Harvard Mental Health Letter

Prescribing during pregnancy

Prenatal drug exposure and an untreated psychiatric disorder both present risks.

Each year, about a half-million pregnant women suffer from psychiatric illnesses such as depression, bipolar disorder, or some type of anxiety disorder. The use of prescription drugs during pregnancy raises a number of difficult ethical and medical issues, sometimes made more challenging by the lack of good data. Clinicians and patients must carefully consider two types of risk: the chance that drug exposure may harm the developing fetus, and the danger (less well recognized) of not adequately treating the mother.

All psychiatric medications cross the placenta and reach the developing fetus, and some of these drugs increase the risk of certain congenital malformations. However, research indicates that the likelihood of birth defects after prenatal exposure to some drugs is not as great as earlier studies had estimated.

Moreover, there has been a growing acknowledgement that an untreated psychiatric disorder during pregnancy also poses risks, to both the mother and the developing fetus. Untreated anxiety disorders, for example, increase the risk of early delivery and miscarriage. And untreated bipolar disorder or depression in mothers may result in babies with low birth weight, increased crying, and greater likelihood of admission to the neonatal intensive care unit.

Another concern is relapse of the psychiatric disorder during pregnancy. Women with psychiatric disorders are at increased risk of relapse when they become pregnant whether or not they remain on medication, but stopping medication increases the likelihood of relapse.

For example, a prospective study of 201 women with a history of major depression, which included monthly assessments throughout pregnancy, found that 68% of those who stopped taking antidepressants after becoming pregnant suffered a relapse of depression, compared with 26% of those who continued taking their antidepressants. And a prospective study of 89 pregnant women with bipolar disorder found that 86% of women who stopped treatment suffered a relapse, compared with 37% of those who remained on their medication.

Of course, drugs aren't the only way to treat psychiatric disorders during pregnancy, but some women will benefit significantly from medication. Although gaps in the medical literature remain, studies and treatment guidelines can help with the decision.

Summary points

  • Research is clarifying the risk of prenatal drug exposure, and some earlier estimates have been revised.

  • The advice about lithium depends on a woman's symptoms and risk of relapse.

  • It's best to taper any psychiatric medication gradually rather than stopping it abruptly, in order to avoid relapse.

Options for women with depression

Studies have mostly focused on use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, although some data exist about risks posed by other drugs.

SSRIs. Although some of the data have been inconsistent, large studies of SSRI use during pregnancy concluded that these drugs can be used during the first trimester without significantly increasing the risk of fetal heart defects or other major congenital malformations.

Several preliminary studies in 2005 and 2006 suggested that paroxetine (Paxil) might increase the risk of several types of rare congenital heart defects. But an analysis of the outcomes of 3,235 women who took paroxetine during the first trimester — the largest study to date — concluded that the drug did not raise the risk of congenital heart defects in offspring. Consensus is growing that, as a class, SSRIs taken in the first trimester pose only a slight increase in risk. About one baby in 125 is born with a heart defect in the general population, and about two additional babies are born with cardiac malformations for every 1,000 exposed to SSRIs during fetal development.

When used late in pregnancy or at the time of delivery, however, SSRIs may cause temporary problems in as many as 25% of newborns. Typical symptoms include tremor, restlessness, mild respiratory problems, and weak cry. In most cases, these symptoms disappear in the first few days after birth, although some infants are admitted to the neonatal intensive care unit as a precaution.

An unresolved question is whether SSRI use later in pregnancy increases the risk of persistent pulmonary hypertension of the newborn (PPHN), a serious but fortunately rare respiratory problem that affects about one baby born to every 1,000 to 2,000 women in the general population. The studies report conflicting results. A 2006 study estimated that about one woman in 100 taking an SSRI late in pregnancy would give birth to a baby with PPHN, while a 2008 study placed that figure at about one to two women in 1,000.

Tricyclic antidepressants. This older class of drugs may be an option for some women. Although early studies and anecdotal reports suggested that tricyclic antidepressant use in pregnancy might cause congenital heart and limb problems and other disorders, more recent studies have not found this to be the case.

Bupropion. Little is known about the risk of other antidepressants during pregnancy. Most of the research involves bupropion (Wellbutrin). GlaxoSmithKline, which manufactures this drug, maintains a database of outcomes of 517 women who took the drug during their first trimester. The risk of congenital malformations in this group is no higher than in the general population. Only one study has been published about bupropion use during the first trimester of pregnancy. Researchers completed follow-up on 136 women and found a significant increase in the risk of miscarriage, but not congenital malformations.

Options for women with bipolar disorder

Like women with major depression, those with bipolar disorder are also at increased risk of relapse during pregnancy, and continued treatment with a mood-stabilizing drug can help reduce that risk. But two of the most commonly used drugs, lithium and valproate, increase risk of congenital defects. Treatment options therefore depend on the nature and severity of the mother's symptoms.

Lithium. Long a mainstay of treatment for bipolar disorder, lithium is still considered the most effective medication for long-term therapy and reducing risk of suicide. But taking lithium during pregnancy increases the risk of congenital heart defects, although it is significantly less than once believed.

In the 1970s, retrospective reports (subject to recall bias) suggested that lithium could increase the risk of congenital heart defects by as much as 400%, and physicians routinely avoided prescribing it during pregnancy for that reason. However, more recent epidemiologic studies, following women over time, suggest that the actual risk is much smaller. The newer studies suggest that, in absolute terms, one additional baby out of every 1,000 to 2,000 exposed to lithium in the first trimester of fetal development will develop a cardiac defect as a result. This drug may also cause premature delivery as well as heart arrhythmias and temporary lethargy in newborns.

In light of the updated evidence, the American College of Obstetricians and Gynecologists recommends the following general approach, with two cautions. First, because pregnancy may alter the metabolism of lithium, it's important to closely monitor lithium levels both during pregnancy and immediately after delivery. Second, if a patient decides to stop taking lithium, it's best to reduce dosage slowly (taking two weeks or longer) rather than stopping it abruptly. Otherwise, the woman may quickly suffer a relapse of symptoms.

  • Mild symptoms, low risk of relapse. Stop taking lithium before conception by tapering gradually to reduce risk of relapse.

  • Severe symptoms, moderate risk of relapse. Taper lithium gradually before conception, then restart after the first trimester to reduce risk of congenital heart defects.

  • Severe symptoms, high risk of relapse. Continue lithium treatment, as long as the patient understands this confers an increased risk of heart defects and other problems in the newborn.

Valproate. It's best to avoid taking valproate (Depakote) during pregnancy, especially during the first trimester, as this drug increases the risk of neural tube defects such as spina bifida. Risk increases with dose. In absolute terms, researchers estimate that one to six babies out of every 100 exposed to valproate in the first trimester of fetal development are born with some type of neural tube defect.

If a woman becomes pregnant while taking valproate, or if this drug is her only treatment choice, the American College of Obstetricians and Gynecologists recommends daily folic acid supplements of 4 mg per day — 10 times greater than the 0.4 mg per day recommended for other women — ideally starting before conception and continuing through the first trimester. Keep in mind, however, that there is no proof that folic acid supplementation prevents drug-induced neural tube defects. For this reason, experts also recommend prenatal testing and counseling about risks of birth defects.

Lamotrigine. The North American Anti-Epileptic Drug Registry indicates that women taking lamotrigine (Lamictal) while pregnant were 24 times as likely as other women to give birth to a child with a cleft lip or cleft palate. In absolute terms, this translates into about one baby born with a cleft lip or palate for every 100 exposed to lamotrigine prenatally. Four other registries, however, have not found an increased risk of cleft lip or cleft palate with this drug. And because lamotrigine protects against depression in bipolar disorder, some experts advise considering it as an option to use during pregnancy.

Options for women with an anxiety disorder

Anxiety disorders include obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. These conditions are often treated with benzodiazepines, such as alprazolam (Xanax), clonazepam (Klonopin), or lorazepam (Ativan).

Prenatal exposure to benzodiazepines may increase the risk of cleft lip and cleft palate, although the studies have been inconsistent on this point. The absolute increase in risk is small, with about seven babies born with cleft lip or palate out of every 10,000 exposed to benzodiazepines in the womb, compared with six babies out of 10,000 without prenatal exposure.

However, benzodiazepines may lead to withdrawal symptoms and other problems for the newborn, particularly when taken late in the pregnancy. One possible complication is "floppy infant syndrome" (infantile hypotonia), characterized by lethargy, poor respiration, and difficulty feeding. Withdrawal symptoms in the newborn include restlessness, breathing problems, diarrhea, and vomiting.

For more information

The Massachusetts General Hospital Center for Women's Mental Health provides frequent updates about research concerning how best to treat psychiatric disorders during pregnancy. Visit the Web site below:

www.womensmentalhealth.org

An individual decision

Given the risks, clinicians and patients who decide that psychiatric drugs are necessary during pregnancy may want to aim for the lowest possible dose. But the American College of Obstetricians and Gynecologists recommends that a single medication at a higher dose is preferable to combining two or more medications.

Information about risks and benefits of drugs taken during pregnancy may be easier to obtain in the future. In May 2008, the FDA announced a proposal to revise labeling for prescription drugs, to provide clearer information about effects during pregnancy and breast-feeding. For now, though, clinicians and patients must try to sift through the findings of studies to decide the best course on an individual basis.

American College of Obstetricians and Gynecologists. "ACOG Practice Bulletin: Use of Psychiatric Medications During Pregnancy and Lactation," Obstetrics and Gynecology (April 2008): Vol. 111, No. 4, pp. 1,001–20.

Louik C, et al. "First-Trimester Use of Selective Serotonin Reuptake Inhibitors and the Risk of Birth Defects," New England Journal of Medicine (June 28, 2007): Vol. 356, No. 26, pp. 2,675–83.

Viguera AC, et al. "Risk of Recurrence in Women with Bipolar Disorder During Pregnancy: Prospective Study of Mood Stabilizer Discontinuation," American Journal of Psychiatry (Dec. 2007): Vol. 164, No. 12, pp. 1,817–24.

For more references, please see www.health.harvard.edu/mentalextra.