cesarean delivery. An earlier delivery could have prevented the child's injuries.

DEFENDANTS' DEFENSE:

The infant's injuries were a result of her mother's failure to keep her GDM under control.

VERDICT:

A $30,545,655 Georgia verdict was returned.

Related article:
10 tips for overcoming common challenges of intrapartum fetal monitoring

Did oxytocin cause child's spastic CP? $14.4M verdict

When a woman went to the hospital in labor, her ObGyn ordered oxytocin to enhance delivery. The FHR monitor showed repetitive decelerations for the next hour, dropping to 60 bpm by 8:00 pm, when the ObGyn expedited delivery but did not stop the oxytocin. By 8:20 pm, the baby's head was crowning, but the ObGyn waited another 10 minutes before performing an episiotomy and delivering the baby.  
The child, intubated 5 minutes after birth, was found to have spastic tetraparesis cerebral palsy (CP) with impaired cognition, seizures, and global aphasia.

PARENTS' CLAIM:

The ObGyn and nurses failed to properly monitor labor and delivery. The ObGyn should not have started oxytocin because the patient's labor was progressing normally. He should have taken the mother off oxytocin at 8:00 pm when the FHR dropped to 60 bpm. He should have performed an operative delivery at 8:20 pm when the baby's head crowned. An earlier delivery would have prevented injury.

DEFENDANTS' DEFENSE:

The ObGyn's treatment was within the standard of care. He properly determined that vaginal delivery would be the quickest. It is his practice to stop oxytocin when the FHR slows, though he had no memory of halting oxytocin administration in this case. The baby's CP stemmed from insufficiencies in the placenta, seizures, and meconium aspiration syndrome. 

VERDICT:

A $14.4 million Pennsylvania verdict was returned. The ObGyn was found 60% liable for the baby's injuries and the hospital 40% responsible.

Related article:
Q: Following cesarean delivery, what is the optimal oxytocin infusion duration to prevent postpartum bleeding?

Woman with preeclampsia dies: $6M verdict

A 34-year-old woman had been a patient of her family practitioner (FP) for many years. Her blood pressure (BP) averaged 105/63 mm Hg over that time. At a regular prenatal visit on February 26, the patient reported a headache and cough. Her BP was 130/90 mm Hg and she had gained 8.6 lb since her last visit 4 weeks earlier. She was told to return in 2 weeks.

She contacted her FP 2 days later to report acute vaginal bleeding and a severe headache. The FP sent her to the hospital, where potential placental abruption was considered. Two US studies demonstrated oligohydramnios, intrauterine growth restriction, and a grade II placenta. She continued to have repeated high BP readings, headaches, variable and late decelerations, and a dropping platelet count.

She was discharged on the morning of March 3 and sent to another hospital for a specialized US. The FP spoke to the physician who was to perform the US, advising him by phone and in writing to evaluate the oligohydramnios and intrauterine growth restriction. No other information was provided.

At 6:00 pm on March 3, the patient's husband called the FP to report that his wife was vomiting, reporting abdominal pain and intense headache. He was advised to call back in 1 hour, and when he did, he was told to take his wife to the hospital. At the hospital at 8:50 pm on March 3, her BP was 128/103 mm Hg. She reported throbbing headache, vomiting, and facial edema. She was admitted for observation. 

At 9:30 pm, when the patient's BP was 155/100 mm Hg, a nurse contacted the FP to report the patient's continued throbbing headache and elevated, labile BP. The FP neither requested a consultation with an attending ObGyn nor went to the hospital until 4:31 am on March 4. 

At 3:15 am on March 4, a nurse found the patient with her head hanging over the side of the bed in an obtunded state, having vomited. The rapid response team and an attending ObGyn were called. The ObGyn diagnosed eclampsia, ordered magnesium sulfate and hydralazine and immediately transported her to the operating room for an emergency cesarean delivery. Although the baby was healthy, the mother remained unresponsive. A computed tomography (CT) scan confirmed a massive intracranial hemorrhage. She was pronounced dead at 5:10 pm.

ESTATE'S CLAIM:

The FP negligently deviated from the standard of care, leading to the mother's death. The FP fraudulently misrepresented her experience and training for obstetric conditions. She was negligent for failing to adequately diagnose and react to the patient's condition or refer her to an ObGyn, per hospital policy.

DEFENDANTS' DEFENSE:

The patient's treatment met the standard of care. The FP was credentialed to practice obstetrics at the hospital. The patient's BP never reached or sustained a level that would require the FP to consult an ObGyn until 3:15 am on March 4. When the patient first presented with a headache, the FP had consulted a board-certified ObGyn and an MFM, who suggested continued antepartum testing and induction at 39 weeks. The patient's death was unforeseeable because her BP values were inconsistent; the FP had no knowledge of a family history of stroke. The autopsy reported that a ruptured aneurysm was the cause of death.

VERDICT:

A $6,067,830 Ohio verdict was returned. The award was reduced to $900,000 due to a high/low agreement.

Related article:
Start offering aspirin to pregnant women at high risk for preeclampsia

Fetal abnormalities not diagnosed: Baby has Down syndrome  

On September 6, at 10 weeks' gestation, a woman began prenatal care at a clinic with Dr. A, an ObGyn. The mother participated in the California Prenatal Screening Program and received test results on October 23 that showed normal risk for birth defects. On November 1, she saw Dr. B, another ObGyn, who confirmed the negative prenatal screening and ordered  an US. A radiologist reported to Dr. Bthat the fetal anatomy was not well visualized. When the mother was at 23 2/7 weeks' gestation (December 6), Dr. B told the parents that the US results were normal.

On January 2, the parents saw Dr. A, who disclosed that the US radiology report indicated an incomplete fetal anatomy scan and ordered a repeat US. The US performed on January 17 showed a cardiac defect. Further testing confirmed that the fetus had Down syndrome. The parents scheduled but did not appear for a late-term abortion because they feared that the procedure was illegal. 

PARENTS' CLAIM:

The parents told both ObGyns that they wanted extensive prenatal testing because of a family history of birth defects and that they would terminate the pregnancy if birth defects were discovered. Because Dr. B did not discuss prenatal testing, the parents did not know their child had Down syndrome until it was too late to legally terminate the pregnancy. The mother testified that she had never heard of amniocentesis until mid-January, when a perinatologist confirmed that the baby had Down syndrome.

DEFENDANTS' DEFENSE:

The ObGyns denied having any discussions with the parents about their request for extensive prenatal tests or desire for termination. Difficulty in visualizing the fetus is common in second trimester US, and therefore Dr. B routinely performs another US later in the pregnancy. He also denied responsibility for discussing prenatal testing with the parents, stating that such discussions should happen in the first trimester. Since the parents saw Dr. A during that time, Dr. B believed that those conversations had already taken place. The prenatal screening pamphlet that the mother signed on September 6 discussed amniocentesis. The child's grandmother testified that she had discussed amniocentesis with the parents early in the pregnancy. A clinic employee testified that in January she asked the mother why she had not chosen amniocentesis earlier in the pregnancy; the mother replied that she had decided against it because her prenatal screening test was normal.

VERDICT:

A California defense verdict was returned.

Related article:
When is cell-free DNA best used as a primary screen?

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Labor and delivery mismanaged, child has CP: $30.5M award

Two days later, the mother reported decreased fetal movement; she was admitted to the hospital for continuous fetal heart-rate (FHR) monitoring, and a maternal-fetal medicine (MFM) specialist was consulted. The mother was not placed on FHR monitoring until 2 hours after admission. Three hours after admission, the MFM, by phone, recommended further testing and later, cesarean delivery.

The child was found to have spastic quadriplegic cerebral palsy, profound developmental delays, a seizure disorder, and cortical blindness.

PARENTS' CLAIM:

The child's injuries were due to mismanagement of labor and delivery. The MFM prescribed ultrasonographic biophysical profiles, but they were not performed until 2 hours after ordered. There were 3 ultrasonography (US) technicians at the hospital when the mother was admitted: 1 was on break, another was performing other tests, and the third was not notified because the hospital's computer system was down. When test results were unfavorable, the MFM recommended emergency cesarean delivery. An earlier delivery could have prevented the child's injuries.

DEFENDANTS' DEFENSE:

The infant's injuries were a result of her mother's failure to keep her GDM under control.

VERDICT:

A $30,545,655 Georgia verdict was returned.

Related article:
10 tips for overcoming common challenges of intrapartum fetal monitoring

Did oxytocin cause child's spastic CP? $14.4M verdict

When a woman went to the hospital in labor, her ObGyn ordered oxytocin to enhance delivery. The FHR monitor showed repetitive decelerations for the next hour, dropping to 60 bpm by 8:00 pm, when the ObGyn expedited delivery but did not stop the oxytocin. By 8:20 pm, the baby's head was crowning, but the ObGyn waited another 10 minutes before performing an episiotomy and delivering the baby.  
The child, intubated 5 minutes after birth, was found to have spastic tetraparesis cerebral palsy (CP) with impaired cognition, seizures, and global aphasia.

PARENTS' CLAIM:

The ObGyn and nurses failed to properly monitor labor and delivery. The ObGyn should not have started oxytocin because the patient's labor was progressing normally. He should have taken the mother off oxytocin at 8:00 pm when the FHR dropped to 60 bpm. He should have performed an operative delivery at 8:20 pm when the baby's head crowned. An earlier delivery would have prevented injury.

DEFENDANTS' DEFENSE:

The ObGyn's treatment was within the standard of care. He properly determined that vaginal delivery would be the quickest. It is his practice to stop oxytocin when the FHR slows, though he had no memory of halting oxytocin administration in this case. The baby's CP stemmed from insufficiencies in the placenta, seizures, and meconium aspiration syndrome. 

VERDICT:

A $14.4 million Pennsylvania verdict was returned. The ObGyn was found 60% liable for the baby's injuries and the hospital 40% responsible.

Related article:
Q: Following cesarean delivery, what is the optimal oxytocin infusion duration to prevent postpartum bleeding?

Woman with preeclampsia dies: $6M verdict

A 34-year-old woman had been a patient of her family practitioner (FP) for many years. Her blood pressure (BP) averaged 105/63 mm Hg over that time. At a regular prenatal visit on February 26, the patient reported a headache and cough. Her BP was 130/90 mm Hg and she had gained 8.6 lb since her last visit 4 weeks earlier. She was told to return in 2 weeks.

She contacted her FP 2 days later to report acute vaginal bleeding and a severe headache. The FP sent her to the hospital, where potential placental abruption was considered. Two US studies demonstrated oligohydramnios, intrauterine growth restriction, and a grade II placenta. She continued to have repeated high BP readings, headaches, variable and late decelerations, and a dropping platelet count.

She was discharged on the morning of March 3 and sent to another hospital for a specialized US. The FP spoke to the physician who was to perform the US, advising him by phone and in writing to evaluate the oligohydramnios and intrauterine growth restriction. No other information was provided.

At 6:00 pm on March 3, the patient's husband called the FP to report that his wife was vomiting, reporting abdominal pain and intense headache. He was advised to call back in 1 hour, and when he did, he was told to take his wife to the hospital. At the hospital at 8:50 pm on March 3, her BP was 128/103 mm Hg. She reported throbbing headache, vomiting, and facial edema. She was admitted for observation. 

At 9:30 pm, when the patient's BP was 155/100 mm Hg, a nurse contacted the FP to report the patient's continued throbbing headache and elevated, labile BP. The FP neither requested a consultation with an attending ObGyn nor went to the hospital until 4:31 am on March 4. 

At 3:15 am on March 4, a nurse found the patient with her head hanging over the side of the bed in an obtunded state, having vomited. The rapid response team and an attending ObGyn were called. The ObGyn diagnosed eclampsia, ordered magnesium sulfate and hydralazine and immediately transported her to the operating room for an emergency cesarean delivery. Although the baby was healthy, the mother remained unresponsive. A computed tomography (CT) scan confirmed a massive intracranial hemorrhage. She was pronounced dead at 5:10 pm.

ESTATE'S CLAIM:

The FP negligently deviated from the standard of care, leading to the mother's death. The FP fraudulently misrepresented her experience and training for obstetric conditions. She was negligent for failing to adequately diagnose and react to the patient's condition or refer her to an ObGyn, per hospital policy.

DEFENDANTS' DEFENSE:

The patient's treatment met the standard of care. The FP was credentialed to practice obstetrics at the hospital. The patient's BP never reached or sustained a level that would require the FP to consult an ObGyn until 3:15 am on March 4. When the patient first presented with a headache, the FP had consulted a board-certified ObGyn and an MFM, who suggested continued antepartum testing and induction at 39 weeks. The patient's death was unforeseeable because her BP values were inconsistent; the FP had no knowledge of a family history of stroke. The autopsy reported that a ruptured aneurysm was the cause of death.

VERDICT:

A $6,067,830 Ohio verdict was returned. The award was reduced to $900,000 due to a high/low agreement.

Related article:
Start offering aspirin to pregnant women at high risk for preeclampsia

Fetal abnormalities not diagnosed: Baby has Down syndrome  

On September 6, at 10 weeks' gestation, a woman began prenatal care at a clinic with Dr. A, an ObGyn. The mother participated in the California Prenatal Screening Program and received test results on October 23 that showed normal risk for birth defects. On November 1, she saw Dr. B, another ObGyn, who confirmed the negative prenatal screening and ordered  an US. A radiologist reported to Dr. Bthat the fetal anatomy was not well visualized. When the mother was at 23 2/7 weeks' gestation (December 6), Dr. B told the parents that the US results were normal.

On January 2, the parents saw Dr. A, who disclosed that the US radiology report indicated an incomplete fetal anatomy scan and ordered a repeat US. The US performed on January 17 showed a cardiac defect. Further testing confirmed that the fetus had Down syndrome. The parents scheduled but did not appear for a late-term abortion because they feared that the procedure was illegal. 

PARENTS' CLAIM:

The parents told both ObGyns that they wanted extensive prenatal testing because of a family history of birth defects and that they would terminate the pregnancy if birth defects were discovered. Because Dr. B did not discuss prenatal testing, the parents did not know their child had Down syndrome until it was too late to legally terminate the pregnancy. The mother testified that she had never heard of amniocentesis until mid-January, when a perinatologist confirmed that the baby had Down syndrome.

DEFENDANTS' DEFENSE:

The ObGyns denied having any discussions with the parents about their request for extensive prenatal tests or desire for termination. Difficulty in visualizing the fetus is common in second trimester US, and therefore Dr. B routinely performs another US later in the pregnancy. He also denied responsibility for discussing prenatal testing with the parents, stating that such discussions should happen in the first trimester. Since the parents saw Dr. A during that time, Dr. B believed that those conversations had already taken place. The prenatal screening pamphlet that the mother signed on September 6 discussed amniocentesis. The child's grandmother testified that she had discussed amniocentesis with the parents early in the pregnancy. A clinic employee testified that in January she asked the mother why she had not chosen amniocentesis earlier in the pregnancy; the mother replied that she had decided against it because her prenatal screening test was normal.

VERDICT:

A California defense verdict was returned.

Related article:
When is cell-free DNA best used as a primary screen?

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Labor and delivery mismanaged, child has CP: $30.5M award

Two days later, the mother reported decreased fetal movement; she was admitted to the hospital for continuous fetal heart-rate (FHR) monitoring, and a maternal-fetal medicine (MFM) specialist was consulted. The mother was not placed on FHR monitoring until 2 hours after admission. Three hours after admission, the MFM, by phone, recommended further testing and later, cesarean delivery.

The child was found to have spastic quadriplegic cerebral palsy, profound developmental delays, a seizure disorder, and cortical blindness.

PARENTS' CLAIM:

The child's injuries were due to mismanagement of labor and delivery. The MFM prescribed ultrasonographic biophysical profiles, but they were not performed until 2 hours after ordered. There were 3 ultrasonography (US) technicians at the hospital when the mother was admitted: 1 was on break, another was performing other tests, and the third was not notified because the hospital's computer system was down. When test results were unfavorable, the MFM recommended emergency cesarean delivery. An earlier delivery could have prevented the child's injuries.

DEFENDANTS' DEFENSE:

The infant's injuries were a result of her mother's failure to keep her GDM under control.

VERDICT:

A $30,545,655 Georgia verdict was returned.

Related article:
10 tips for overcoming common challenges of intrapartum fetal monitoring

Did oxytocin cause child's spastic CP? $14.4M verdict

When a woman went to the hospital in labor, her ObGyn ordered oxytocin to enhance delivery. The FHR monitor showed repetitive decelerations for the next hour, dropping to 60 bpm by 8:00 pm, when the ObGyn expedited delivery but did not stop the oxytocin. By 8:20 pm, the baby's head was crowning, but the ObGyn waited another 10 minutes before performing an episiotomy and delivering the baby.  
The child, intubated 5 minutes after birth, was found to have spastic tetraparesis cerebral palsy (CP) with impaired cognition, seizures, and global aphasia.

PARENTS' CLAIM:

The ObGyn and nurses failed to properly monitor labor and delivery. The ObGyn should not have started oxytocin because the patient's labor was progressing normally. He should have taken the mother off oxytocin at 8:00 pm when the FHR dropped to 60 bpm. He should have performed an operative delivery at 8:20 pm when the baby's head crowned. An earlier delivery would have prevented injury.

DEFENDANTS' DEFENSE:

The ObGyn's treatment was within the standard of care. He properly determined that vaginal delivery would be the quickest. It is his practice to stop oxytocin when the FHR slows, though he had no memory of halting oxytocin administration in this case. The baby's CP stemmed from insufficiencies in the placenta, seizures, and meconium aspiration syndrome. 

VERDICT:

A $14.4 million Pennsylvania verdict was returned. The ObGyn was found 60% liable for the baby's injuries and the hospital 40% responsible.

Related article:
Q: Following cesarean delivery, what is the optimal oxytocin infusion duration to prevent postpartum bleeding?

Woman with preeclampsia dies: $6M verdict

A 34-year-old woman had been a patient of her family practitioner (FP) for many years. Her blood pressure (BP) averaged 105/63 mm Hg over that time. At a regular prenatal visit on February 26, the patient reported a headache and cough. Her BP was 130/90 mm Hg and she had gained 8.6 lb since her last visit 4 weeks earlier. She was told to return in 2 weeks.

She contacted her FP 2 days later to report acute vaginal bleeding and a severe headache. The FP sent her to the hospital, where potential placental abruption was considered. Two US studies demonstrated oligohydramnios, intrauterine growth restriction, and a grade II placenta. She continued to have repeated high BP readings, headaches, variable and late decelerations, and a dropping platelet count.

She was discharged on the morning of March 3 and sent to another hospital for a specialized US. The FP spoke to the physician who was to perform the US, advising him by phone and in writing to evaluate the oligohydramnios and intrauterine growth restriction. No other information was provided.

At 6:00 pm on March 3, the patient's husband called the FP to report that his wife was vomiting, reporting abdominal pain and intense headache. He was advised to call back in 1 hour, and when he did, he was told to take his wife to the hospital. At the hospital at 8:50 pm on March 3, her BP was 128/103 mm Hg. She reported throbbing headache, vomiting, and facial edema. She was admitted for observation. 

At 9:30 pm, when the patient's BP was 155/100 mm Hg, a nurse contacted the FP to report the patient's continued throbbing headache and elevated, labile BP. The FP neither requested a consultation with an attending ObGyn nor went to the hospital until 4:31 am on March 4. 

At 3:15 am on March 4, a nurse found the patient with her head hanging over the side of the bed in an obtunded state, having vomited. The rapid response team and an attending ObGyn were called. The ObGyn diagnosed eclampsia, ordered magnesium sulfate and hydralazine and immediately transported her to the operating room for an emergency cesarean delivery. Although the baby was healthy, the mother remained unresponsive. A computed tomography (CT) scan confirmed a massive intracranial hemorrhage. She was pronounced dead at 5:10 pm.

ESTATE'S CLAIM:

The FP negligently deviated from the standard of care, leading to the mother's death. The FP fraudulently misrepresented her experience and training for obstetric conditions. She was negligent for failing to adequately diagnose and react to the patient's condition or refer her to an ObGyn, per hospital policy.

DEFENDANTS' DEFENSE:

The patient's treatment met the standard of care. The FP was credentialed to practice obstetrics at the hospital. The patient's BP never reached or sustained a level that would require the FP to consult an ObGyn until 3:15 am on March 4. When the patient first presented with a headache, the FP had consulted a board-certified ObGyn and an MFM, who suggested continued antepartum testing and induction at 39 weeks. The patient's death was unforeseeable because her BP values were inconsistent; the FP had no knowledge of a family history of stroke. The autopsy reported that a ruptured aneurysm was the cause of death.

VERDICT:

A $6,067,830 Ohio verdict was returned. The award was reduced to $900,000 due to a high/low agreement.

Related article:
Start offering aspirin to pregnant women at high risk for preeclampsia

Fetal abnormalities not diagnosed: Baby has Down syndrome  

On September 6, at 10 weeks' gestation, a woman began prenatal care at a clinic with Dr. A, an ObGyn. The mother participated in the California Prenatal Screening Program and received test results on October 23 that showed normal risk for birth defects. On November 1, she saw Dr. B, another ObGyn, who confirmed the negative prenatal screening and ordered  an US. A radiologist reported to Dr. Bthat the fetal anatomy was not well visualized. When the mother was at 23 2/7 weeks' gestation (December 6), Dr. B told the parents that the US results were normal.

On January 2, the parents saw Dr. A, who disclosed that the US radiology report indicated an incomplete fetal anatomy scan and ordered a repeat US. The US performed on January 17 showed a cardiac defect. Further testing confirmed that the fetus had Down syndrome. The parents scheduled but did not appear for a late-term abortion because they feared that the procedure was illegal. 

PARENTS' CLAIM:

The parents told both ObGyns that they wanted extensive prenatal testing because of a family history of birth defects and that they would terminate the pregnancy if birth defects were discovered. Because Dr. B did not discuss prenatal testing, the parents did not know their child had Down syndrome until it was too late to legally terminate the pregnancy. The mother testified that she had never heard of amniocentesis until mid-January, when a perinatologist confirmed that the baby had Down syndrome.

DEFENDANTS' DEFENSE:

The ObGyns denied having any discussions with the parents about their request for extensive prenatal tests or desire for termination. Difficulty in visualizing the fetus is common in second trimester US, and therefore Dr. B routinely performs another US later in the pregnancy. He also denied responsibility for discussing prenatal testing with the parents, stating that such discussions should happen in the first trimester. Since the parents saw Dr. A during that time, Dr. B believed that those conversations had already taken place. The prenatal screening pamphlet that the mother signed on September 6 discussed amniocentesis. The child's grandmother testified that she had discussed amniocentesis with the parents early in the pregnancy. A clinic employee testified that in January she asked the mother why she had not chosen amniocentesis earlier in the pregnancy; the mother replied that she had decided against it because her prenatal screening test was normal.

VERDICT:

A California defense verdict was returned.

Related article:
When is cell-free DNA best used as a primary screen?

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Editor’s Note: This is the final installment of a six-part series that reviews key concepts and articles that ob.gyns. can use to prepare for the American Board of Obstetrics and Gynecology Maintenance of Certification examination. The series is adapted from Ob/Gyn Board Master (obgynboardmaster.com), an online board review course created by Erudyte. This month’s edition of the Board Corner focuses on narcotic analgesia for breastfeeding women.

The American College of Obstetrics and Gynecologists “Practice Advisories” are released when there is an important clinical issue that needs immediate attention from ob.gyn. clinicians. On April 27, 2017, ACOG joined with the Society for Maternal-Fetal Medicine and the Academy of Breastfeeding Medicine to issue a new practice advisory with recommendations on opiate analgesia in breastfeeding women.¹ These Practice Advisories contain material that may be tested on a board exam. We recommend that you read this Practice Advisory and review it carefully.

A. Morphine IV

B. Butorphanol

C. Acetaminophen with codeine

D. Hydromorphone

E. Morphine (given orally)

The correct answer is C.

Acetaminophen with codeine (aka Tylenol #3 or Tylenol #4) is the least appropriate first-choice narcotic in a breastfeeding postpartum patient after Cesarean delivery as it is the only narcotic among the choices that is metabolized by the enzyme CYP2D6. Morphine, butorphanol, and hydromorphone are all metabolized by CYP450. If a narcotic is indicated, it is better to choose one that is not metabolized by CYP2D6 because of potential side effects in both mothers and infants who may be “CYP2D6 ultrametabolizers” or “CYP2D6 poor metabolizers.”
 

Key points

The key points to remember are:

1. Do not use codeine or tramadol as a first-line narcotic choice in breastfeeding mothers, if possible, because of variable side effects in mothers and infants.

2. The preferred narcotics to use when breastfeeding are butorphanol, morphine, or hydromorphone.

Literature summary

In April, the Food and Drug Administration issued a safety alert and said it is requiring labeling changes for prescription medications containing codeine and tramadol. Specifically, the agency warned against use of codeine and tramadol when breastfeeding. This change is the result of the fact that certain people metabolize codeine and tramadol differently. There are some people – considered CYP2D6 “ultrarapid metabolizers” – who can have levels of the drug in their breast milk that can cause excessive sleepiness and depressed breathing in infants. There is one report of an infant death resulting from codeine use. The frequency of these “rapid metabolizers” is about 4%-5% in the United States.

In addition to the effects on breastfed infants, there are effects on the mother as well. This is because 6% of patients in the United States are “poor metabolizers” who have insufficient pain relief, as well as greater side effects.

Hydrocodone and oxycodone are not addressed in the recent labeling changes. However, “ultrarapid metabolizers” do show more pain relief and pupil restriction.

When comparing codeine with nonsteroidal anti-inflammatory medications (NSAIDs) in abdominal surgery, nine randomized trials failed to show that codeine provided superior pain relief.

Hydromorphone, butorphanol, and morphine are not metabolized by CYP2D6 so the problems faced by “ultrarapid metabolizers” or “poor metabolizers” is not an issue.

oksun70/ThinkStock

Dr. Kairis is an assistant professor in the department of gynecology and obstetrics at Loma Linda (Calif.) University Health and is the director of the Women’s Sexual Medicine Program there. She is on the editorial committee of the Ob/Gyn Board Master. Dr. Siddighi is editor in chief of the Ob/Gyn Board Master and director of female pelvic medicine and reconstructive surgery and director of grand rounds at Loma Linda University Health. Ob.Gyn. News and Ob/Gyn Board Master are owned by the same parent company, Frontline Medical Communications.
 

Reference

1. Practice Advisory on Codeine and Tramadol for Breastfeeding Women. April 27, 2017. American College of Obstetricians and Gynecologists.

Editor’s Note: This is the final installment of a six-part series that reviews key concepts and articles that ob.gyns. can use to prepare for the American Board of Obstetrics and Gynecology Maintenance of Certification examination. The series is adapted from Ob/Gyn Board Master (obgynboardmaster.com), an online board review course created by Erudyte. This month’s edition of the Board Corner focuses on narcotic analgesia for breastfeeding women.

The American College of Obstetrics and Gynecologists “Practice Advisories” are released when there is an important clinical issue that needs immediate attention from ob.gyn. clinicians. On April 27, 2017, ACOG joined with the Society for Maternal-Fetal Medicine and the Academy of Breastfeeding Medicine to issue a new practice advisory with recommendations on opiate analgesia in breastfeeding women.¹ These Practice Advisories contain material that may be tested on a board exam. We recommend that you read this Practice Advisory and review it carefully.

A. Morphine IV

B. Butorphanol

C. Acetaminophen with codeine

D. Hydromorphone

E. Morphine (given orally)

The correct answer is C.

Acetaminophen with codeine (aka Tylenol #3 or Tylenol #4) is the least appropriate first-choice narcotic in a breastfeeding postpartum patient after Cesarean delivery as it is the only narcotic among the choices that is metabolized by the enzyme CYP2D6. Morphine, butorphanol, and hydromorphone are all metabolized by CYP450. If a narcotic is indicated, it is better to choose one that is not metabolized by CYP2D6 because of potential side effects in both mothers and infants who may be “CYP2D6 ultrametabolizers” or “CYP2D6 poor metabolizers.”
 

Key points

The key points to remember are:

1. Do not use codeine or tramadol as a first-line narcotic choice in breastfeeding mothers, if possible, because of variable side effects in mothers and infants.

2. The preferred narcotics to use when breastfeeding are butorphanol, morphine, or hydromorphone.

Literature summary

In April, the Food and Drug Administration issued a safety alert and said it is requiring labeling changes for prescription medications containing codeine and tramadol. Specifically, the agency warned against use of codeine and tramadol when breastfeeding. This change is the result of the fact that certain people metabolize codeine and tramadol differently. There are some people – considered CYP2D6 “ultrarapid metabolizers” – who can have levels of the drug in their breast milk that can cause excessive sleepiness and depressed breathing in infants. There is one report of an infant death resulting from codeine use. The frequency of these “rapid metabolizers” is about 4%-5% in the United States.

In addition to the effects on breastfed infants, there are effects on the mother as well. This is because 6% of patients in the United States are “poor metabolizers” who have insufficient pain relief, as well as greater side effects.

Hydrocodone and oxycodone are not addressed in the recent labeling changes. However, “ultrarapid metabolizers” do show more pain relief and pupil restriction.

When comparing codeine with nonsteroidal anti-inflammatory medications (NSAIDs) in abdominal surgery, nine randomized trials failed to show that codeine provided superior pain relief.

Hydromorphone, butorphanol, and morphine are not metabolized by CYP2D6 so the problems faced by “ultrarapid metabolizers” or “poor metabolizers” is not an issue.

oksun70/ThinkStock

Dr. Kairis is an assistant professor in the department of gynecology and obstetrics at Loma Linda (Calif.) University Health and is the director of the Women’s Sexual Medicine Program there. She is on the editorial committee of the Ob/Gyn Board Master. Dr. Siddighi is editor in chief of the Ob/Gyn Board Master and director of female pelvic medicine and reconstructive surgery and director of grand rounds at Loma Linda University Health. Ob.Gyn. News and Ob/Gyn Board Master are owned by the same parent company, Frontline Medical Communications.
 

Reference

1. Practice Advisory on Codeine and Tramadol for Breastfeeding Women. April 27, 2017. American College of Obstetricians and Gynecologists.

Editor’s Note: This is the final installment of a six-part series that reviews key concepts and articles that ob.gyns. can use to prepare for the American Board of Obstetrics and Gynecology Maintenance of Certification examination. The series is adapted from Ob/Gyn Board Master (obgynboardmaster.com), an online board review course created by Erudyte. This month’s edition of the Board Corner focuses on narcotic analgesia for breastfeeding women.

The American College of Obstetrics and Gynecologists “Practice Advisories” are released when there is an important clinical issue that needs immediate attention from ob.gyn. clinicians. On April 27, 2017, ACOG joined with the Society for Maternal-Fetal Medicine and the Academy of Breastfeeding Medicine to issue a new practice advisory with recommendations on opiate analgesia in breastfeeding women.¹ These Practice Advisories contain material that may be tested on a board exam. We recommend that you read this Practice Advisory and review it carefully.

A. Morphine IV

B. Butorphanol

C. Acetaminophen with codeine

D. Hydromorphone

E. Morphine (given orally)

The correct answer is C.

Acetaminophen with codeine (aka Tylenol #3 or Tylenol #4) is the least appropriate first-choice narcotic in a breastfeeding postpartum patient after Cesarean delivery as it is the only narcotic among the choices that is metabolized by the enzyme CYP2D6. Morphine, butorphanol, and hydromorphone are all metabolized by CYP450. If a narcotic is indicated, it is better to choose one that is not metabolized by CYP2D6 because of potential side effects in both mothers and infants who may be “CYP2D6 ultrametabolizers” or “CYP2D6 poor metabolizers.”
 

Key points

The key points to remember are:

1. Do not use codeine or tramadol as a first-line narcotic choice in breastfeeding mothers, if possible, because of variable side effects in mothers and infants.

2. The preferred narcotics to use when breastfeeding are butorphanol, morphine, or hydromorphone.

Literature summary

In April, the Food and Drug Administration issued a safety alert and said it is requiring labeling changes for prescription medications containing codeine and tramadol. Specifically, the agency warned against use of codeine and tramadol when breastfeeding. This change is the result of the fact that certain people metabolize codeine and tramadol differently. There are some people – considered CYP2D6 “ultrarapid metabolizers” – who can have levels of the drug in their breast milk that can cause excessive sleepiness and depressed breathing in infants. There is one report of an infant death resulting from codeine use. The frequency of these “rapid metabolizers” is about 4%-5% in the United States.

In addition to the effects on breastfed infants, there are effects on the mother as well. This is because 6% of patients in the United States are “poor metabolizers” who have insufficient pain relief, as well as greater side effects.

Hydrocodone and oxycodone are not addressed in the recent labeling changes. However, “ultrarapid metabolizers” do show more pain relief and pupil restriction.

When comparing codeine with nonsteroidal anti-inflammatory medications (NSAIDs) in abdominal surgery, nine randomized trials failed to show that codeine provided superior pain relief.

Hydromorphone, butorphanol, and morphine are not metabolized by CYP2D6 so the problems faced by “ultrarapid metabolizers” or “poor metabolizers” is not an issue.

oksun70/ThinkStock

Dr. Kairis is an assistant professor in the department of gynecology and obstetrics at Loma Linda (Calif.) University Health and is the director of the Women’s Sexual Medicine Program there. She is on the editorial committee of the Ob/Gyn Board Master. Dr. Siddighi is editor in chief of the Ob/Gyn Board Master and director of female pelvic medicine and reconstructive surgery and director of grand rounds at Loma Linda University Health. Ob.Gyn. News and Ob/Gyn Board Master are owned by the same parent company, Frontline Medical Communications.
 

Reference

1. Practice Advisory on Codeine and Tramadol for Breastfeeding Women. April 27, 2017. American College of Obstetricians and Gynecologists.

FROM AN ACIP MEETING

New draft recommendations on influenza vaccines for children and pregnant women were unanimously passed by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) after a lengthy debate over specifics regarding recommendations for pregnant women.

The proposed recommendation that sparked the debate would change the wording of the previous recommendation for pregnant women to receive a seasonal inactivated vaccine (IIV) to “any licensed, recommended, and age-appropriate, trivalent or quadrivalent IIV or RIV [recombinant influenza vaccine] may be used.”

Steve Mann/Thinkstock

[email protected]

On Twitter @eaztweets

FROM AN ACIP MEETING

New draft recommendations on influenza vaccines for children and pregnant women were unanimously passed by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) after a lengthy debate over specifics regarding recommendations for pregnant women.

The proposed recommendation that sparked the debate would change the wording of the previous recommendation for pregnant women to receive a seasonal inactivated vaccine (IIV) to “any licensed, recommended, and age-appropriate, trivalent or quadrivalent IIV or RIV [recombinant influenza vaccine] may be used.”

Steve Mann/Thinkstock

[email protected]

On Twitter @eaztweets

FROM AN ACIP MEETING

New draft recommendations on influenza vaccines for children and pregnant women were unanimously passed by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) after a lengthy debate over specifics regarding recommendations for pregnant women.

The proposed recommendation that sparked the debate would change the wording of the previous recommendation for pregnant women to receive a seasonal inactivated vaccine (IIV) to “any licensed, recommended, and age-appropriate, trivalent or quadrivalent IIV or RIV [recombinant influenza vaccine] may be used.”

Steve Mann/Thinkstock

[email protected]

On Twitter @eaztweets

Breastfeeding not only benefits babies; it also may lower the risk for a heart attack or stroke later in life for mothers who breastfeed more than for women who don’t.

The findings, which were published online June 21 in the Journal of the American Heart Association, are based on data from a prospective study of nearly 300,000 women in China.

©Jupiterimages/Thinkstock

Breastfeeding not only benefits babies; it also may lower the risk for a heart attack or stroke later in life for mothers who breastfeed more than for women who don’t.

The findings, which were published online June 21 in the Journal of the American Heart Association, are based on data from a prospective study of nearly 300,000 women in China.

©Jupiterimages/Thinkstock

Breastfeeding not only benefits babies; it also may lower the risk for a heart attack or stroke later in life for mothers who breastfeed more than for women who don’t.

The findings, which were published online June 21 in the Journal of the American Heart Association, are based on data from a prospective study of nearly 300,000 women in China.

©Jupiterimages/Thinkstock

A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression (HAM-D) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores, the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.

A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression (HAM-D) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores, the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.

A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression (HAM-D) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores, the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.

NEW ORLEANS – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.

“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”

Dr. Coyle, director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center, said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.

The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”

Counseling tips

She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”

Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”

Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
 

Disease-modifying therapies

When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.

The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”

Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.

Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”

Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.

Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.

Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.

[email protected]

NEW ORLEANS – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.

“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”

Dr. Coyle, director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center, said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.

The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”

Counseling tips

She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”

Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”

Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
 

Disease-modifying therapies

When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.

The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”

Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.

Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”

Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.

Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.

Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.

[email protected]

NEW ORLEANS – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.

“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”

Dr. Coyle, director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center, said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.

The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”

Counseling tips

She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”

Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”

Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
 

Disease-modifying therapies

When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.

The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”

Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.

Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”

Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.

Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.

Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.

[email protected]