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Preventing postpartum depression: Start with women at greatest risk
The last decade has brought appropriate attention to the high prevalence of postpartum mood and anxiety disorders, with postpartum depression (PPD) constituting the most common complication in modern obstetrics.
There have been very substantial efforts in more than 40 states in the United States to enhance screening for PPD and to increase support groups for women with postpartum depressive or anxiety symptoms. However, less focus has been paid to the outcomes of these screening initiatives.
A question that comes to mind is whether patients who are screened actually get referred for treatment, and if they do receive treatment, whether they recover and become well. One study referenced previously in this column noted that even in settings where women are screened for PPD, the vast majority of women are not referred, and of those who are referred, even fewer of those are treated or become well.1
It is noteworthy, then, that the U.S. Preventive Services Task Force has recommended screening for perinatal depression (just before and after birth) and issued draft recommendations regarding prevention of perinatal depression where it is suggested that patients at risk for perinatal depression be referred for appropriate “counseling interventions” – specifically, either cognitive-behavioral therapy (CBT) or interpersonal psychotherapy (IPT).2
The recommendation is a striking one because of the volume of patients who would be included. For example, the USPSTF recommends patients with histories of depression, depression during pregnancy, a history of child abuse, or even a family history of depression should receive preventive interventions with CBT or IPT. The recommendation is puzzling because of the data on risk for perinatal depression in those populations and the lack of available resources for patients who would be deemed “at risk.” Women with histories of depression are at a threefold increased risk for PPD (25%-30%). Depression during pregnancy is the strongest predictor of PPD and risk for PPD among these patients is as high as 75%.
So, there are a vast number of women who may be “at risk” for perinatal depression. But even with some data suggesting that IPT and CBT may be able to prevent perinatal depression, the suggestion that resources be made available to patients who are at risk is naive, because counseling interventions such as IPT or CBT, or even simply referrals to psychiatrists are not available even to patients who screen in for perinatal depression in real time during pregnancy and the postpartum period. I have previously written that the follow-up of women post partum who suffer from PPD is still far from meeting the needs who suffer from the disorder, and early detection and referrals to appropriate clinicians who are facile with both pharmacologic and nonpharmacologic interventions seem the most effective way to manage these patients and to see that they receive treatment.
The question then becomes: If the numbers or scale of the prevention initiative suggested in this draft recommendation from the USPSTF is an overreach, is there a group of patients for whom a preventive intervention could be pursued? The patients at highest risk for PPD include those with a history of PPD (50%), bipolar disorder (50%-60%), or postpartum psychosis (80%). And while there is not substantial literature for specifically using IPT, CBT, or other counseling interventions to mitigate risk for recurrence in women with histories of PPD, bipolar disorder, or postpartum psychosis, there are ways of identifying this population at risk and following them closely to mitigate the risk for recurrence.
To make this recommendation feasible, an infrastructure needs to be in place in both low resource settings and in all communities so that these patients can be referred and effectively treated. If we move to prevention, we ought to start with the populations that we already know are at greatest risk and that we can inquire about, and there are very easy-to-use screens that screen for bipolar disorder or that screen for past history of depression with which these women can be identified.
In committee opinion 757, the American College of Obstetricians and Gynecologists recommends women be screened at least once during the perinatal period for depression and anxiety symptoms and highlighted several validated tools, such as the Edinburgh Postnatal Depression Scale.3 We also need a better system of early detection and early intervention so that women at less-considerable risk for perinatal depression would have the opportunity for early identification, treatment, and referral, which we do not have at the current time.
An update of the ACOG committee opinion also states, “It is recommended that all obstetrician-gynecologists and other obstetric care providers complete a full assessment of mood and emotional well-being (including screening for PPD and anxiety with a validated instrument) during the comprehensive postpartum visit for each patient.” This is recommended in addition to any screening for depression and anxiety during the pregnancy.
It is exciting that after decades of failing to attend to such a common complication of modern obstetrics, particularly now that we understand the adverse effects of PPD as it affects child development, family functioning, and risk for later childhood psychopathology. But in addition to recognizing the problem, we must come up with methods to carefully identify a navigable route for the women suffering from PPD to get their needs met. The route includes publicly identifying the illness, understanding which treatments are most effective and can be scaled for delivery to large numbers of women, and then, most critically, configuring social systems to absorb, effectively manage, and monitor the women we identify as needing treatment.
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. Email him at [email protected].
References
1. J Clin Psychiatry. 2016 Sep;77[9]:1189-200.
2. Draft Recommendation Statement: Perinatal Depression: Preventive Interventions. U.S. Preventive Services Task Force. Aug 2018.
The last decade has brought appropriate attention to the high prevalence of postpartum mood and anxiety disorders, with postpartum depression (PPD) constituting the most common complication in modern obstetrics.
There have been very substantial efforts in more than 40 states in the United States to enhance screening for PPD and to increase support groups for women with postpartum depressive or anxiety symptoms. However, less focus has been paid to the outcomes of these screening initiatives.
A question that comes to mind is whether patients who are screened actually get referred for treatment, and if they do receive treatment, whether they recover and become well. One study referenced previously in this column noted that even in settings where women are screened for PPD, the vast majority of women are not referred, and of those who are referred, even fewer of those are treated or become well.1
It is noteworthy, then, that the U.S. Preventive Services Task Force has recommended screening for perinatal depression (just before and after birth) and issued draft recommendations regarding prevention of perinatal depression where it is suggested that patients at risk for perinatal depression be referred for appropriate “counseling interventions” – specifically, either cognitive-behavioral therapy (CBT) or interpersonal psychotherapy (IPT).2
The recommendation is a striking one because of the volume of patients who would be included. For example, the USPSTF recommends patients with histories of depression, depression during pregnancy, a history of child abuse, or even a family history of depression should receive preventive interventions with CBT or IPT. The recommendation is puzzling because of the data on risk for perinatal depression in those populations and the lack of available resources for patients who would be deemed “at risk.” Women with histories of depression are at a threefold increased risk for PPD (25%-30%). Depression during pregnancy is the strongest predictor of PPD and risk for PPD among these patients is as high as 75%.
So, there are a vast number of women who may be “at risk” for perinatal depression. But even with some data suggesting that IPT and CBT may be able to prevent perinatal depression, the suggestion that resources be made available to patients who are at risk is naive, because counseling interventions such as IPT or CBT, or even simply referrals to psychiatrists are not available even to patients who screen in for perinatal depression in real time during pregnancy and the postpartum period. I have previously written that the follow-up of women post partum who suffer from PPD is still far from meeting the needs who suffer from the disorder, and early detection and referrals to appropriate clinicians who are facile with both pharmacologic and nonpharmacologic interventions seem the most effective way to manage these patients and to see that they receive treatment.
The question then becomes: If the numbers or scale of the prevention initiative suggested in this draft recommendation from the USPSTF is an overreach, is there a group of patients for whom a preventive intervention could be pursued? The patients at highest risk for PPD include those with a history of PPD (50%), bipolar disorder (50%-60%), or postpartum psychosis (80%). And while there is not substantial literature for specifically using IPT, CBT, or other counseling interventions to mitigate risk for recurrence in women with histories of PPD, bipolar disorder, or postpartum psychosis, there are ways of identifying this population at risk and following them closely to mitigate the risk for recurrence.
To make this recommendation feasible, an infrastructure needs to be in place in both low resource settings and in all communities so that these patients can be referred and effectively treated. If we move to prevention, we ought to start with the populations that we already know are at greatest risk and that we can inquire about, and there are very easy-to-use screens that screen for bipolar disorder or that screen for past history of depression with which these women can be identified.
In committee opinion 757, the American College of Obstetricians and Gynecologists recommends women be screened at least once during the perinatal period for depression and anxiety symptoms and highlighted several validated tools, such as the Edinburgh Postnatal Depression Scale.3 We also need a better system of early detection and early intervention so that women at less-considerable risk for perinatal depression would have the opportunity for early identification, treatment, and referral, which we do not have at the current time.
An update of the ACOG committee opinion also states, “It is recommended that all obstetrician-gynecologists and other obstetric care providers complete a full assessment of mood and emotional well-being (including screening for PPD and anxiety with a validated instrument) during the comprehensive postpartum visit for each patient.” This is recommended in addition to any screening for depression and anxiety during the pregnancy.
It is exciting that after decades of failing to attend to such a common complication of modern obstetrics, particularly now that we understand the adverse effects of PPD as it affects child development, family functioning, and risk for later childhood psychopathology. But in addition to recognizing the problem, we must come up with methods to carefully identify a navigable route for the women suffering from PPD to get their needs met. The route includes publicly identifying the illness, understanding which treatments are most effective and can be scaled for delivery to large numbers of women, and then, most critically, configuring social systems to absorb, effectively manage, and monitor the women we identify as needing treatment.
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. Email him at [email protected].
References
1. J Clin Psychiatry. 2016 Sep;77[9]:1189-200.
2. Draft Recommendation Statement: Perinatal Depression: Preventive Interventions. U.S. Preventive Services Task Force. Aug 2018.
The last decade has brought appropriate attention to the high prevalence of postpartum mood and anxiety disorders, with postpartum depression (PPD) constituting the most common complication in modern obstetrics.
There have been very substantial efforts in more than 40 states in the United States to enhance screening for PPD and to increase support groups for women with postpartum depressive or anxiety symptoms. However, less focus has been paid to the outcomes of these screening initiatives.
A question that comes to mind is whether patients who are screened actually get referred for treatment, and if they do receive treatment, whether they recover and become well. One study referenced previously in this column noted that even in settings where women are screened for PPD, the vast majority of women are not referred, and of those who are referred, even fewer of those are treated or become well.1
It is noteworthy, then, that the U.S. Preventive Services Task Force has recommended screening for perinatal depression (just before and after birth) and issued draft recommendations regarding prevention of perinatal depression where it is suggested that patients at risk for perinatal depression be referred for appropriate “counseling interventions” – specifically, either cognitive-behavioral therapy (CBT) or interpersonal psychotherapy (IPT).2
The recommendation is a striking one because of the volume of patients who would be included. For example, the USPSTF recommends patients with histories of depression, depression during pregnancy, a history of child abuse, or even a family history of depression should receive preventive interventions with CBT or IPT. The recommendation is puzzling because of the data on risk for perinatal depression in those populations and the lack of available resources for patients who would be deemed “at risk.” Women with histories of depression are at a threefold increased risk for PPD (25%-30%). Depression during pregnancy is the strongest predictor of PPD and risk for PPD among these patients is as high as 75%.
So, there are a vast number of women who may be “at risk” for perinatal depression. But even with some data suggesting that IPT and CBT may be able to prevent perinatal depression, the suggestion that resources be made available to patients who are at risk is naive, because counseling interventions such as IPT or CBT, or even simply referrals to psychiatrists are not available even to patients who screen in for perinatal depression in real time during pregnancy and the postpartum period. I have previously written that the follow-up of women post partum who suffer from PPD is still far from meeting the needs who suffer from the disorder, and early detection and referrals to appropriate clinicians who are facile with both pharmacologic and nonpharmacologic interventions seem the most effective way to manage these patients and to see that they receive treatment.
The question then becomes: If the numbers or scale of the prevention initiative suggested in this draft recommendation from the USPSTF is an overreach, is there a group of patients for whom a preventive intervention could be pursued? The patients at highest risk for PPD include those with a history of PPD (50%), bipolar disorder (50%-60%), or postpartum psychosis (80%). And while there is not substantial literature for specifically using IPT, CBT, or other counseling interventions to mitigate risk for recurrence in women with histories of PPD, bipolar disorder, or postpartum psychosis, there are ways of identifying this population at risk and following them closely to mitigate the risk for recurrence.
To make this recommendation feasible, an infrastructure needs to be in place in both low resource settings and in all communities so that these patients can be referred and effectively treated. If we move to prevention, we ought to start with the populations that we already know are at greatest risk and that we can inquire about, and there are very easy-to-use screens that screen for bipolar disorder or that screen for past history of depression with which these women can be identified.
In committee opinion 757, the American College of Obstetricians and Gynecologists recommends women be screened at least once during the perinatal period for depression and anxiety symptoms and highlighted several validated tools, such as the Edinburgh Postnatal Depression Scale.3 We also need a better system of early detection and early intervention so that women at less-considerable risk for perinatal depression would have the opportunity for early identification, treatment, and referral, which we do not have at the current time.
An update of the ACOG committee opinion also states, “It is recommended that all obstetrician-gynecologists and other obstetric care providers complete a full assessment of mood and emotional well-being (including screening for PPD and anxiety with a validated instrument) during the comprehensive postpartum visit for each patient.” This is recommended in addition to any screening for depression and anxiety during the pregnancy.
It is exciting that after decades of failing to attend to such a common complication of modern obstetrics, particularly now that we understand the adverse effects of PPD as it affects child development, family functioning, and risk for later childhood psychopathology. But in addition to recognizing the problem, we must come up with methods to carefully identify a navigable route for the women suffering from PPD to get their needs met. The route includes publicly identifying the illness, understanding which treatments are most effective and can be scaled for delivery to large numbers of women, and then, most critically, configuring social systems to absorb, effectively manage, and monitor the women we identify as needing treatment.
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. Email him at [email protected].
References
1. J Clin Psychiatry. 2016 Sep;77[9]:1189-200.
2. Draft Recommendation Statement: Perinatal Depression: Preventive Interventions. U.S. Preventive Services Task Force. Aug 2018.
Options for treatment of bipolar disorder during pregnancy
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
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. Email him at [email protected].
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
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. Email him at [email protected].
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
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. Email him at [email protected].
Fetal exposure to depression: How does ‘dose’ figure in?
The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.
When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.
The ability to factor “dose and duration” of exposure to perinatal psychiatric illness into a model predicting risk for a number of obstetrical or neonatal outcomes allows for a more refined risk-benefit decision with respect to use of antidepressants during pregnancy. For example, there may be a threshold over which it’s even more imperative to treat depression during pregnancy than in women who do not suffer from such severe histories of psychiatric disorder.
Research along these lines has been published in a study in Nursing Research in which the question of the effect of maternal mood on infant outcomes was examined, specifically looking at stress, depression, and intimate partner violence, and not just the presence of these elements, but their duration and intensity both before and during the pregnancy (2015 Sep-Oct;64[5]:331-41).
To do this, researchers examined survey data from Utah’s Pregnancy Risk Assessment Monitoring System of 4,296 women who gave birth during 2009-2011. Stress, depression, and intimate partner violence, and the duration and severity of each, were determined by questionnaire. Those determinations were compared with the outcomes of gestational age, birth weight, neonatal ICU admission, and the symptoms and diagnosis of postpartum depression.
Results of the study included the following: Increased duration of depression was associated with a greater risk of neonatal ICU admission, particularly in women who were depressed both before and during their pregnancy (adjusted odds ratio, 2.48), compared with women who had no depression.
We’ve known for a long time that a history of depression predicts increased risk for postpartum depression. In this particular study, it was actually shown that not just a history of depression, but the duration of experienced depression influenced the risk for postpartum depression.
For example, compared with women with no depression, women who were depressed before but not during their pregnancy had an aOR of 7.67, women depressed during pregnancy but not before had an aOR of 17.65, and women depressed both before and during pregnancy had an aOR of 58.35 – an extraordinary stratification of risk, basically.
What these data begin to suggest is that there may be a continuum of risk when it comes to the effects of exposure to depression (factoring in now dose and duration of exposure) during pregnancy. If risk of adverse outcome increases with greater severity of perinatal psychiatric illness, then a mandate to treat depression during pregnancy, whether with pharmacologic or nonpharmacologic interventions (or, commonly, a combination of the two) becomes that much more imperative. Regardless of the treatment interventions that are used, Such a recommendation dovetails with the literature showing the intergenerational effects of untreated depression. Maternal depression is one of the strongest predictors of later childhood psychopathology. With current national trends moving toward mandating screening initiatives for postpartum depression, the appreciation of the extent to which depression before and during pregnancy drives risk for postpartum mood disorder broadens how we think about mitigating risk for puerperal mood disturbance. Specifically, mitigating the effects of postpartum depression on women, their children, and their families must include more effective management of depression both before and during pregnancy.
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.
The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.
When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.
The ability to factor “dose and duration” of exposure to perinatal psychiatric illness into a model predicting risk for a number of obstetrical or neonatal outcomes allows for a more refined risk-benefit decision with respect to use of antidepressants during pregnancy. For example, there may be a threshold over which it’s even more imperative to treat depression during pregnancy than in women who do not suffer from such severe histories of psychiatric disorder.
Research along these lines has been published in a study in Nursing Research in which the question of the effect of maternal mood on infant outcomes was examined, specifically looking at stress, depression, and intimate partner violence, and not just the presence of these elements, but their duration and intensity both before and during the pregnancy (2015 Sep-Oct;64[5]:331-41).
To do this, researchers examined survey data from Utah’s Pregnancy Risk Assessment Monitoring System of 4,296 women who gave birth during 2009-2011. Stress, depression, and intimate partner violence, and the duration and severity of each, were determined by questionnaire. Those determinations were compared with the outcomes of gestational age, birth weight, neonatal ICU admission, and the symptoms and diagnosis of postpartum depression.
Results of the study included the following: Increased duration of depression was associated with a greater risk of neonatal ICU admission, particularly in women who were depressed both before and during their pregnancy (adjusted odds ratio, 2.48), compared with women who had no depression.
We’ve known for a long time that a history of depression predicts increased risk for postpartum depression. In this particular study, it was actually shown that not just a history of depression, but the duration of experienced depression influenced the risk for postpartum depression.
For example, compared with women with no depression, women who were depressed before but not during their pregnancy had an aOR of 7.67, women depressed during pregnancy but not before had an aOR of 17.65, and women depressed both before and during pregnancy had an aOR of 58.35 – an extraordinary stratification of risk, basically.
What these data begin to suggest is that there may be a continuum of risk when it comes to the effects of exposure to depression (factoring in now dose and duration of exposure) during pregnancy. If risk of adverse outcome increases with greater severity of perinatal psychiatric illness, then a mandate to treat depression during pregnancy, whether with pharmacologic or nonpharmacologic interventions (or, commonly, a combination of the two) becomes that much more imperative. Regardless of the treatment interventions that are used, Such a recommendation dovetails with the literature showing the intergenerational effects of untreated depression. Maternal depression is one of the strongest predictors of later childhood psychopathology. With current national trends moving toward mandating screening initiatives for postpartum depression, the appreciation of the extent to which depression before and during pregnancy drives risk for postpartum mood disorder broadens how we think about mitigating risk for puerperal mood disturbance. Specifically, mitigating the effects of postpartum depression on women, their children, and their families must include more effective management of depression both before and during pregnancy.
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.
The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.
When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.
The ability to factor “dose and duration” of exposure to perinatal psychiatric illness into a model predicting risk for a number of obstetrical or neonatal outcomes allows for a more refined risk-benefit decision with respect to use of antidepressants during pregnancy. For example, there may be a threshold over which it’s even more imperative to treat depression during pregnancy than in women who do not suffer from such severe histories of psychiatric disorder.
Research along these lines has been published in a study in Nursing Research in which the question of the effect of maternal mood on infant outcomes was examined, specifically looking at stress, depression, and intimate partner violence, and not just the presence of these elements, but their duration and intensity both before and during the pregnancy (2015 Sep-Oct;64[5]:331-41).
To do this, researchers examined survey data from Utah’s Pregnancy Risk Assessment Monitoring System of 4,296 women who gave birth during 2009-2011. Stress, depression, and intimate partner violence, and the duration and severity of each, were determined by questionnaire. Those determinations were compared with the outcomes of gestational age, birth weight, neonatal ICU admission, and the symptoms and diagnosis of postpartum depression.
Results of the study included the following: Increased duration of depression was associated with a greater risk of neonatal ICU admission, particularly in women who were depressed both before and during their pregnancy (adjusted odds ratio, 2.48), compared with women who had no depression.
We’ve known for a long time that a history of depression predicts increased risk for postpartum depression. In this particular study, it was actually shown that not just a history of depression, but the duration of experienced depression influenced the risk for postpartum depression.
For example, compared with women with no depression, women who were depressed before but not during their pregnancy had an aOR of 7.67, women depressed during pregnancy but not before had an aOR of 17.65, and women depressed both before and during pregnancy had an aOR of 58.35 – an extraordinary stratification of risk, basically.
What these data begin to suggest is that there may be a continuum of risk when it comes to the effects of exposure to depression (factoring in now dose and duration of exposure) during pregnancy. If risk of adverse outcome increases with greater severity of perinatal psychiatric illness, then a mandate to treat depression during pregnancy, whether with pharmacologic or nonpharmacologic interventions (or, commonly, a combination of the two) becomes that much more imperative. Regardless of the treatment interventions that are used, Such a recommendation dovetails with the literature showing the intergenerational effects of untreated depression. Maternal depression is one of the strongest predictors of later childhood psychopathology. With current national trends moving toward mandating screening initiatives for postpartum depression, the appreciation of the extent to which depression before and during pregnancy drives risk for postpartum mood disorder broadens how we think about mitigating risk for puerperal mood disturbance. Specifically, mitigating the effects of postpartum depression on women, their children, and their families must include more effective management of depression both before and during pregnancy.
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.
Postpartum depression: Moving toward improved screening with a new app
Over the last several years, there’s been increasing interest and ultimately a growing number of mandates across dozens of states to screen women for postpartum depression (PPD). As PPD is the most common, and often devastating, complication in modern obstetrics, screening for it is a movement that I fully support.
What’s been challenging is how to roll out screening in a widespread fashion using a standardized tool that is both easy to use and to score, and that has only a modest number of false positives (i.e., it has good specificity).
The first version of the MGHPDS app combines the Edinburgh Postpartum Depression Scale (EPDS) – the most commonly used screen for PPD – with screening tools that measure sleep disturbance, anxiety, and stress. And while the Edinburgh scale has been an enormous contribution to psychiatry, its implementation in obstetric settings and community settings using pen and pencil has been a challenge at times given the inclusion of some questions that are “reverse scored”; other problems when the EPDS has been scaled for use in large settings include rates of false positives as high as 25%.
Our app, which gives users an opportunity to let us review their scores after giving informed consent, ultimately will lead to the development of a shortened set of questions that zero in on the symptoms most commonly associated with PPD. That information will derive from a validation study looking at how well the questions on the MGHPDS correlate with major depression; we hope to launch version 2.0 in mid-2018. The second version of the app is likely to include some items from the Edinburgh scale and also selected symptoms of anxiety, sleep problems, and perceived stress. Thus, the goal of the second version will be realized: a more specific scale with targeted symptoms that correlate with the clinical diagnosis of depression.
Automatic scoring of the questionnaires leads to an app-generated result across a spectrum from “no evidence of depressive symptoms,” to a message noting concern and instructing the user to seek medical attention. There are also links to educational resources about PPD within the app.
The task of referring women with PPD for treatment and then getting them well is a huge undertaking, and one where we currently are falling short. I have been heartened across the last decade to see the focus land on the issue of PPD screening, but failing to couple screening with evidence-based treatment is an incomplete victory. So with the next version of the app, we want to include treatment tools and a way to track women over time, looking at whether they were treated and if they got well.
We want clinicians to be aware of our app and to share it with their patients. But even more importantly, we want to reach out directly to women because they will lead the way on this effort.
The stakes for unrecognized and untreated PPD are simply too great for women, children, and their families.
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 several years, there’s been increasing interest and ultimately a growing number of mandates across dozens of states to screen women for postpartum depression (PPD). As PPD is the most common, and often devastating, complication in modern obstetrics, screening for it is a movement that I fully support.
What’s been challenging is how to roll out screening in a widespread fashion using a standardized tool that is both easy to use and to score, and that has only a modest number of false positives (i.e., it has good specificity).
The first version of the MGHPDS app combines the Edinburgh Postpartum Depression Scale (EPDS) – the most commonly used screen for PPD – with screening tools that measure sleep disturbance, anxiety, and stress. And while the Edinburgh scale has been an enormous contribution to psychiatry, its implementation in obstetric settings and community settings using pen and pencil has been a challenge at times given the inclusion of some questions that are “reverse scored”; other problems when the EPDS has been scaled for use in large settings include rates of false positives as high as 25%.
Our app, which gives users an opportunity to let us review their scores after giving informed consent, ultimately will lead to the development of a shortened set of questions that zero in on the symptoms most commonly associated with PPD. That information will derive from a validation study looking at how well the questions on the MGHPDS correlate with major depression; we hope to launch version 2.0 in mid-2018. The second version of the app is likely to include some items from the Edinburgh scale and also selected symptoms of anxiety, sleep problems, and perceived stress. Thus, the goal of the second version will be realized: a more specific scale with targeted symptoms that correlate with the clinical diagnosis of depression.
Automatic scoring of the questionnaires leads to an app-generated result across a spectrum from “no evidence of depressive symptoms,” to a message noting concern and instructing the user to seek medical attention. There are also links to educational resources about PPD within the app.
The task of referring women with PPD for treatment and then getting them well is a huge undertaking, and one where we currently are falling short. I have been heartened across the last decade to see the focus land on the issue of PPD screening, but failing to couple screening with evidence-based treatment is an incomplete victory. So with the next version of the app, we want to include treatment tools and a way to track women over time, looking at whether they were treated and if they got well.
We want clinicians to be aware of our app and to share it with their patients. But even more importantly, we want to reach out directly to women because they will lead the way on this effort.
The stakes for unrecognized and untreated PPD are simply too great for women, children, and their families.
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 several years, there’s been increasing interest and ultimately a growing number of mandates across dozens of states to screen women for postpartum depression (PPD). As PPD is the most common, and often devastating, complication in modern obstetrics, screening for it is a movement that I fully support.
What’s been challenging is how to roll out screening in a widespread fashion using a standardized tool that is both easy to use and to score, and that has only a modest number of false positives (i.e., it has good specificity).
The first version of the MGHPDS app combines the Edinburgh Postpartum Depression Scale (EPDS) – the most commonly used screen for PPD – with screening tools that measure sleep disturbance, anxiety, and stress. And while the Edinburgh scale has been an enormous contribution to psychiatry, its implementation in obstetric settings and community settings using pen and pencil has been a challenge at times given the inclusion of some questions that are “reverse scored”; other problems when the EPDS has been scaled for use in large settings include rates of false positives as high as 25%.
Our app, which gives users an opportunity to let us review their scores after giving informed consent, ultimately will lead to the development of a shortened set of questions that zero in on the symptoms most commonly associated with PPD. That information will derive from a validation study looking at how well the questions on the MGHPDS correlate with major depression; we hope to launch version 2.0 in mid-2018. The second version of the app is likely to include some items from the Edinburgh scale and also selected symptoms of anxiety, sleep problems, and perceived stress. Thus, the goal of the second version will be realized: a more specific scale with targeted symptoms that correlate with the clinical diagnosis of depression.
Automatic scoring of the questionnaires leads to an app-generated result across a spectrum from “no evidence of depressive symptoms,” to a message noting concern and instructing the user to seek medical attention. There are also links to educational resources about PPD within the app.
The task of referring women with PPD for treatment and then getting them well is a huge undertaking, and one where we currently are falling short. I have been heartened across the last decade to see the focus land on the issue of PPD screening, but failing to couple screening with evidence-based treatment is an incomplete victory. So with the next version of the app, we want to include treatment tools and a way to track women over time, looking at whether they were treated and if they got well.
We want clinicians to be aware of our app and to share it with their patients. But even more importantly, we want to reach out directly to women because they will lead the way on this effort.
The stakes for unrecognized and untreated PPD are simply too great for women, children, and their families.
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.
Evolving practice in perinatal psychopharmacology: Lessons learned
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.
Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.
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.
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.
Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.
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.
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.
Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.
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.
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.
Perinatal depression screening is just the start
Over the last decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.
The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.
The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.
There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?
This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression (J Clin Psychiatry. 2016 Sep;77[9]:1189-1200).
The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.
Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.
Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.
It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.
This is a wake-up call to consider a refocusing of effort. The importance of identification of women suffering from postpartum depression is clear and intuitive. We should certainly not abandon screening, but perhaps there has been an overemphasis on identification and incomplete attention to ensuring that referral networks and opportunities for clinical follow-up are in place following positive screening. There also has been inadequate focus on the obstacles to getting women in to see clinicians and getting those clinicians up to speed on the evidence base that supports treatment, both pharmacologic or nonpharmacologic.
Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort (MCPAP [Massachusetts Child Psychiatry Access Program] for Moms) to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.
The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
Dr. Cohen is the director of the 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 decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.
The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.
The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.
There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?
This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression (J Clin Psychiatry. 2016 Sep;77[9]:1189-1200).
The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.
Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.
Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.
It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.
This is a wake-up call to consider a refocusing of effort. The importance of identification of women suffering from postpartum depression is clear and intuitive. We should certainly not abandon screening, but perhaps there has been an overemphasis on identification and incomplete attention to ensuring that referral networks and opportunities for clinical follow-up are in place following positive screening. There also has been inadequate focus on the obstacles to getting women in to see clinicians and getting those clinicians up to speed on the evidence base that supports treatment, both pharmacologic or nonpharmacologic.
Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort (MCPAP [Massachusetts Child Psychiatry Access Program] for Moms) to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.
The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
Dr. Cohen is the director of the 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 decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.
The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.
The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.
There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?
This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression (J Clin Psychiatry. 2016 Sep;77[9]:1189-1200).
The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.
Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.
Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.
It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.
This is a wake-up call to consider a refocusing of effort. The importance of identification of women suffering from postpartum depression is clear and intuitive. We should certainly not abandon screening, but perhaps there has been an overemphasis on identification and incomplete attention to ensuring that referral networks and opportunities for clinical follow-up are in place following positive screening. There also has been inadequate focus on the obstacles to getting women in to see clinicians and getting those clinicians up to speed on the evidence base that supports treatment, both pharmacologic or nonpharmacologic.
Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort (MCPAP [Massachusetts Child Psychiatry Access Program] for Moms) to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.
The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
Dr. Cohen is the director of the 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.
The 50-year quest for better pregnancy data
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).
The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Dr. Cohen is the director of the 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.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).
The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Dr. Cohen is the director of the 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.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).
The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Dr. Cohen is the director of the 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.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.
SAGE-547 for depression: Cause for caution and optimism
The importance of postpartum depression, both in terms of its prevalence and the need for appropriate screening and effective treatments, has become an increasingly important area of focus for clinicians, patients, and policymakers. This derives from more than a decade of data on the significant prevalence of the condition, with roughly 10% of women meeting the criteria for major or minor depression during the first 3-6 months post partum.
Over the last 5 years, interest has centered around establishing mechanisms for appropriate perinatal depression screening, most notably the January 2016 recommendation from the U.S. Preventive Services Task Force that all adults should be screened for depression, including the at-risk populations of pregnant and postpartum women. In 2015, the American College of Obstetricians and Gynecologists endorsed screening women for depression and anxiety symptoms at least once during the perinatal period using a validated tool. Unfortunately, we still lack data to support whether screening is effective in getting patients referred for treatment and if it leads to women accessing therapies that will actually get them well.
As we wait for that data and consider ways to best implement enhanced screening, it’s important to take stock of the available treatments for postpartum depression.
Seeking a rapid treatment
The current literature supports efficacy for nonpharmacologic therapies, such as interpersonal psychotherapy and cognitive-behavioral therapy, as well as several antidepressants. The efficacy of antidepressants – such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors – has been demonstrated for postpartum depression, but these agents carry the typical limitations and concerns in terms of side effects and the amount of time required to ascertain if there is benefit. While these are the same challenges seen in treating depression in general, the time to response – often 4-8 weeks – is particularly problematic for postpartum women where the impact of depression on maternal morbidity and child development is so critical.
The field has been clamoring for agents that work more quickly. One possibility in that area is ketamine, which is being studied as a rapid treatment in major depression. The National Institutes of Health also has an initiative underway called RAPID (Rapidly Acting Treatments for Treatment-Resistant Depression), aimed at identifying and testing pharmacologic and nonpharmacologic treatments that produce a response within days rather than weeks.
Recently, considerable interest has focused on SAGE-547, manufactured by Sage Therapeutics, which is a different type of antidepressant. The so-called neurosteriod is an allosteric modulator of the GABAA (gamma-aminobutyric acid type A) receptors. The product was granted fast-track status by the Food and Drug Administration to speed its development as a possible treatment for superrefractory status epilepticus, but it also is being studied for its potential in treating severe postpartum depression.
Approximately a year ago, there was preliminary evidence from an open-label study suggesting rapid response to SAGE-547 for women who received this medicine intravenously in a controlled hospital environment. And in July 2016, the manufacturer announced in a press release unpublished positive results from a small phase II controlled trial of SAGE-547 for the treatment of severe postpartum depression.
Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.
Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.
Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.
Next steps
These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.
One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.
But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.
The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information and resources and conducts clinical care and research in reproductive mental health. He has no financial relationship with SAGE Therapeutics, but he has been a consultant to manufacturers of psychiatric medications.
The importance of postpartum depression, both in terms of its prevalence and the need for appropriate screening and effective treatments, has become an increasingly important area of focus for clinicians, patients, and policymakers. This derives from more than a decade of data on the significant prevalence of the condition, with roughly 10% of women meeting the criteria for major or minor depression during the first 3-6 months post partum.
Over the last 5 years, interest has centered around establishing mechanisms for appropriate perinatal depression screening, most notably the January 2016 recommendation from the U.S. Preventive Services Task Force that all adults should be screened for depression, including the at-risk populations of pregnant and postpartum women. In 2015, the American College of Obstetricians and Gynecologists endorsed screening women for depression and anxiety symptoms at least once during the perinatal period using a validated tool. Unfortunately, we still lack data to support whether screening is effective in getting patients referred for treatment and if it leads to women accessing therapies that will actually get them well.
As we wait for that data and consider ways to best implement enhanced screening, it’s important to take stock of the available treatments for postpartum depression.
Seeking a rapid treatment
The current literature supports efficacy for nonpharmacologic therapies, such as interpersonal psychotherapy and cognitive-behavioral therapy, as well as several antidepressants. The efficacy of antidepressants – such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors – has been demonstrated for postpartum depression, but these agents carry the typical limitations and concerns in terms of side effects and the amount of time required to ascertain if there is benefit. While these are the same challenges seen in treating depression in general, the time to response – often 4-8 weeks – is particularly problematic for postpartum women where the impact of depression on maternal morbidity and child development is so critical.
The field has been clamoring for agents that work more quickly. One possibility in that area is ketamine, which is being studied as a rapid treatment in major depression. The National Institutes of Health also has an initiative underway called RAPID (Rapidly Acting Treatments for Treatment-Resistant Depression), aimed at identifying and testing pharmacologic and nonpharmacologic treatments that produce a response within days rather than weeks.
Recently, considerable interest has focused on SAGE-547, manufactured by Sage Therapeutics, which is a different type of antidepressant. The so-called neurosteriod is an allosteric modulator of the GABAA (gamma-aminobutyric acid type A) receptors. The product was granted fast-track status by the Food and Drug Administration to speed its development as a possible treatment for superrefractory status epilepticus, but it also is being studied for its potential in treating severe postpartum depression.
Approximately a year ago, there was preliminary evidence from an open-label study suggesting rapid response to SAGE-547 for women who received this medicine intravenously in a controlled hospital environment. And in July 2016, the manufacturer announced in a press release unpublished positive results from a small phase II controlled trial of SAGE-547 for the treatment of severe postpartum depression.
Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.
Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.
Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.
Next steps
These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.
One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.
But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.
The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information and resources and conducts clinical care and research in reproductive mental health. He has no financial relationship with SAGE Therapeutics, but he has been a consultant to manufacturers of psychiatric medications.
The importance of postpartum depression, both in terms of its prevalence and the need for appropriate screening and effective treatments, has become an increasingly important area of focus for clinicians, patients, and policymakers. This derives from more than a decade of data on the significant prevalence of the condition, with roughly 10% of women meeting the criteria for major or minor depression during the first 3-6 months post partum.
Over the last 5 years, interest has centered around establishing mechanisms for appropriate perinatal depression screening, most notably the January 2016 recommendation from the U.S. Preventive Services Task Force that all adults should be screened for depression, including the at-risk populations of pregnant and postpartum women. In 2015, the American College of Obstetricians and Gynecologists endorsed screening women for depression and anxiety symptoms at least once during the perinatal period using a validated tool. Unfortunately, we still lack data to support whether screening is effective in getting patients referred for treatment and if it leads to women accessing therapies that will actually get them well.
As we wait for that data and consider ways to best implement enhanced screening, it’s important to take stock of the available treatments for postpartum depression.
Seeking a rapid treatment
The current literature supports efficacy for nonpharmacologic therapies, such as interpersonal psychotherapy and cognitive-behavioral therapy, as well as several antidepressants. The efficacy of antidepressants – such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors – has been demonstrated for postpartum depression, but these agents carry the typical limitations and concerns in terms of side effects and the amount of time required to ascertain if there is benefit. While these are the same challenges seen in treating depression in general, the time to response – often 4-8 weeks – is particularly problematic for postpartum women where the impact of depression on maternal morbidity and child development is so critical.
The field has been clamoring for agents that work more quickly. One possibility in that area is ketamine, which is being studied as a rapid treatment in major depression. The National Institutes of Health also has an initiative underway called RAPID (Rapidly Acting Treatments for Treatment-Resistant Depression), aimed at identifying and testing pharmacologic and nonpharmacologic treatments that produce a response within days rather than weeks.
Recently, considerable interest has focused on SAGE-547, manufactured by Sage Therapeutics, which is a different type of antidepressant. The so-called neurosteriod is an allosteric modulator of the GABAA (gamma-aminobutyric acid type A) receptors. The product was granted fast-track status by the Food and Drug Administration to speed its development as a possible treatment for superrefractory status epilepticus, but it also is being studied for its potential in treating severe postpartum depression.
Approximately a year ago, there was preliminary evidence from an open-label study suggesting rapid response to SAGE-547 for women who received this medicine intravenously in a controlled hospital environment. And in July 2016, the manufacturer announced in a press release unpublished positive results from a small phase II controlled trial of SAGE-547 for the treatment of severe postpartum depression.
Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.
Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.
Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.
Next steps
These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.
One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.
But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.
The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information and resources and conducts clinical care and research in reproductive mental health. He has no financial relationship with SAGE Therapeutics, but he has been a consultant to manufacturers of psychiatric medications.
Perinatal depression screening: New recommendations and challenges
It was almost a year ago that the American College of Obstetricians and Gynecologists came out unequivocally in favor of universal screening for perinatal depression.
In the revised policy statement from ACOG’s Committee on Obstetric Practice, the college recommended that physicians screen women for depression and anxiety symptoms at least once during the perinatal period using a standard, validated tool. ACOG also noted that screening must be coupled with appropriate follow-up and that clinical staff must be prepared to start therapy or refer patients to treatment (Obstet. Gynecol. 2015;125:1268-71).
This move toward routine screening was intuitive given the prevalence of perinatal mood and anxiety disorders.
Fast forward to January 2016 and the U.S. Preventive Services Task Force final recommendation calling for screening all adults for depression, including the at-risk populations of pregnant and postpartum women. Much like the ACOG guidelines, the USPSTF recommendations call for adequate systems to ensure treatment and follow-up (JAMA. 2016 Jan. 26;315[4]:380-7).
These recommendations, although timely, derive from relatively sparse data on the actual effectiveness of perinatal screening. Although the move toward screening is welcome and simply commonsense, it is concerning that there has been very little systematic study of the effectiveness of screening for such a prevalent and impactful illness. At the end of the day, the question remains: Will screening for perinatal depression in obstetric and possibly pediatric settings lead to improved outcomes for patients and families?
We’re screening, but will it make a difference?
As more U.S. states, along with other countries around the world, have begun routine screening of women in the perinatal period, it’s become clear that screening itself is easy to do. What has yet to be adequately demonstrated is how screening moves us toward getting women into treatment and ultimately toward getting women well.
New Jersey and Illinois are good examples of states that should be applauded for recognizing early on how important it is to identify women with perinatal depression. But even in these early-adopter states, the actual implementation of referral systems has been lacking.
Here in Massachusetts, we have a state-funded program designed to teach local women’s health providers – including ob.gyns. – about diagnosing perinatal depression. The MCPAP (Massachusetts Child Psychiatry Access Project) for Moms program also offers resources for consultation and referral. The program is fairly new, so it’s still unclear whether ob.gyns. and primary care physicians will accept the role of de facto mental health treaters, as well as whether the women who are identified through screening will go on to recover acutely and, more importantly, over the long term.
These experiences among the states highlight how great a challenge it is to go from screening to positive health outcomes for women.
Downstream difficulties
A lack of evidence isn’t the only problem. A recent editorial in the Lancet raised the concern that the currently available screening tests are not suitable for clinical practice. The suggestion read to some like heresy.
The Edinburgh Postnatal Depression Scale, which is the most commonly used screening instrument, has a positive predictive value of detecting major depressive disorder of 47%-64%, according to the editorial, making it prone to delivering false positives (doi: 10.1016/S0140-6736[16]00265-8).
“This situation is potentially dangerous,” the Lancet editorial noted, since results of qualitative studies “suggest that women are extremely concerned about depression screening, about the stigma associated with a diagnosis of depression, and that a positive result might lead to an automatic social service referral, and potentially removal of their baby.”
A recent article, published in the New York Times, raises an additional concern about what a depression diagnosis could mean for insurability. The article highlights the experience of a woman whose diagnosis of postpartum depression is creating difficulties for her in getting life insurance. The point is underscored that it is perfectly legal for life and disability insurers to charge more to patients with a diagnosis of mental illness or to deny coverage outright.
No going back
The whole issue of perinatal depression screening has opened a Pandora’s box, and that is a good thing. The conversation is long overdue in America. It is time for greater national awareness and focus on a disease that is as prevalent as perinatal depression and as disabling for women and their families.
The focus up to this point has been on perinatal depression screening, but we’re about to see a shift toward building the community infrastructure that will be critical for managing patients, including those women who have previously been marginalized and have had very poor access to care.
Widespread screening and treatment will also require a level of cooperation between advocacy groups and providers who are multidisciplinary in their approach, taking advantage of both pharmacologic and nonpharmacologic approaches. A model of crossdisciplinary collaboration will include, for example, providers from psychiatrists to therapists to doulas to social workers to clinicians who focus on mother-infant interaction. It is a long list and models for such collaboration are somewhat lacking.
One good example of a pilot effort for such a collaboration is the Massachusetts Postpartum Depression Commission, which includes a full spectrum of participants from doulas, social workers, and perinatal psychiatrists to lay people. The partnerships and the networking that’s going on across disciplines is absolutely new and is going to be essential if we’re going to manage an issue as large as the treatment of perinatal depression.
The enhanced awareness of the need to screen for, identify, and treat postpartum depression will also lead to better tools with greater specificity, perhaps using new technologies for better identification and treatment, everything from telemedicine to smartphone applications.
There will certainly be growing pains as we gather evidence, refine our screening instruments, and build referral systems, but I don’t see this as a reason not to identify illness in this vulnerable population. Rather, it is a charge to the field that there is work to be done.
Dr. Cohen is the director of the 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.
It was almost a year ago that the American College of Obstetricians and Gynecologists came out unequivocally in favor of universal screening for perinatal depression.
In the revised policy statement from ACOG’s Committee on Obstetric Practice, the college recommended that physicians screen women for depression and anxiety symptoms at least once during the perinatal period using a standard, validated tool. ACOG also noted that screening must be coupled with appropriate follow-up and that clinical staff must be prepared to start therapy or refer patients to treatment (Obstet. Gynecol. 2015;125:1268-71).
This move toward routine screening was intuitive given the prevalence of perinatal mood and anxiety disorders.
Fast forward to January 2016 and the U.S. Preventive Services Task Force final recommendation calling for screening all adults for depression, including the at-risk populations of pregnant and postpartum women. Much like the ACOG guidelines, the USPSTF recommendations call for adequate systems to ensure treatment and follow-up (JAMA. 2016 Jan. 26;315[4]:380-7).
These recommendations, although timely, derive from relatively sparse data on the actual effectiveness of perinatal screening. Although the move toward screening is welcome and simply commonsense, it is concerning that there has been very little systematic study of the effectiveness of screening for such a prevalent and impactful illness. At the end of the day, the question remains: Will screening for perinatal depression in obstetric and possibly pediatric settings lead to improved outcomes for patients and families?
We’re screening, but will it make a difference?
As more U.S. states, along with other countries around the world, have begun routine screening of women in the perinatal period, it’s become clear that screening itself is easy to do. What has yet to be adequately demonstrated is how screening moves us toward getting women into treatment and ultimately toward getting women well.
New Jersey and Illinois are good examples of states that should be applauded for recognizing early on how important it is to identify women with perinatal depression. But even in these early-adopter states, the actual implementation of referral systems has been lacking.
Here in Massachusetts, we have a state-funded program designed to teach local women’s health providers – including ob.gyns. – about diagnosing perinatal depression. The MCPAP (Massachusetts Child Psychiatry Access Project) for Moms program also offers resources for consultation and referral. The program is fairly new, so it’s still unclear whether ob.gyns. and primary care physicians will accept the role of de facto mental health treaters, as well as whether the women who are identified through screening will go on to recover acutely and, more importantly, over the long term.
These experiences among the states highlight how great a challenge it is to go from screening to positive health outcomes for women.
Downstream difficulties
A lack of evidence isn’t the only problem. A recent editorial in the Lancet raised the concern that the currently available screening tests are not suitable for clinical practice. The suggestion read to some like heresy.
The Edinburgh Postnatal Depression Scale, which is the most commonly used screening instrument, has a positive predictive value of detecting major depressive disorder of 47%-64%, according to the editorial, making it prone to delivering false positives (doi: 10.1016/S0140-6736[16]00265-8).
“This situation is potentially dangerous,” the Lancet editorial noted, since results of qualitative studies “suggest that women are extremely concerned about depression screening, about the stigma associated with a diagnosis of depression, and that a positive result might lead to an automatic social service referral, and potentially removal of their baby.”
A recent article, published in the New York Times, raises an additional concern about what a depression diagnosis could mean for insurability. The article highlights the experience of a woman whose diagnosis of postpartum depression is creating difficulties for her in getting life insurance. The point is underscored that it is perfectly legal for life and disability insurers to charge more to patients with a diagnosis of mental illness or to deny coverage outright.
No going back
The whole issue of perinatal depression screening has opened a Pandora’s box, and that is a good thing. The conversation is long overdue in America. It is time for greater national awareness and focus on a disease that is as prevalent as perinatal depression and as disabling for women and their families.
The focus up to this point has been on perinatal depression screening, but we’re about to see a shift toward building the community infrastructure that will be critical for managing patients, including those women who have previously been marginalized and have had very poor access to care.
Widespread screening and treatment will also require a level of cooperation between advocacy groups and providers who are multidisciplinary in their approach, taking advantage of both pharmacologic and nonpharmacologic approaches. A model of crossdisciplinary collaboration will include, for example, providers from psychiatrists to therapists to doulas to social workers to clinicians who focus on mother-infant interaction. It is a long list and models for such collaboration are somewhat lacking.
One good example of a pilot effort for such a collaboration is the Massachusetts Postpartum Depression Commission, which includes a full spectrum of participants from doulas, social workers, and perinatal psychiatrists to lay people. The partnerships and the networking that’s going on across disciplines is absolutely new and is going to be essential if we’re going to manage an issue as large as the treatment of perinatal depression.
The enhanced awareness of the need to screen for, identify, and treat postpartum depression will also lead to better tools with greater specificity, perhaps using new technologies for better identification and treatment, everything from telemedicine to smartphone applications.
There will certainly be growing pains as we gather evidence, refine our screening instruments, and build referral systems, but I don’t see this as a reason not to identify illness in this vulnerable population. Rather, it is a charge to the field that there is work to be done.
Dr. Cohen is the director of the 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.
It was almost a year ago that the American College of Obstetricians and Gynecologists came out unequivocally in favor of universal screening for perinatal depression.
In the revised policy statement from ACOG’s Committee on Obstetric Practice, the college recommended that physicians screen women for depression and anxiety symptoms at least once during the perinatal period using a standard, validated tool. ACOG also noted that screening must be coupled with appropriate follow-up and that clinical staff must be prepared to start therapy or refer patients to treatment (Obstet. Gynecol. 2015;125:1268-71).
This move toward routine screening was intuitive given the prevalence of perinatal mood and anxiety disorders.
Fast forward to January 2016 and the U.S. Preventive Services Task Force final recommendation calling for screening all adults for depression, including the at-risk populations of pregnant and postpartum women. Much like the ACOG guidelines, the USPSTF recommendations call for adequate systems to ensure treatment and follow-up (JAMA. 2016 Jan. 26;315[4]:380-7).
These recommendations, although timely, derive from relatively sparse data on the actual effectiveness of perinatal screening. Although the move toward screening is welcome and simply commonsense, it is concerning that there has been very little systematic study of the effectiveness of screening for such a prevalent and impactful illness. At the end of the day, the question remains: Will screening for perinatal depression in obstetric and possibly pediatric settings lead to improved outcomes for patients and families?
We’re screening, but will it make a difference?
As more U.S. states, along with other countries around the world, have begun routine screening of women in the perinatal period, it’s become clear that screening itself is easy to do. What has yet to be adequately demonstrated is how screening moves us toward getting women into treatment and ultimately toward getting women well.
New Jersey and Illinois are good examples of states that should be applauded for recognizing early on how important it is to identify women with perinatal depression. But even in these early-adopter states, the actual implementation of referral systems has been lacking.
Here in Massachusetts, we have a state-funded program designed to teach local women’s health providers – including ob.gyns. – about diagnosing perinatal depression. The MCPAP (Massachusetts Child Psychiatry Access Project) for Moms program also offers resources for consultation and referral. The program is fairly new, so it’s still unclear whether ob.gyns. and primary care physicians will accept the role of de facto mental health treaters, as well as whether the women who are identified through screening will go on to recover acutely and, more importantly, over the long term.
These experiences among the states highlight how great a challenge it is to go from screening to positive health outcomes for women.
Downstream difficulties
A lack of evidence isn’t the only problem. A recent editorial in the Lancet raised the concern that the currently available screening tests are not suitable for clinical practice. The suggestion read to some like heresy.
The Edinburgh Postnatal Depression Scale, which is the most commonly used screening instrument, has a positive predictive value of detecting major depressive disorder of 47%-64%, according to the editorial, making it prone to delivering false positives (doi: 10.1016/S0140-6736[16]00265-8).
“This situation is potentially dangerous,” the Lancet editorial noted, since results of qualitative studies “suggest that women are extremely concerned about depression screening, about the stigma associated with a diagnosis of depression, and that a positive result might lead to an automatic social service referral, and potentially removal of their baby.”
A recent article, published in the New York Times, raises an additional concern about what a depression diagnosis could mean for insurability. The article highlights the experience of a woman whose diagnosis of postpartum depression is creating difficulties for her in getting life insurance. The point is underscored that it is perfectly legal for life and disability insurers to charge more to patients with a diagnosis of mental illness or to deny coverage outright.
No going back
The whole issue of perinatal depression screening has opened a Pandora’s box, and that is a good thing. The conversation is long overdue in America. It is time for greater national awareness and focus on a disease that is as prevalent as perinatal depression and as disabling for women and their families.
The focus up to this point has been on perinatal depression screening, but we’re about to see a shift toward building the community infrastructure that will be critical for managing patients, including those women who have previously been marginalized and have had very poor access to care.
Widespread screening and treatment will also require a level of cooperation between advocacy groups and providers who are multidisciplinary in their approach, taking advantage of both pharmacologic and nonpharmacologic approaches. A model of crossdisciplinary collaboration will include, for example, providers from psychiatrists to therapists to doulas to social workers to clinicians who focus on mother-infant interaction. It is a long list and models for such collaboration are somewhat lacking.
One good example of a pilot effort for such a collaboration is the Massachusetts Postpartum Depression Commission, which includes a full spectrum of participants from doulas, social workers, and perinatal psychiatrists to lay people. The partnerships and the networking that’s going on across disciplines is absolutely new and is going to be essential if we’re going to manage an issue as large as the treatment of perinatal depression.
The enhanced awareness of the need to screen for, identify, and treat postpartum depression will also lead to better tools with greater specificity, perhaps using new technologies for better identification and treatment, everything from telemedicine to smartphone applications.
There will certainly be growing pains as we gather evidence, refine our screening instruments, and build referral systems, but I don’t see this as a reason not to identify illness in this vulnerable population. Rather, it is a charge to the field that there is work to be done.
Dr. Cohen is the director of the 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.
Assessing longer-term effects of SSRI exposure in pregnancy
Over the last 2 decades, the medical community has accumulated more information regarding fetal exposure to selective serotonin reuptake inhibitors than almost any medicine that women take during pregnancy.
Data on the risks for major congenital malformations and even specific malformations, such as cardiac defects, are so vast that they can be confusing for clinicians and researchers alike to digest. Yet the consensus among experts in reproductive safety is that the risk of teratogenesis following fetal exposure to SSRIs is small in terms of absolute risks (N Engl J Med. 2007;356:2732-3.).
But women and their partners are worried about more than the risk of malformations. They also are concerned about how fetal exposure to SSRIs will impact long-term neurobehavioral sequelae. It turns out that is a much more challenging question, and the data available to inform our answers still are relatively sparse.
Research gaps
There have been several reports in the literature that suggest there are modest effects on motor function in children whose mothers used SSRIs during pregnancy, but these reports have not been particularly systematic and have excluded some relevant variables, such as the presence or absence of a psychiatric disorder during pregnancy.
In what is considered a seminal examination of this topic performed more than a decade ago, Dr. Irena Nulman and her colleagues at the Motherisk program in Toronto demonstrated the importance of accounting for postpartum maternal depression and mood. Among a group of children exposed to fluoxetine (Prozac) or tricyclic antidepressants throughout pregnancy, there were no differences in IQ or language development, compared with unexposed children between 15 and 71 months of age. However, children with lower cognitive and language achievement were more likely to have mothers with higher ratings of postpartum mood disturbance (Am J Psychiatry. 2002 Nov;159[11]:1889-95.).
The charge to the field is to tackle this next clinical research frontier: the longer-term effects of fetal exposure to antidepressants and maternal psychiatric illness. Only by factoring in both of these important variables will we be able to get a true model of risk for this very critical issue of longer-term behavioral function.
Recently, researchers attempted to look at this question using data from the Norwegian Mother and Child Cohort study, a large population-based, prospective pregnancy cohort study. Children were assessed at age 3 years and motor development was assessed by maternal reports of fine and gross motor development using items from the Ages and Stages Questionnaire (ASQ). Maternal ASQ scores were compared with data from another Norwegian study in which clinicians assessed motor development using the gross and fine motor Mullen Scales of Early Learning (MSEL).
The strength of the study is that it included a very large number of children – more than 50,000 – although it is noteworthy that only a small percentage of women actually used SSRIs during pregnancy. A total of 381 women reported the use of SSRIs during pregnancy, with about half of the women reporting prolonged use (defined as exposure at two points of observation in the study).
The findings are noteworthy. The study showed that children with prolonged SSRI exposure were more likely to exhibit delays in fine motor development, compared with children with no fetal exposure to SSRIs (odds ratio, 1.42; 95% confidence interval, 1.07-1.87). The association persisted even after adjusting for symptoms of anxiety and depression before and during pregnancy. The severity of maternal depression provided only a partial explanation for the association, and depression after pregnancy appeared to have no impact on the estimated effect of SSRIs during pregnancy (BJOG. 2015 Sep 15. doi: 10.1111/1471-0528.13582).
Personal medicine
So how does the clinician translate these findings into practice? While the study indicates that prolonged prenatal exposure to SSRIs was associated with delayed motor development at age 3 years, the association was very weak, and only a few children had clinically significant impairment in motor development. The finding should be reassuring to many women who are faced with this decision.
The researchers should be commended for trying to at least begin to tackle this critical frontier with respect to the risk-benefit decision in using these medicines during pregnancy. The problem is that in the absence of robust data quantifying the exposure to maternal psychiatric illness, the quality of the data still is somewhat limited.
So far the data indicate that there is not a major signal for neurobehavioral dysregulation associated with fetal exposure to SSRIs. That being said, to adequately answer the question for the field it will be important to conduct a single, prospective study where we can accurately quantify exposure to medicine and exposure to maternal psychiatric illness during pregnancy. That type of study will allow us to assess the relative exposures and come up with a much more refined risk estimate. We also will be able to fold in a critical piece – the role of genomics.
Genomics will play a significant role in determining risk because vulnerability to potential disruption in central nervous system development may be a factor in determining the development of the brain in utero. We know, for example, that prenatal stress affects neuromodulation in the brain, and that vulnerability to disruption will be variable from patient to patient. Prospective studies where we not only quantify what medicines women are taking and the severity of psychiatric illness, but also vulnerability to central nervous system disruption, if any, at the level of the genome will be a critical missing piece for future investigators.
Even similar exposure to medicine and psychiatric disorders may have variable effects on the developing brain. If we can identify that variability at the level of the genome, then we will be able to create a refined model of risk that will dictate personalized medicine with respect to reproductive psychopharmacology.
Dr. Cohen is the director of the 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. To comment, email him at [email protected].
Over the last 2 decades, the medical community has accumulated more information regarding fetal exposure to selective serotonin reuptake inhibitors than almost any medicine that women take during pregnancy.
Data on the risks for major congenital malformations and even specific malformations, such as cardiac defects, are so vast that they can be confusing for clinicians and researchers alike to digest. Yet the consensus among experts in reproductive safety is that the risk of teratogenesis following fetal exposure to SSRIs is small in terms of absolute risks (N Engl J Med. 2007;356:2732-3.).
But women and their partners are worried about more than the risk of malformations. They also are concerned about how fetal exposure to SSRIs will impact long-term neurobehavioral sequelae. It turns out that is a much more challenging question, and the data available to inform our answers still are relatively sparse.
Research gaps
There have been several reports in the literature that suggest there are modest effects on motor function in children whose mothers used SSRIs during pregnancy, but these reports have not been particularly systematic and have excluded some relevant variables, such as the presence or absence of a psychiatric disorder during pregnancy.
In what is considered a seminal examination of this topic performed more than a decade ago, Dr. Irena Nulman and her colleagues at the Motherisk program in Toronto demonstrated the importance of accounting for postpartum maternal depression and mood. Among a group of children exposed to fluoxetine (Prozac) or tricyclic antidepressants throughout pregnancy, there were no differences in IQ or language development, compared with unexposed children between 15 and 71 months of age. However, children with lower cognitive and language achievement were more likely to have mothers with higher ratings of postpartum mood disturbance (Am J Psychiatry. 2002 Nov;159[11]:1889-95.).
The charge to the field is to tackle this next clinical research frontier: the longer-term effects of fetal exposure to antidepressants and maternal psychiatric illness. Only by factoring in both of these important variables will we be able to get a true model of risk for this very critical issue of longer-term behavioral function.
Recently, researchers attempted to look at this question using data from the Norwegian Mother and Child Cohort study, a large population-based, prospective pregnancy cohort study. Children were assessed at age 3 years and motor development was assessed by maternal reports of fine and gross motor development using items from the Ages and Stages Questionnaire (ASQ). Maternal ASQ scores were compared with data from another Norwegian study in which clinicians assessed motor development using the gross and fine motor Mullen Scales of Early Learning (MSEL).
The strength of the study is that it included a very large number of children – more than 50,000 – although it is noteworthy that only a small percentage of women actually used SSRIs during pregnancy. A total of 381 women reported the use of SSRIs during pregnancy, with about half of the women reporting prolonged use (defined as exposure at two points of observation in the study).
The findings are noteworthy. The study showed that children with prolonged SSRI exposure were more likely to exhibit delays in fine motor development, compared with children with no fetal exposure to SSRIs (odds ratio, 1.42; 95% confidence interval, 1.07-1.87). The association persisted even after adjusting for symptoms of anxiety and depression before and during pregnancy. The severity of maternal depression provided only a partial explanation for the association, and depression after pregnancy appeared to have no impact on the estimated effect of SSRIs during pregnancy (BJOG. 2015 Sep 15. doi: 10.1111/1471-0528.13582).
Personal medicine
So how does the clinician translate these findings into practice? While the study indicates that prolonged prenatal exposure to SSRIs was associated with delayed motor development at age 3 years, the association was very weak, and only a few children had clinically significant impairment in motor development. The finding should be reassuring to many women who are faced with this decision.
The researchers should be commended for trying to at least begin to tackle this critical frontier with respect to the risk-benefit decision in using these medicines during pregnancy. The problem is that in the absence of robust data quantifying the exposure to maternal psychiatric illness, the quality of the data still is somewhat limited.
So far the data indicate that there is not a major signal for neurobehavioral dysregulation associated with fetal exposure to SSRIs. That being said, to adequately answer the question for the field it will be important to conduct a single, prospective study where we can accurately quantify exposure to medicine and exposure to maternal psychiatric illness during pregnancy. That type of study will allow us to assess the relative exposures and come up with a much more refined risk estimate. We also will be able to fold in a critical piece – the role of genomics.
Genomics will play a significant role in determining risk because vulnerability to potential disruption in central nervous system development may be a factor in determining the development of the brain in utero. We know, for example, that prenatal stress affects neuromodulation in the brain, and that vulnerability to disruption will be variable from patient to patient. Prospective studies where we not only quantify what medicines women are taking and the severity of psychiatric illness, but also vulnerability to central nervous system disruption, if any, at the level of the genome will be a critical missing piece for future investigators.
Even similar exposure to medicine and psychiatric disorders may have variable effects on the developing brain. If we can identify that variability at the level of the genome, then we will be able to create a refined model of risk that will dictate personalized medicine with respect to reproductive psychopharmacology.
Dr. Cohen is the director of the 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. To comment, email him at [email protected].
Over the last 2 decades, the medical community has accumulated more information regarding fetal exposure to selective serotonin reuptake inhibitors than almost any medicine that women take during pregnancy.
Data on the risks for major congenital malformations and even specific malformations, such as cardiac defects, are so vast that they can be confusing for clinicians and researchers alike to digest. Yet the consensus among experts in reproductive safety is that the risk of teratogenesis following fetal exposure to SSRIs is small in terms of absolute risks (N Engl J Med. 2007;356:2732-3.).
But women and their partners are worried about more than the risk of malformations. They also are concerned about how fetal exposure to SSRIs will impact long-term neurobehavioral sequelae. It turns out that is a much more challenging question, and the data available to inform our answers still are relatively sparse.
Research gaps
There have been several reports in the literature that suggest there are modest effects on motor function in children whose mothers used SSRIs during pregnancy, but these reports have not been particularly systematic and have excluded some relevant variables, such as the presence or absence of a psychiatric disorder during pregnancy.
In what is considered a seminal examination of this topic performed more than a decade ago, Dr. Irena Nulman and her colleagues at the Motherisk program in Toronto demonstrated the importance of accounting for postpartum maternal depression and mood. Among a group of children exposed to fluoxetine (Prozac) or tricyclic antidepressants throughout pregnancy, there were no differences in IQ or language development, compared with unexposed children between 15 and 71 months of age. However, children with lower cognitive and language achievement were more likely to have mothers with higher ratings of postpartum mood disturbance (Am J Psychiatry. 2002 Nov;159[11]:1889-95.).
The charge to the field is to tackle this next clinical research frontier: the longer-term effects of fetal exposure to antidepressants and maternal psychiatric illness. Only by factoring in both of these important variables will we be able to get a true model of risk for this very critical issue of longer-term behavioral function.
Recently, researchers attempted to look at this question using data from the Norwegian Mother and Child Cohort study, a large population-based, prospective pregnancy cohort study. Children were assessed at age 3 years and motor development was assessed by maternal reports of fine and gross motor development using items from the Ages and Stages Questionnaire (ASQ). Maternal ASQ scores were compared with data from another Norwegian study in which clinicians assessed motor development using the gross and fine motor Mullen Scales of Early Learning (MSEL).
The strength of the study is that it included a very large number of children – more than 50,000 – although it is noteworthy that only a small percentage of women actually used SSRIs during pregnancy. A total of 381 women reported the use of SSRIs during pregnancy, with about half of the women reporting prolonged use (defined as exposure at two points of observation in the study).
The findings are noteworthy. The study showed that children with prolonged SSRI exposure were more likely to exhibit delays in fine motor development, compared with children with no fetal exposure to SSRIs (odds ratio, 1.42; 95% confidence interval, 1.07-1.87). The association persisted even after adjusting for symptoms of anxiety and depression before and during pregnancy. The severity of maternal depression provided only a partial explanation for the association, and depression after pregnancy appeared to have no impact on the estimated effect of SSRIs during pregnancy (BJOG. 2015 Sep 15. doi: 10.1111/1471-0528.13582).
Personal medicine
So how does the clinician translate these findings into practice? While the study indicates that prolonged prenatal exposure to SSRIs was associated with delayed motor development at age 3 years, the association was very weak, and only a few children had clinically significant impairment in motor development. The finding should be reassuring to many women who are faced with this decision.
The researchers should be commended for trying to at least begin to tackle this critical frontier with respect to the risk-benefit decision in using these medicines during pregnancy. The problem is that in the absence of robust data quantifying the exposure to maternal psychiatric illness, the quality of the data still is somewhat limited.
So far the data indicate that there is not a major signal for neurobehavioral dysregulation associated with fetal exposure to SSRIs. That being said, to adequately answer the question for the field it will be important to conduct a single, prospective study where we can accurately quantify exposure to medicine and exposure to maternal psychiatric illness during pregnancy. That type of study will allow us to assess the relative exposures and come up with a much more refined risk estimate. We also will be able to fold in a critical piece – the role of genomics.
Genomics will play a significant role in determining risk because vulnerability to potential disruption in central nervous system development may be a factor in determining the development of the brain in utero. We know, for example, that prenatal stress affects neuromodulation in the brain, and that vulnerability to disruption will be variable from patient to patient. Prospective studies where we not only quantify what medicines women are taking and the severity of psychiatric illness, but also vulnerability to central nervous system disruption, if any, at the level of the genome will be a critical missing piece for future investigators.
Even similar exposure to medicine and psychiatric disorders may have variable effects on the developing brain. If we can identify that variability at the level of the genome, then we will be able to create a refined model of risk that will dictate personalized medicine with respect to reproductive psychopharmacology.
Dr. Cohen is the director of the 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. To comment, email him at [email protected].
