Pregnancy and Psychiatry – Literature Review

Literature Review on Pregnancy and Psychiatry

C. R. Hillenbrand, M.D.

Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. (Perinatal and Reproductive Psychiatry Clinical Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Mass 02114, USA. lcohen2@partners.org) Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. Erratum in: JAMA. 2006 Jul 12;296(2):170. Comment in: JAMA. 2006 Jul 12;296(2):165; author reply 166-7; JAMA. 2006 Jul 12;296(2):166; author reply 166-7; JAMA. 2006 Jul 12;296(2):165-6; author reply 166-7. CONTEXT: Pregnancy has historically been described as a time of emotional well-being, providing “protection” against psychiatric disorder. However, systematic delineation of risk of relapse in women who maintain or discontinue pharmacological treatment during pregnancy is necessary. OBJECTIVE: To describe risk of relapse in pregnant women who discontinued antidepressant medication proximate to conception compared with those who maintained treatment with these medications. DESIGN, SETTING, AND PATIENTS: A prospective naturalistic investigation using longitudinal psychiatric assessments on a monthly basis across pregnancy; a survival analysis was conducted to determine time to relapse of depression during pregnancy. A total of 201 pregnant women were enrolled between March 1999 and April 2003 from 3 centers with specific expertise in the treatment of psychiatric illness during pregnancy. The cohort of women was recruited from (1) within the hospital clinics, (2) self-referral via advertisements and community outreach detailing the study, and (3) direct referrals from the community. Participants were considered eligible if they (1) had a history of major depression prior to pregnancy, (2) were less than 16 weeks’ gestation, (3) were euthymic for at least 3 months prior to their last menstrual period, and (4) were currently or recently (<12 weeks prior to last menstrual period) receiving antidepressant treatment. Of the 201 participants, 13 miscarried, 5 electively terminated their pregnancy, 12 were lost to follow-up prior to completion of pregnancy, and 8 chose to discontinue participation in the study. MAIN OUTCOME MEASURE: Relapse of major depression defined as fulfilling Structured Clinical Interview for DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition] Diagnosis (SCID) criteria. RESULTS: Among the 201 women in the sample, 86 (43%) experienced a relapse of major depression during pregnancy. Among the 82 women who maintained their medication throughout their pregnancy, 21 (26%) relapsed compared with 44 (68%) of the 65 women who discontinued medication. Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared with women who maintained their medication (hazard ratio, 5.0; 95% confidence interval, 2.8-9.1; P<.001). CONCLUSIONS: Pregnancy is not “protective” with respect to risk of relapse of major depression. Women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation.

Andrade C. (Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore 560 029, India.) Continuing medical education: SSRIs and pregnancy. Indian J Psychiatry. 2010 Jan; 52 (1): 83-86. (This article can be purchased for $5 at http://www.indianjpsychiatry.org/article.asp?issn=0019-5545;year=2010;volume=52;issue=1;spage=83;epage=86;aulast=Andrade …and may not be worth it.)

Science Update
March 19, 2009

Premature Birth Risk Higher for Pregnant Women Taking SSRIs or Suffering from Untreated Depression
Untreated major depression, as well as the use of antidepressant medications, may increase the risk for premature (preterm) birth, but the risk of other problems in fetuses such as breathing, gastrointestinal, or motor problems, may not be increased, according to a study of pregnant women published online ahead of print March 15, 2009, in the American Journal of Psychiatry.

Background
Use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), is common among women of childbearing age. Although there is some concern regarding the use of SSRIs during pregnancy and their effects on the growing fetus, research results have been mixed. Overall, it appears the risk for major birth defects is very low, but the risk for other complications, such as minor physical anomalies—a specific type of birth defect—or preterm birth (before 37 weeks gestation), has not been consistently established.

Katherine L. Wisner, M.D., of the University of Pittsburgh, and colleagues aimed to determine whether the use of SSRIs or the existence of major depression during pregnancy was associated with minor physical anomalies in the baby, low infant birth weight, preterm birth or other issues. In this observational study, the researchers categorized 238 pregnant women in Cleveland, Ohio, and Pittsburgh, Pa., into one of three groups:

• no use of SSRIs and no major depression during pregnancy (131 women);
• use of SSRIs either at some point (23 women) or throughout the pregnancy (48 women);
• those who had major depression—either at some point (22 women) or throughout the pregnancy (14 women)—but who remained unmedicated.

The researchers gave general advice to the women about managing major depression and use of SSRIs, but they did not interfere in treatment decisions made by the women and their doctors. Wisner and colleagues examined various outcomes, such as maternal weight gain, pregnancy duration, minor physical anomalies in the infant, infant birth weight, and other infant characteristics.

Results of the Study
Wisner and colleagues found that for both pregnant women with untreated major depression and for those who were taking SSRIs throughout their pregnancy, more than 20 percent of infants were delivered preterm. In comparison, only 4 percent of infants partially exposed to SSRIs during gestation and 6 percent not exposed at all to SSRIs or depression during gestation were delivered pre-term.

Neither the use of SSRIs nor major depression was associated with an increase in minor physical anomalies; short-term medication-associated issues like breathing, gastrointestinal or motor problems; or reduced weight gain among the women during pregnancy. Birth weight of infants also did not differ across groups.

Significance
The results support other studies that have found a link between continuous SSRI treatment and an increase in risk of preterm birth, but they are not consistent with studies that have found an increased risk of drug-associated issues in infants exposed to SSRIs while in the womb. However, the researchers note that untreated depression among pregnant women may present the same risk to infants as SSRI use, reiterating the need for doctors to work with individual patients to balance the risks and benefits of SSRI use and the treatment of major depression during pregnancy.

What’s Next
More research is needed to better determine whether women with major depression who are treated with SSRIs and experience remission during pregnancy have more favorable outcomes compared to unmedicated depressed women. In addition, larger studies may be able to determine differences in outcomes among SSRIs. Finally, more research into non-medication interventions for treating depression during pregnancy, including psychotherapy and other approaches, is also needed.
Reference: Wisner KL, Sit DKY, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Jones-Ivy S, Bodnar LM, Singer LT. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. American Journal of Psychiatry. Online ahead of print March 15, 2009.

Science Update
February 01, 2006

Stopping Antidepressant Use While Pregnant May Pose Risks
Pregnant women who discontinue antidepressant medications may significantly increase their risk of relapse during pregnancy, a new study funded by the National Institute of Health’s National Institute of Mental Health found.

Women in the study who stopped taking antidepressants while pregnant were five times more likely than those who continued use of these medications to experience episodes of depression during pregnancy, reported Lee Cohen, M.D. of Massachusetts General Hospital and colleagues in the February 1 issue of the Journal of the American Medical Association.

Depression is a disabling disorder that has been estimated to affect approximately 10 percent of pregnant women in the United States. Recently there has been concern about the use of antidepressants during pregnancy; however what has not been addressed is the risk of depression recurrence should someone discontinue antidepressant use. This study sheds light on the risk of relapse associated with discontinuing antidepressant therapy during pregnancy.

In the study, Cohen and colleagues enrolled pregnant women already taking antidepressants and then noted how many of the women decided to stop taking their medications. They then assessed the risk of relapse for the women who stopped versus maintained antidepressant therapy.

Contrary to the belief that hormonal changes shield pregnant women from depression, this study demonstrates that pregnancy itself is not protective. Among the pregnant women who stopped taking antidepressants, 68 percent relapsed during pregnancy compared to 26 percent who relapsed despite continuing their antidepressants. Among the women who discontinued use and relapsed, 50 percent experienced a relapse during the first trimester and 90 percent did so by the end of the second trimester.

This study demonstrates the importance of weighing the risks not only of antidepressant use, but also the risk of relapse should antidepressants be discontinued. It highlights the importance of women discussing with their physicians their own individual risks verses benefits of continuing antidepressant use during pregnancy.

 

Press Release – July 30, 2008

Mechanism for Postpartum Depression Found in Mice
Discovery May Lead to Better Treatments
Researchers have pinpointed a mechanism in the brains of mice that could explain why some human mothers become depressed following childbirth. The discovery could lead to improved treatment for postpartum depression. Supported in part by the National Institute of Mental Health, of the National Institutes of Health, the study used genetically engineered mice lacking a protein critical for adapting to the sex hormone fluctuations of pregnancy and the postpartum period.

“For the first time, we may have a highly useful model of postpartum depression,” said NIMH Director Thomas R. Insel, M.D. “The new research also points to a specific potential new target in the brain for medications to treat this disorder that affects 15 percent of women after they give birth.”

“After giving birth, female mice deficient in the suspect protein showed depression-like behaviors and neglected their newborn pups,” explained Istvan Mody, Ph.D., of the University of California at Los Angeles (UCLA), who led the research. “Giving a drug that restored the protein’s function improved maternal behavior and reduced pup mortality.”

Mody and Jamie Maguire, Ph.D., UCLA, report on their findings in the July 31, 2008 issue of Neuron.

Researchers had suspected that postpartum depression stemmed from the marked fluctuations in the reproductive hormones estrogen and progesterone that accompany pregnancy and childbirth. Yet manipulating the hormones experimentally triggers depression only in women with a history of the disorder. The roots of their vulnerability remain a mystery.

Evidence suggested that the hormones exert their effects on mood through the brain’s major inhibitory chemical messenger system, called GABA, which dampens neural activity, helping to regulate when a neuron fires.

Mody and Maguire discovered that a GABA receptor component, called the delta subunit, fluctuated conspicuously during pregnancy and postpartum in the brains of female mice, hinting that it might have pivotal behavioral effects. To find out, they used mice lacking the gene for this subunit and studied them in situations that can elicit responses similar to human depression and anxiety.

Much like human mothers suffering from postpartum depression, the genetically altered mouse mothers were more lethargic and less pleasure-seeking than normal mice. They also shunned their pups and failed to make proper nests for them.

This abnormal maternal behavior was reversed and pup survival increased after the researchers gave the animals a drug called THIP that acts on the receptor in a way that specifically restores its function in spite of the reduced number of subunits.

“Improper functioning of the delta subunit could impair the GABA system’s ability to adapt to hormone fluctuations during the highly vulnerable post partum period,” explained Maguire. “Targeting this subunit might be a promising strategy in developing new treatments for postpartum depression.”
Reference: Maguire J, Mody I. GABAAR plasticity during pregnancy: relevance to postpartum depression. Neuron. 2008 Jul 31; 59

Massachusetts General Hospital Center for Women’s Mental Health
Reproductive Psychiatry Resource and Information Center

http://www.womensmentalhealth.org/specialty-clinics/psychiatric-disorders-during-pregnancy/?gclid=CKyGto3z26ACFcvV5wodbzUVCA

Psychiatric Disorders During Pregnancy
General
Although pregnancy has typically been considered a time of emotional well being, recent studies suggest that up to 20% of women suffer from mood or anxiety disorders during pregnancy. Particularly vulnerable are those women with histories of psychiatric illness who discontinue psychotropic medications during pregnancy. Although data accumulated over the last 30 years suggest that some medications may be used safely during pregnancy, knowledge regarding the risks of prenatal exposure to psychotropic medications is incomplete. Thus, it is relatively common for patients to discontinue or to avoid pharmacologic treatment during pregnancy.

What are the risks of medication exposure?
Frequently women with histories of psychiatric illness seek consultations regarding the use of medications during pregnancy, either prior to conception or early in the course of pregnancy. In other cases, women present with recurrent or new onset of mood or anxiety symptoms during pregnancy. In both of these settings, the clinician faces certain challenges when making recommendations regarding the treatment of psychiatric illness during pregnancy.

All medications diffuse readily across the placenta, and no psychotropic drug has yet been approved by the Food and Drug Administration (FDA) for use during pregnancy. When prescribing medications during pregnancy, one must consider the following risks associated with prenatal exposure: risk of teratogenesis, risk of neonatal toxicity, and risk of long-term neurobehavioral sequelae.

Risk of Teratogenesis
The baseline incidence of major congenital malformations in newborns born in the United States is estimated to be between 2 and 4%. During the earliest stages of pregnancy, formation of major organ systems takes place and is complete within the first 12 weeks after conception. A teratogen is defined as an agent that interferes with this process and produces some type of organ malformation or dysfunction. Exposure to a toxic agent before two weeks of gestation does not typically result in a congenital malformation but is more likely to result in a non-viable blighted ovum. For each organ or organ system, there exists a critical period during which development takes place and is susceptible to the effects of a teratogen. For example, neural tube folding and closure, forming the brain and spinal cord, occur within the first four weeks of gestation. Formation of the heart and great vessels takes place from four to nine weeks after conception.

Risk of Neonatal Symptoms
Neonatal toxicity or perinatal syndromes refer to a spectrum of physical and behavioral symptoms observed in the acute neonatal period that can be attributed to drug exposure at or near the time of delivery. Recently attention has focused on a range of transient neonatal distress syndromes associated with exposure to (or withdrawal from) antidepressants in utero. These syndromes appear to affect about 25% of babies exposed to antidepressants in utero. Anecdotal reports that attribute these syndromes to drug exposure must be cautiously interpreted, and larger samples must be studied in order to establish a causal link between exposure to a particular medication and a perinatal syndrome.

Risk of Long-Term Effects
Although the data suggest that some medications may be used safely during pregnancy, our knowledge regarding the long-term effects of prenatal exposure to psychotropic medications is incomplete. Because neuronal migration and differentiation occur throughout pregnancy and into the early years of life, the central nervous system (CNS) remains particularly vulnerable to toxic agents throughout pregnancy. While insults that occur early in pregnancy may result in gross abnormalities, exposures that occur after neural tube closure (at 32 days of gestation) may produce more subtle changes in behavior and functioning.

Behavioral teratogenesis refers to the potential of a psychotropic drug administered during pregnancy to have long-term neurobehavioral effects. For example, are children who have been exposed to an antidepressant in utero at risk for cognitive or behavioral problems at a later point during their development? To date, few studies have systematically investigated the impact of exposure to psychotropic medications in utero on development and behavior in humans.

Antidepressants and Pregnancy
Although early case reports suggested a possible association between first trimester exposure to tricyclic antidepressants (TCAs) and limb malformation, three prospective and more than 10 retrospective studies have examined the risk of organ malformation in over 400 cases of first trimester exposure to TCAs. When evaluated on an individual basis and when pooled, these studies fail to indicate a significant association between fetal exposure to TCAs and risk for any major congenital anomaly. Among the TCAs, desipramine and nortriptyline are preferred since they are less anti-cholinergic and the least likely to exacerbate orthostatic hypotension that occurs during pregnancy.

Off all the antidepressants fluoxetine (Prozac) is the best characterized. Data collected from over 2500 cases indicate no increase in risk of major congenital malformation in fluoxetine-exposed infants. One prospective study of 531 infants with first trimester exposure to SSRIs (mostly citalopram, n=375) did not demonstrate an increased risk of organ malformation. Several meta-analyses combining studies with exposures to tricyclic antidepressants and SSRIs do not demonstrate an increase in risk of congenital malformation in children exposed to these antidepressants, with the exception of paroxetine. Recent reports have suggested that first trimester exposure to paroxetine is associated with an increased risk of cardiac defects including atrial and ventricular septal defects. Other published studies have not demonstrated increased teratogenicity of paroxetine. Even so, these findings prompted the FDA to change the category label of paroxetine from C to D.

Bupropion may be an option for women who have not responded to fluoxetine or a tricyclic antidepressant, as data thus far have not indicated an increased risk of malformations associated with bupropion use during pregnancy. The most recent information from the Bupropion Pregnancy Registry maintained by the manufacturer GlaxoSmithKline includes data from 517 pregnancies involving first trimester exposure to bupropion. In this sample, there were 20 infants with major malformations. This represents a 3.9% risk of congenital malformation that is consistent with what is observed in women with no known teratogen exposure. While this information regarding the overall risk of malformation is reassuring, earlier reports had revealed an unexpectedly high number of malformations of the heart and great vessels in bupropion-exposed infants. A retrospective cohort study including over 1200 infants exposed to bupropion during the first trimester did not reveal an increased risk of malformations in the bupropion-exposed group of infants nor did it demonstrate an increased risk for cardiovascular malformations. Further studies are required to assess the risk of neonatal symptoms in bupropion-exposed infants and to better evaluate the long-term neurobehavioral effects of bupropion exposure.

With regard to the other antidepressants, prospective data on 150 women exposed to venlafaxine during the first trimester of pregnancy suggest no increase in risk of major malformation as compared to non-exposed controls. In another prospective study, outcomes in 147 women taking either nefazodone (n=89) or trazodone (n-58) were enrolled during their first trimester of pregnancy were compared to two control groups of women exposed to either non-teratogenic drugs (n = 147) or to other antidepressants (n=147). There were no significant differences among exposed and non-exposed groups with regard to rates of congenital malformations. While these initial reports are reassuring, larger samples are required to establish the reproductive safety of these newer antidepressants. It is estimated that at least 500 to 600 exposures must be collected to demonstrate a two-fold increase in risk for a particular malformation over what is observed in the general population.

To date, the literature does not include prospective data on the use of mirtazapine (Remeron) or duloxetine (Cymbalta). Scant information is available regarding the reproductive safety of monoamine oxidase inhibitors (MAOIs), and these agents are generally not used in pregnancy as they may produce a hypertensive crisis when combined with tocolytic medications, such as terbutaline.

Several recent studies have suggested that exposure to SSRIs at the time of delivery may be associated with poor perinatal outcomes in about 25% of infants, with several studies reporting increased rates of admission to the special care nursery among SSRI-exposed infants. The most commonly reported symptoms in the newborns include tremor, restlessness, increased muscle tone, and increased crying. Several, but not all, studies have also reported slightly lower Apgar scores in SSRI-exposed infants. Reassuringly, these syndromes appear to be relatively benign and short-lived, resolving within 1 to 4 days after birth without any specific medical intervention.

These studies deserve careful consideration, yet one of the major shortcomings is that most have failed to use raters blinded to the mother’s treatment status. The decision to admit a newborn to a special care nursery may represent a reasonable precaution for an infant exposed to medication in utero and may not be an indication of a serious problem. Another limitation is that few studies have attempted to assess maternal mood during pregnancy or at the time of delivery. There is ample evidence to suggest that depression or anxiety in the mother may contribute to poor neonatal outcomes, including premature delivery and low birth weight, and it is important to evaluate the contribution of maternal mood to neonatal outcomes.

Another study has suggested that maternal SSRI use after the 20th week of gestation is associated with a higher than expected number of cases of persistent pulmonary hypertension of the newborn (PPHN). Although body mass index, diabetes, NSAID use, and smoking have been identified as maternal factors associated with PPHN, controlling for these potential confounders did not significantly attenuate the association between SSRI use and PPHN. Neither the use of SSRIs before the 20th week of gestation nor the use of non-SSRI antidepressants at any time during the pregnancy was associated with an increased risk of PPHN. If we assume that these findings are correct, the risk is still relatively small; the authors estimate the risk of PPHN to be less than 1% in infants exposed to SSRIs in utero. Further investigation is warranted to clarify the association between SSRI use and PPHN.

To date only two studies have systematically investigated the impact of exposure to antidepressants in utero on development and behavior in humans. The first of these studies followed a cohort of 135 children who had been exposed to either tricyclic antidepressants or fluoxetine (Prozac) during pregnancy (most commonly during the first trimester) and compared these subjects to a cohort of non-exposed controls. Results indicated no significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level between exposed and non-exposed children followed up to 7 years of age. A more recent report from the same group that followed a cohort of children exposed to fluoxetine or tricyclic antidepressants for the entire duration of the pregnancy yielded similar results. The authors concluded that their findings support the hypothesis that fluoxetine and tricyclic antidepressants are not behavioral teratogens and do not have a significant effect on cognitive development, language or behavior.

Mood Stabilizers
For women with bipolar disorder, maintenance treatment with a mood stabilizer during pregnancy can significantly reduce the risk of relapse; however, many of the medications commonly used in this setting, including lithium and valproic acid, carry some degree of teratogenic risk. First trimester exposure to lithium has been associated with an increased risk of cardiovascular malformation estimated to be between 1 in 2000 (0.05%) and 1 in 1000 (0.1%). The anticonvulsant valproic acid carries a much higher risk of teratogenesis, with rates of neural tube defect ranging from 1 to 6%. Prenatal exposure to valproic acid has also been associated with characteristic craniofacial abnormalities, cardiovascular malformation, limb defects and genital anomalies, as well as other central nervous system structural abnormalities.

While other anticonvulsants are being used more frequently in the treatment of bipolar disorder, there is limited information on the reproductive safety of these newer anticonvulsants, specifically gabapentin (Neurontin), oxcarbazepine (Trileptal), topiramate (Topamax), tigabine (Gabitril), levetiracetam (Keppra), zonisamide (Zonegran).

However, there is a growing body of information the reproductive safety of lamotrigine (Lamictal), and this may be a useful alternative for some women. The International Lamotrigine Pregnancy Registry was created by GlaxoSmithKline (GSK) in 1992 to monitor pregnancies exposed to lamotrigine for the occurrence of major birth defects. Data from the Registry did not show an elevated risk of malformations associated with lamotrigine exposure. Other data from the North-American Anti-Epileptic Drug Registry indicates the prevalence of major malformations in a total of 564 children exposed to lamotrigine monotherapy was 2.7%; however, five infants had oral clefts, indicating a prevalence rate of 8.9 per 1000 births. In a comparison group of 221,746 unexposed births, the prevalence rate for oral clefts was 0.37/1000, indicating a 24-fold increase in risk of oral cleft in infants exposed to lamotrigine. However, other registries have not demonstrated such a significant increase in risk for oral clefts. It is important to put this risk into perspective. If we assume that the findings from the North American registry are true, the absolute risk of having a child with cleft lip or palate is about 0.9%. Clearly more data are essential to better evaluate the reproductive safety of lamotrigine; important questions regarding the safety of lamotrigine and other anticonvulsants might be best addressed by collaboration between multiple registries, including EURAP and the North-American Anti-Epileptic Drug Registry.

Anti-Anxiety Medications
The consequences of prenatal exposure to benzodiazepines have been debated for over twenty years. Three prospective studies support the absence of increased risk of organ malformation following first trimester exposure to benzodiazepines. More controversial has been the issue of whether first trimester exposure to benzodiazepines increases risk for specific malformations. Although initial reports suggested that there may be an increased risk of cleft lip and cleft palate, more recent reports have shown no association between exposure to benzodiazepines and risk for cleft lip or palate. This risk– if it exists — is calculated to be 0.7%, approximately a ten-fold increase in risk for oral cleft over that observed in the general population. Nonetheless, the likelihood that a woman exposed to benzodiazepines during the first trimester will give birth to a child with this congenital anomaly, although significantly increased, remains less that 1%.

Currently, no systematic data are available on the reproductive safety of non-benzodiazepine anxiolytic agents such as buspirone and hypnotic agents zolpidem (Ambien) and zalepion (Sonata). Therefore, these medications are not recommended for use in pregnancy.

Anti-Psychotic Medications
Recent studies have not demonstrated teratogenic risk associated with high- or medium-potency neuroleptic medications; however, a recent meta-analysis of the available studies noted a higher risk of congenital malformations after first trimester exposure to low-potency neuroleptic agents. In clinical practice, higher potency neuroleptic agents such as haloperidol (Haldol), perphenazine (Trilafon), and trifluoperazine (Stelazine) are recommended over the lower potency agents in managing pregnant women with psychiatric illness.

Information on the reproductive safety of the newer or “atypical” anti-psychotic medications is sparse but the body of data is growing. Thus far, most of the data on the reproductive safety of atypical agents has been limited to manufacturers’ accumulated case series and spontaneous reports. Among the 242 reports of olanzapine-exposed pregnancies collected by the manufacturer, there was no increase in risk of major malformations above baseline. Of 523 clozapine-exposed pregnancies, there were reported 22 “unspecified malformations.” In 151 reported quetiapine-exposed pregnancies, 8 infants were observed to have congenital anomalies. Eight malformations were reported among the infants born to approximately 250 women taking risperidone; however, pregnancy outcomes were not known in many of these cases reported to the manufacturer. Taken together, these reports do not suggest an increase in the risk of major malformation above the baseline 2% to 4% risk of malformations seen in the general population, nor do they indicate any specific pattern of abnormalities among drug-exposed infants.

The first published prospective study on the reproductive safety of the atypical agents provides reassuring data regarding the risk of malformations in infants exposed to these drugs. In this study, investigators prospectively followed a group of 151 women taking olanzapine, risperidone, quetiapine, or clozapine during pregnancy; all women had taken the medication during the first trimester. A comparison group of 151 healthy pregnant women were also followed. Rates of spontaneous abortion and therapeutic abortion were higher in the exposed group than in the comparison group, although this finding was not statistically significant. There were no differences between the two groups in terms of rates of major malformations, mean gestational age, birth weight, rates of complications at labor or neonatal complications. However, we can make only limited conclusions based on this type of information; larger numbers are needed to indicate safety. Atypical antipsychotics are best avoided if possible, although they are not absolutely contraindicated during pregnancy. Atypical antipsychotics should be reserved for use in more challenging clinical situations where treatment with more conventional agents has not been helpful.

Weighing the Risks
Women with histories of psychiatric illness frequently present for consultations regarding the use of psychotropic medications during pregnancy. Not infrequently, women present with the first onset of psychiatric illness while pregnant. Decisions regarding the initiation or maintenance of treatment during pregnancy must reflect an understanding of the risks associated fetal exposure to a particular medication but must also take into consideration the risks associated with untreated psychiatric illness in the mother. Psychiatric illness in the mother is not a benign event and may cause significant morbidity for both the mother and her child; thus, discontinuing or withholding medication during pregnancy is not always the safest option.

For More Information
Please visit our Pregnancy Library for relevant articles on this specialty area [http://www.womensmentalhealth.org/library/psychiatric-disorders-during-pregnancy/]

For the latest information on psychiatric disorders during pregnancy please visit our blog. [http://www.womensmentalhealth.org/blog/]

Psychiatric Disorders During Pregnancy
General:

1. Cohen LS, Rosenbaum JF. Psychotropic drug use during pregnancy: weighing the risks. J Clin Psychiatry 1998; 59 [suppl 2]: 18-28.
2. Nonacs R, Cohen LS. Depression during pregnancy: diagnosis and treatment options. J Clin Psychiatry. 2002;63 Suppl 7:24-30.
3. Cohen LS, Altshuler LL. Pharmacologic management of psychiatric illness during pregnancy and the postpartum period. Psychiatr Clin North Am 1997; 4:21-59.
4. Current Interviews with Dr. Lee Cohen, Volume XX, May 2001: Update on Reproductive Safety of Psychotropic Medications: (Part I) (Part II)
5. Koren G, Goh Y, Klieger C. Folic Acid. Motherisk Update November 2008.

Drugs, Pregnancy and Lactation: Reprinted with permission from Ob. Gyn. News 

© International Medical News Group, an Elsevier company

1. NEW!Drugs, Pregnancy and Lactation: Perinatal Depression: APA and ACOG Weigh In
   October 2009
2. Drugs, Pregnancy and Lactation: Depression and SSRI Exposure
   June 2009
3. Drugs, Pregnancy and Lactation: SSRIs and PPHN Revisited
   March 2009
4. Drugs, Pregnancy and Lactation: SSRIs and Pulmonary Hypertension Risk
   October 2008
5. Drugs, Pregnancy and Lactation: Atypical Antipychotics During Pregnancy
   April 2008
6. Drugs, Pregnancy and Lactation: Yet More Reproductive Data on SSRIs
   October 2007
7. >>To read more “Drugs, Pregnancy and Lactation” articles from ObGyn News, please click here.

Course of Depression During Pregnancy:

1. Altshuler L, Cohen L, Moline M, et al: Expert consensus guideline series: Treatment of depression in women. Postgrad Med Special Report:1-116, 2001.
2. Altshuler LL, Hendrick V, Cohen LS. Course of mood and anxiety disorders during pregnancy and the postpartum period. J Clin Psychiatry 1998; 59[suppl 2]: 29-33.
3. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 295(5):499-507, 2006.
4. Evans J, Heron J, Francomb H, et al: Cohort study of depressed mood during pregnancy and after childbirth. Br Med J 323(7307):257-260, 2001.
5. O’Hara MW: Social support, life events, and depression during pregnancy and the pueperium. Arch Gen Psychiatry 43:569-573, 1986.

Effects of Untreated Maternal Depression and Pregnancy:

1. Altshuler LL, Cohen LS, Moline ML, Kahn DA, Carpenter D, Docherty JP. The Expert Consensus Panel for Depression in Women. The Expert Consensus Guideline Series. Treatment of depression in women. Postgraduate Medicine 2001 March;(Spec No):1-107.
2. Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G. Perinatal Risks of Untreated Depression during Pregnancy. Can J Psychiatry, Vol 49, No 11, November 2004.
3. Chung TK, et al. Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. Psychosomatic Medicine 2001.
4. Dayan J, et al. Prenatal depression, prenatal anxiety, and spontaneous preterm birth: A prospective cohort study among women with early and regular care. Psychosomatic Medicine 2006.
5. Hoffman H, Hatch M. Depressive symptomatology during pregnancy: evidence for an association with decreased fetal growth in pregnancies of lower social class women. Health Psychology 2000.
6. Kurki T, et al. Depression and anxiety in early pregnancy and risk for preeclampsia. Obstetrics and Gynecology 2000.
7. Orr ST. Maternal prenatal depressive symptoms and spontaneous preterm births among African-American women in Baltimore, Maryland. Am J Epidemiol 2002.
8. Rondo PHC, et al. Maternal psychological stress and distress as predictors of low birth weight, prematurity, and intrauterine growth retardation. Eur J Clin Nutrition 2003.

Nonpharmacologic Intervention During Pregnancy

1. Ferrill MJ, Kehoe WA, Jacisin JJ: ECT during pregnancy: Physiologic and pharmacologic considerations. Convul Ther 8(3):186-200, 1992.
2. Miller LJ: Use of electroconvulsive therapy during pregnancy. Hosp Comm Psychiatry 45(5):444-450, 1994.
3. Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS, Terman JS, Terman M. An open trial of morning light therapy for treatment of antepartum depression. Am J Psychiatry 2002 Apr;159(4):666-9.
4. Editor’s Comments on above article
5. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003 Mar;160(3):555-62.
6. Spinelli MG. Interpersonal psychotherapy for depressed antepartum women: a pilot study. Am J Psychiatry. 1997 Jul;154(7):1028-30.
7. Editor’s Comments on above articles

Antidepressant Use During Pregnancy

General

1. Einarson TR, Einarson A: Newer antidepressants in pregnancy and rates of major malformations: A meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 14(12):823-827, 2005.
   Hallberg P, Sjoblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breastfeeding: a review and clinical aspects. Journal of Clinical Psychopharmacology 2005; 25 (1): 59-73.
2. Lamberg L. Risks and Benefits Key to Psychotropic Drug Use during Pregnancy and Postpartum Period. JAMA 2005 Oct;294(13):1604-8.
3. Drugs, Pregnancy and Lactation: Antidepressants in Pregnancy
   By Elizabeth Mechcatie, Senior Writer Ob. Gyn. News. Reprinted with Permission from Ob. Gyn. News (www.eobgynnews.com) (May 1, 2000, Internation al Medical News Group, a division of W. B. Saunders Co.)
4. Yaris F, Kadioglu M, Kesim M, Ulku C, Yaris E, Kalyoncu NI, Unsal M. Newer antidepressants in pregnancy: prospective outcome of a case series. Reproductive Toxicology 2004(19)235–238.

Neonatal Outcome Studies:

1. Alwan S, Reefhuis J, Rasmussen S, Olney RS, Friedman, JM. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of defects. N Engl J Med 2007; 356:2684-92.
2. Boyles S. Taking SSRIs in Pregnancy Affects Infant Restlessness: Rigidity Commonly Seen, but Problems Seem to Fade Quickly. (WebMD comments on above article.)
3. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354(6):579-87.
4. Chun-Fai-Chan B, Koren G, Fayez I, et al: Pregnancy outcome of women exposed to bupropion during pregnancy: A prospective comparative study. Am J Obstet Gynecol 192(3):932-936, 2005.
5. Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS, Bouffard SM. Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry. 2000;48:996-1000. (Fluoxetine (Prozac))
6. Cole JA, Modell JG, Haight BR, et al: Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf, 2006.
7. Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med. 2003 Jun;157(6):601. (Paroxetine)
8. Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, Koren G. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry. 2003 Mar;48(2):106-10. (Nefazodone (Serzone) and Trazodone (Desyryl))
9. Editor’s comments on above article
10. Einarson A, Fatoye B, Sarkar M, Lavigne SV, Brochu J, Chambers C, Mastroiacovo P, Addis A, Matsui D, Schuler L, Einarson TR, Koren G. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry 2001 Oct;158(10):1728-30. (Venlafaxine (Effexor))
11. Ferreira E, Carceller AM, Agogue C, Martin BZ, St-Andre M, Francoeur D, Berard A. Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates. Pediatrics. 2007; 119(1): 52-9.
12. GlaxoSmithKline. New safety information regarding paroxetine: Second large study shows and increased risk of cardiac defects, over other antidepressants, following first trimester exposure to paroxetine. 2005. Available by clicking here. Accessed June 15, 2006.
13. GlaxoSmithKline. Updated preliminary report on bupropion and other antidepressants, including paroxetine, in pregnancy and the occurrence of cardiovascular and major congenital malformation. 2005. Available at http://www.gsk.com/media/paroxetine/ingenix_study.pdf. Accessed 2007.
14. Källén B, Otterblad OP: Maternal use of selective serotonin reuptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Research Part A: Clinical and Molecular Teratology 79:301-308, 2007.
15. Koren G, Matsui D, Einarson A, Knoppert D, Steiner M. Is maternal use of selective serotonin reuptake inhibitors in the third trimester of pregnancy harmful to neonates? CMAJ 2005 May 24;172(11):1457-1459.
16. Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond K, Matsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA 1998 Feb 25;279(8):609-10. (Fluvoxamine, Paroxetine, Sertraline)
17. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry. 2003 Jul;60(7):720-6.
18. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006; 160:173-76.
19. Louik C, Lin AE, Werler MM, et al: First-trimester use of selective serotonin reuptake inhibitors and the risk of birth defects. N Engl J Med 356(26):2675-2683, 2007.
20. Moses-Kolko EL, Bogen D, Perel J, et al: Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: Literature review and implications for clinical applications. JAMA 293(19):2372-2383, 2005.
21. Pastuszak A, Schick-Boschetto B, Zuber C, et al: Pregnancy outcome following first-trimester exposure to fluoxetine (prozac). JAMA 269(17):2246-2248, 1993.
22. Pearson KH, Nonacs RM, Viguera AC, Heller VL, Petrillo LF, Brandes M, Hennen J, Cohen LS. Birth outcomes following prenatal exposure to antidepressants. J Clin Psychiatry. 2007 Aug 68(8): 1284-9.
23. Suri R, Altshuler L, Hendrick V, et al: The impact of depression and fluoxetine treatment on obstetrical outcome. Arch Women Ment Health 7(3):193-200, 2004.
24. Wogelius P, Norgaard M, Gislum M, et al: Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 17(6):701-704, 2006.
25. Zeskind P, Stephens L: Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 113(2):368-375, 2004.

Neurodevelopmental Outcome of Children Exposed to Antidepressants in Utero:

1. Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr. 2003 Apr;142(4):402-8. <!–[if !vml]–> <!–[endif]–>
2. Misri S, Reebye P, Kendrick K, et al: Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry 163(6):1026-1032, 2006.
3. Nulman I, Rovet J, Stewart D, et al: Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 336:258-262, 1997.
4. Nulman I, Rovet J, Stewart DE, et al: Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study. Am J Psychiatry 159(11):1889-1895, 2002.

Bipolar Disorder and Pregnancy:

1. Baethge C, Tondo L, Bratti IM, Bschor T, Bauer M, Viguera AC, Baldessarini RJ. Prophylaxis latency and outcome in bipolar disorders. Canadian Journal of Psychiatry – Revue Canadienne de Psychiatrie. 48(7):449-57, 2003 Aug
2. Cohen LS, Friedman JM, et al. A reevaluation of risk of in utero exposure to lithium. JAMA 1994; 271: 146-150.
3. Cunnington M, Tennis P: Lamotrigine and the risk of malformations in pregnancy. Neurology 64(6):955-960, 2005.
4. Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 2002;63 Suppl 4:42-55.
5. Holmes LB, Baldwin EJ, Smith CR, Habecker E, Glassman L, Wong SL, Wyszynski DF. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology. 2008 May 27;70(22 Pt 2):2152-8. Epub 2008 Apr 30.
6. Holmes LB, Wyszynski DF, Baldwin EJ, et al: Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy, in 46th Annual Meeting of the Teratology Society. Tucson, AZ, June 2006.
7. Shor S, Koren G, Nulman I. Teratogenicity of lamotrigine.  Motherisk Update, June 2007.
8. Tennis P, Eldridge RR. International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia 2002 Oct;43(10):1161-7.
9. Viguera AC, Cohen LS, Bouffard S, Whitfield TH, Baldessarini RJ. Reproductive decisions by women with bipolar disorder after prepregnancy psychiatric consultation. Am J Psychiatry 2002; 159:2102–2104.
10. Wyszynski D, Nambisan M, Surve T, et al: Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 64(6):291-295, 2005.
11. Medscape Psychiatry Expert Interview with Dr. Adele Viguera: Women and Bipolar Disorder: Special Considerations
12. Viguera AC, Cohen LS, Baldessarini RJ, Nonacs R. Managing bipolar disorder during pregnancy: weighing the risks and benefits. Can J Psychiatry 2002 Jun;47(5):426-36.
13. Drugs, Pregnancy and Lactation: Update on Bipolar Disorder
    Reprinted with permission from Ob.Gyn. News (www.eobgynnews.com) (June 1, 2002, International Medical News Group, a division of W.B. Saunders Co.)
14. Drugs, Pregnancy and Lactation: Antipsychotics in Pregnancy
    By Elizabeth Mechcatie, Senior Writer Ob. Gyn. News
    Reprinted with Permission from Ob. Gyn. News (www.obgynnews.com) (July 1, 2000, International Medical News Group, a division of W. B. Saunders Co.)
15. Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarni RJ. Risk of Recurrence of Bipolar Disorder in Pregnant and Nonpregnant Women After Discontinuing Lithium Maintenance. Am J Psychiatry Feb 2000; 157: 179-184.

Anxiety Disorders and Pregnancy:

1. Dolovich LR, Antonio A, et al. Benzodiazepine use in pregnancy and major malformations of oral cleft: Meta-analysis of cohort and case-control studies. Br Med J 1998; 317: 839-843.
2. Cohen LS, Sichel DA, Faraone SV, et al: Course of panic disorder during pregnancy and the puerperium: A preliminary study. Biol Psychiatry 1996; 39: 950-954.
3. Glover V. O’Connor TG. Effects of antenatal stress and anxiety: Implications for development and psychiatry. British Journal of Psychiatry. 180:389-91, 2002.

Psychotic Disorders and Pregnancy:

1. Coppola D, Russo LJ, Kwarta RF, et al: Evaluating the postmarketing experience of risperidone use during pregnancy: Pregnancy and neonatal outcomes. Drug Safety 30(3):247-264, 2007.
2. Gentile, S. Clinical Utilization of Atypical Antipsychotics in Pregnancy and Lactation. Annals of Psychiatry, 2004. 38:1265-1271. antipsychotic administration during late pregnancy: Placental passage and obstetrical outcomes. Am J Psychiatry 2007 Aug; 164(8):1214-20.
3. McKenna K, Koren G, Tetelbaum M, et al: Pregnancy outcome of women using atypical antipsychotic drugs: A prospective comparative study. J Clin Psychiatry 66(4):444-449, 2005.
4. Newport DJ, Calamaras MR, DeVane CL, Donovan J, Beach AJ, Winn S, Knight BT, Gibson BB, Viguera AC, Owens MJ, Nemeroff CB, Stowe ZN. Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes. Am J Psychiatry. 2007 Aug;164(8):1214-20.

Eating Disorders and Pregnancy

1. Blais MA, et al. Pregnancy: outcome and impact on symptomatology in a cohort of eating-disordered women. Int J Eat Disord 2000; 27:140-9.
2. Kouba S, et al. Pregnancy and neonatal outcomes in women with eating disorders. Obstet Gynecol 2005; 105:255-260.
3. Larrson, G, Andersson-Ellstron A. Experiences of pregnancy-related body shape changes and of breast-feeding in women with a history of eating disorders. Eur Eat Disord Rev 2003; 11:116-24.
4. Micali N, et al. Eating disorders symptoms in pregnancy: a longitudinal study of women with recent and past eating disorders and obesity. J Psychosom Res 2007; 63:297-303.
5. Micali N, et al. Risk of major adverse perinatal outcomes in women with eating disorders, Br J Psychiatry 2007; 190:255-9.
6. Morgan JF, et al. Risk of postnatal depression miscarriage and preterm birth in bulimia nervosa: retrospective controlled study. Psychosom Med 2006;68:487-92.
7. Mazzeo SE, et al. Associations among postpartum depression, eating disorders and perfectionism in a population-based sample of adult women. Int J Eat Disord 2006; 39:202-11.
8. Rocco PL, et al. Effects of pregnancy on eating attitudes and disorders: a prospective study. J Psychosom Res 2005; 59:175-9.
9. Stein A, et al. An observational study of mothers with eating disorders and their infants. J Child Psychol Psychiatry 1994;35:733-48.
10. Ward V. Pregnancy Plus: Eating disorders in pregnancy. BMJ 2008; 336:93-96.