In 1996, Chambers and colleagues (1) reported that exposure to fluoxetine in the third trimester of pregnancy was associated with an increased risk of preterm birth, small-for-gestational-age infants, admission to special care nurseries, and poor neonatal adaptation, including respiratory difficulty, cyanosis on feeding, and jitteriness. This landmark article generated substantial concern among clinicians that third-trimester exposure to fluoxetine (and potentially other selective serotonin reuptake inhibitors [SSRIs]) was contributing to adverse outcomes in pregnancy. Of interest, no adverse effects from first-trimester exposure were observed. The offspring of women who discontinued fluoxetine before 25 weeks’ gestation had neonatal outcomes that were similar to those of comparison subjects. Similarly, in a study of maternity hospital discharge and pharmacy records, Simon et al. (2) reported that exposure to SSRIs was associated with a 0.9-week decrease in mean gestational age, a 175-g decrease in mean birth weight, and a 0.29 decrease in mean APGAR score 5 minutes after birth. The differences in birth weights and APGAR scores were not significant after adjustment for gestational age. Less favorable APGAR scores were limited to those with third-trimester exposure. Neither tricyclic antidepressant nor SSRI exposure was significantly associated with congenital malformations or developmental delay. There were no differences in infant outcome among tricyclic-exposed infants compared to unexposed newborns, which suggested a specific effect of the SSRI rather than maternal depression. In infants born to women treated with antidepressants throughout pregnancy, CNS, motor, respiratory, and gastrointestinal signs that are usually mild and subside by 2 weeks of age have been reported (3, 4). This neonatal behavioral syndrome resulted in the Food and Drug Administration’s (FDA’s) recommendation for inclusion of this risk in the labeling of these agents.

In contrast, the Canadian Motherisk group prospective study of exposure to tricyclic antidepressants or fluoxetine during the entirety of pregnancy revealed no differences in either maternal weight gain or infant birth weights in treated versus healthy comparison mothers (5). An intriguing aspect of this study is that the mean scores for the Center for Epidemiologic Studies Depression Scale were reported for the subjects: fluoxetine-exposed group=39.9, tricyclic-exposed group=28.0, and comparison group=10.7. Because a score of 16 is used as the cutoff point to signal significant depression, the implication is that antidepressant medications are not fully effective for remission of depression in the average pregnant patient. Therefore, studies of reproductive outcomes related to drug exposure likely include exposures to both the drug and the active (underlying) disorder in a substantial number of women. If SSRIs are contributing to reduced fetal growth, understanding the mechanism(s) that explain this relationship is of major clinical importance. Chambers and colleagues (1) could not attribute the reduced birth weight and length exclusively to the effects of fluoxetine. Mothers exposed to fluoxetine in late gestation also gained less weight than unexposed mothers. Entry of the weight gain variable into the multivariable models for birth weight and length reduced the effect of the drug, which suggested that weight gain may be in the causal pathway from fluoxetine exposure to size at birth. Chambers et al. speculated that maternal weight gain was reduced either because fluoxetine lowered appetite as a direct side effect or because third-trimester drug use was a marker for serious depression (C.D. Chambers, personal communication, 2005), which can also cause poor appetite and weight loss. The women who were taking medication through the third trimester were more likely to have severe depression than those who discontinued the drug. Women with histories of suicide attempts, marked functional impairment without medication, or partial response are less likely to stop medication during pregnancy.

For psychiatrists, a conundrum is the inclusion of these disparate findings within a comprehensive risk-benefit discussion for SSRIs or use of serotonin-norepinephrine reuptake inhibitors during pregnancy. Monitoring maternal weight gain along with other potential side effects has been recommended (6), with intervention strategies should suboptimal weight gain emerge. Inadequate weight gain during pregnancy has been shown to consistently increase the risk of preterm birth and infant growth restriction (7), which are among the main contributors to perinatal morbidity and mortality in the United States. In an effort to optimize birth outcomes, the Institute of Medicine recommended ranges for the rate of maternal weight gain and total weight gain (7). Because the effect of gestational weight gain on birth outcomes is modified by the mother’s prepregnancy weight and height, weight gain recommendations vary based on maternal prepregnancy body mass index (kg/m²). For instance, the Institute of Medicine recommended that women with a prepregnancy body mass index of 19.8 to 25.9 kg/m² (considered normal weight) should gain a total of 25 to 35 lb during pregnancy at a rate of 0.9 lb per week in the second and third trimesters. To implement these guidelines, the Institute of Medicine encouraged health care providers to do the following:

A depressed pregnant woman who was enrolled in a research protocol that involved antidepressant use during pregnancy provided the opportunity to longitudinally dissect the contributions of SSRI use, appetite change, and depressive symptoms to weight gain trajectory and to implement the guidelines recommended by the Institute of Medicine.

In this case conference, we described a depressed pregnant woman with normal prepregnant weight for her height who had appropriate gestational weight gain throughout 22 weeks of gestation, despite having significant depressive symptoms, nausea, and vomiting. After starting sertraline treatment at 22 weeks’ gestation for major depression, the patient’s depression rapidly remitted, but she reported a complete loss of appetite and a sense of feeling full after eating very little; her weight gain abruptly decelerated. A behavioral intervention of six scheduled nutritious meals of small volumes remedied the slowing of her weight gain and allowed her to achieve a total weight gain within the range recommended by the Institute of Medicine. She delivered a healthy full-term infant who developed normally. The patient’s slowing weight gain clearly was not due to depression but rather to treatment with sertraline, which caused reduced appetite as a direct side effect. This case illustrates that appropriate weight gain is achievable with an individualized nutrition intervention that overrides dependence upon appetite cues for eating. As demonstrated by our patient’s pregnancy course, lower weight gain in women treated with fluoxetine or other SSRIs may be because of appetite suppression and decreased food intake. Although weight gain has been the primary weight-related side effect of concern in the psychiatric literature, weight loss also occurs with SSRI treatment (19).

In 176 patients treated with sertraline, the frequency of weight changes reported on a side effect interview after 24 weeks of treatment was 20.2% with weight gain and 12.4% with weight loss (19). Weight changes across short- and long-term treatment with SSRIs also vary. In women, the rates of meaningful weight change (defined as ≥7% from baseline) after 6 to 8 weeks, 16 weeks, and 24 weeks of SSRI treatment were increases among 1.7%, 7.1%, and 14.2% of women, respectively, and decreases among 12.4%, 7.1%, and 8.4%, respectively (20). It is noteworthy that the patient continued to take sertraline in the postpartum period, but her appetite returned to normal after delivery. This observation suggests that there was either an interaction between the drug and her appetite that was specific to pregnancy or that the initial appetite suppression was a short-term side effect that subsided coincidentally near the time of the birth. The patient was treated for the final 15 gestational weeks, which corresponds to the time at which the proportion of women who lose weight in a population treated across time diminishes (12.4% to 7.1% at 16 weeks). Research with larger groups of women should examine longitudinally changes in appetite and weight during pregnancy and the postpartum period in medicated women to investigate a potential interaction rigorously. The success of our behavioral intervention with six small structured meals suggests that sertraline was physiologically increasing energy needs that could not be met with increased dietary intake and that the process of appetite loss and intake reduction was balanced. This hypothesis dictates that treatment with any SSRI could present a risk of poor maternal weight gain in some women, which could affect fetal growth and development. Therefore, the mother and fetus should be monitored closely throughout SSRI treatment. Based on our experience with this patient, we present the following recommendations to psychiatrists who care for pregnant patients.

Monitor gestational weight gain with a weight gain grid (13) or work with the patient’s obstetrician to monitor weight gain in all pregnant patients who are treated with an SSRI. Appetite and weight should also be monitored after delivery. If weight loss and appetite suppression have occurred, reduction below a normal body mass index may compromise the recovery of postpartum maternal nutritional reserves and the nutritional composition of breast milk in lactating women. Women who used fluoxetine during breast-feeding had infants with reduced growth throughout the first 6 months of life compared with infants of mothers who breast-fed but did not take fluoxetine after birth (1). The differential diagnosis of poor weight gain in pregnancy includes appetite loss as a side effect of SSRI treatment. It is appropriate for physicians to refer patients to a registered dietitian for a nutrition consultation to improve weight gain. Registered dietitians in local areas can be found through the search engine provided by the American Dietetic Association (www.eatright.org, click on "Find a Nutrition Professional"). Additionally, the American Dietetic Association provided a summary that physicians can use to guide women in making healthy food choices throughout pregnancy (21).