Antidepressant Use During Pregnancy: Exploring the Issues

By Arline Kaplan © 2013 (All Rights Reserved)

The extent to which antidepressant use during pregnancy is associated with increased risks of postnatal adaptation syndrome (PNAS), persistent pulmonary hypertension in the newborn (PPHN), first-trimester teratogenicity, stillbirth and infant mortality is explored in two recent journal articles.1, 2

In a recent interview, Nancy Byatt, DO, MBA, a perinatal psychiatrist and Assistant Professor of Psychiatry and Obstetrics & Gynecology at the University of Massachusetts Medical School, said that depression and anxiety are very common during pregnancy and the postpartum period. Approximately 18.4% of women suffer from antenatal depression, and as many as 19.2% experience postpartum depression.  One in five (21.7%) experience anxiety disorders in the third trimester and 11.1% during the first three postpartum months.

In economically developed countries, the prevalence for depression during pregnancy ranges between 7% and 19%, according to obstetrician and epidemiologist Olof Stephansson MD, PhD of the Karolinska University Hospital Solna in Stockholm, Sweden, who is also lead author on a recent major study assessing the relative risks of stillbirth and infant mortality associated with SSRI use during pregnancy.

Conflicting data have led to major controversies regarding antidepressant use during pregnancy, Byatt said.  To help providers “understand the risks and benefits of using antidepressants during pregnancy and apply that knowledge to enhance clinical care,” she and colleagues conducted an extensive review of the literature from 1966 to 2012.

Antidepressants considered in the review included SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs).

The review authors focused on outcomes that “have the most controversy surrounding them,” Byatt said.  These are congenital malformations, postnatal adaptation syndrome and persistent pulmonary hypertension in the newborn.


“The current evidence for malformations is limited because of inconsistent findings and limited methodology of the published studies,” the review authors wrote. “Few studies have controlled for maternal illness, and therefore do not take into account whether reproductive outcomes are due to maternal illness or antidepressant exposure.”

“There are some individual studies that show a risk between specific SSRIs and birth defects, but if you look at the overall evidence, it has not been consistently observed, which is very reassuring,” Byatt said.  “There has not been any single malformation that has been consistently observed across studies with any commonly used antidepressant.”

With regard to PNAS, Byatt said, “our conclusion is that it occurs in up to 30% of neonates who are exposed to antidepressants in late pregnancy.”  It is a transient syndrome, she added, that typically resolves in days and in rare cases, a few weeks.

“The PPHN literature is limited by small and/or uncontrolled studies,” according to the review authors.  Additionally, “there are other reported risk factors, including race, method of delivery, obesity, asthma and diabetes that many studies do not take into account.”

The evidence regarding the risk of PPHN because of in utero antidepressant exposure remains inconclusive, Byatt said.  Some studies suggest a small association, and other studies suggest no association.

Byatt pointed to changes in drug safety advisories on SSRIs and PPHN over the years.  In 2006, the U.S. Food and Drug Administration (FDA) issued a Public Health Advisory warning of a possible link between SSRI antidepressant use during pregnancy and reports of PPHN.  However in 2011, the FDA in a Drug Safety Communications said that given conflicting results from different studies, it is “premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.”

“Overall, we do not recommend discontinuing SSRIs in pregnant women due to the risk of PPHN,” Byatt said.

The overall literature and her communications with other experts in the women’s mental health field, Byatt said,  indicate that “the overall data on SSRI use in pregnancies is reassuring.  SSRIs are considered to be relatively safe for use during pregnancy and the postpartum period.”

As regards other classes of antidepressants, there is limited data, she said.
“Overall, the available studies are reassuring, but not definitive,” she said.

Risks of untreated depression/anxiety

“Pregnant women often present,” Byatt said, because their prior mental health providers, concerned about medication risks, are uncomfortable treating them.
Understandably, providers may worry about the medication risks for the pregnant woman and her fetus/child, Byatt said, but equally important are the risks of untreated depression and anxiety.

“Prenatal depression and anxiety can lead to missed obstetrical appointments, poor nutrition, poor sleep and substance abuse,” she said. “Depression also has been associated with poor birth outcomes, including preterm birth, preeclampsia and an increased risk for delivery of a low birth weight infant.”

Other studies

At about the same time as their literature review on antidepressant use in pregnancy was published, Byatt said there was an article by Nulman and others3 on the neurodevelopment of children following prenatal exposure to the SNRI venlafaxine (Effexor), to SSRIs or to untreated maternal depression.

“This is an excellent study,” Byatt said.  The authors concluded that factors other than antidepressant exposure during pregnancy predicted children’s intellect and behavior and that children of depressed mothers may be at risk of future psychopathology.

“You can extrapolate from the study that if you can help mom go into the postpartum period well and healthy with her symptoms in remission as much as possible, you can set the stage for mom to be in a position to care for the baby in such a way that would mitigate the child’s risk of having their own future mental health symptoms,” she added.

Byatt was somewhat critical of a review by Domar and colleagues4 that discussed the impact of SSRIs on fertility, pregnancy and neonatal health.  Domar et al. contended that there is evidence of risk with the use of SSRI antidepressants by pregnant women, that there is no evidence of improved pregnancy outcomes with SSRIs and that pregnant women along with providers and the public should be advised of this.

Rather than conducting a systematic review of all the available evidence and coming to a nonbiased conclusion, Byatt said, Domar and colleagues cited a “few articles that support their conclusions” which can worsen the stigma and confusion surrounding depression treatment during pregnancy.

The recent population-based cohort study by Stephansson and colleagues conducted in Nordic countries, Byatt described as a “well done and very reassuring study.”

SSRIs and infant death

Analyzing data from Denmark, Finland, Iceland, Norway and Sweden, Stephansson and colleagues looked at the use of SSRIs during pregnancy and the risk of stillbirth and infant mortality.  The large size (more than 1.6 million births) facilitated the study of rare pregnancy outcomes, such as stillbirth, neonatal death and postneonatal death, Stephansson explained.

For the study funded by the Swedish Pharmacy Company and the authors’ affiliations, the researchers obtained information on maternal use of SSRIs from prescription registries.  Exposure was defined as one or more filled prescriptions for an SSRI from three months before the start of pregnancy until birth.  The researchers also gathered information on maternal characteristics, pregnancy and neonatal outcomes from patient and medical birth registries. They then estimated relative risks of stillbirth, neonatal death and postneonatal death associated with SSRI use during pregnancy taking into account maternal characteristics and previous psychiatric hospitalizations.

Among 1,633,877 singleton births in the study from 1996 to 2007, there were 6,054 stillbirths; 3,609 neonatal deaths; and 1,578 postneonatal deaths. A total of 29,228 (1.79%) of mothers had filled a prescription for an SSRI during pregnancy.

“Women taking SSRIs had slightly increased rates of stillbirth and postneonatal death,” said Stephansson, Associate Professor at Karolinska University’s Clinical Epidemiology Unit.   Women exposed to an SSRI had higher rates of stillbirth (4.62 vs. 3.69 per 1000) and postneonatal death (1.38 vs. 0.96 per 1000) than those who did not. The rate of neonatal death was similar between groups (2.54 vs. 2.21 per 1000).

But when the researchers considered maternal factors, there was no association with SSRIs and stillbirth or infant death rates, Stephansson said.  Such factors included the severity of the psychiatric disease history among women taking SSRI drugs during pregnancy, their older age, the tendency for them to be smokers and the greater incidence of diabetes and high blood pressure.

The researchers did acknowledge that they might have overestimated the actual use of antidepressants, because being prescribed a drug doesn’t always equate with using it.  Stephansson noted that the study findings need confirmation by other studies in different settings.

The Nordic team of researchers, Stephansson added, has been looking at various issues involving SSRI use and pregnancy.  Last year, in a large, multinational cohort study, Kieler and colleagues5 found the risk of PPHN “after exposure to any SSRI in late pregnancy was more than doubled.”

The results indicated that out of 11,014 mothers who used antidepressants in late pregnancy (later than gestational week 20), 33 babies (0.2%) were born with PPHN (absolute risk 3 per 1000 live born infants compared with the background incidence of 1.2 per 1000).  With regard to SSRI use in early pregnancy, the results indicated that risk for PPHN was “slightly increased.”   Specific SSRIs had similar increased risks of PPHN, suggesting a class effect.

Currently, the Nordic collaboration team, according to Stephansson, is investigating spontaneous abortions and congenital malformations and their possible association to antidepressant exposure.

Treatment recommendations

For psychiatrists and other physicians working with pregnant women who are depressed and anxious, Stephansson and Byatt offered some recommendations:
General psychiatrists grappling with treatment options for their pregnant patients who are depressed or anxious can be guided by some general principles, Byatt said.

“Consider the risks of exposure to illness itself, the risk of exposure to medications, and work with the patient to minimize the risk of exposure to both,” she said, adding that preconception counseling and psychoeducation can mitigate exposure to untreated illness and medications.

With regard to medications, Byatt said that past medication trials, previous success with symptom remission and women’s preferences should guide treatment decisions.  Additionally, she recommended avoiding polypharmacy when possible.

“It is also important to maximize non-medication treatments, such as cognitive behavior therapy or interpersonal psychotherapy,” she said.

If necessary because of the severity of the illness, Stephansson said, physicians may prescribe SSRIs for their depressed pregnant patients, but they should always maintain close contact with the pregnant patient.”  Pregnant patients, he added, should receive the minimal effective SSRI dose possible, and paroxetine (Paxil) should generally be avoided, because it has been associated with cardiac malformations in some studies.

In her clinical practice, Byatt said that she makes decisions about specific medications on a case-by-case basis. “A current response or history of a positive response to medication should help determine which medication to continue or initiate.  I recommend that providers strongly consider using an antidepressant that the woman is currently responding to or has responded to in the past, to avoid unnecessary exposures during pregnancy.  If a pregnant woman has never been on an antidepressant before, my first-line treatment would be an SSRI.”

Treatment with SSRIs during pregnancy should be a team effort involving the obstetrician and the general practitioner or psychiatrist, Stephansson said, adding that after delivery, the pediatrician also should be informed about the mother taking SSRIs.

1. Byatt N, Deligiannidis KM, Freeman MP.  Antidepressant use in pregnancy: a critical review focused on risks and controversies. Acta Psychiatr Scand. 2013;127(2):94-114.
2.  Stephansson O, Kieler H, Haglund B, et al.  Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013;309(1):48-54.
3.  Nulman I, Koren G, Rovet J, et al.  Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression.  Am J Psychiatry. 2012;169(11):1165-1174.
4.  Domar AD, Moragianni VA, Ryley DA, Urato AC. The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond.  Hum Reprod. 2013;28(1):160-171.
5.  Kieler H, Artama M, Engeland A, et al.  Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population-based cohort study from the five Nordic countries.  BMJ. 2012;344:d8012.

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