ADHD and Pregnancy

It is debatable whether women experience neurocognitive changes across pregnancy. There have been observations that neurocognitive functions, including memory, may be negatively affected by pregnancy, and pregnant women are more likely than nonpregnant women to assess their memory as impaired (5, 6). Indeed, it is widely believed that there is a syndrome of “pregnancy brain” with memory impairment during pregnancy, the hypothesis being that changes in sex hormone production lead to worsening cognition (7). We lack studies assessing women with ADHD during pregnancy, but there have been small animal and human studies from which to draw. Some suggest impaired neurocognitive functioning during pregnancy, although these results are inconsistent, and no clear relationships have been elucidated between changes in any one hormone and cognition during pregnancy.

For example, in a study of 19 pregnant women (8), participants performed better on verbal memory tasks after delivery than they did 2 months before delivery. No associations were found between sex hormones and cognitive performance, although higher levels of progesterone were associated with a higher rate of negative mood states. However, in another study (9), in which women were assessed in the third trimester and again postpartum (N=55) and compared with nonpregnant comparison women (N=21), investigators found lower verbal memory and processing speed scores for women during pregnancy and the postpartum period relative to the comparison subjects. Prolactin levels were associated with verbal memory and executive functioning scores during pregnancy, while estrogen and cortisol were negatively associated with attention scores in the postpartum period. The timing of such impairments varies among studies (e.g., throughout pregnancy, in late pregnancy only), as does whether such findings extend to the postpartum period (6, 10, 11). A meta-analysis on this topic (12) demonstrated that study findings have been inconsistent, and overall there may be impairments among both pregnant and postpartum women on some specific neurocognitive tests of memory, particularly those that draw on executive functioning.

In some animal studies, higher progesterone and estrogen levels have been demonstrated to improve memory. For example, pregnant rats have been reported to outperform nonpregnant female rats on tests of memory and cognition (13). Other animal studies have shown morphological brain changes during pregnancy in the absence of functional memory impairment (14).

The inconsistencies in the literature suggest that neurocognitive impairments associated with pregnancy are subtle and unlikely to be experienced universally by pregnant and postpartum women. It is possible that women with preexisting ADHD constitute a vulnerable subgroup for neurocognitive worsening during pregnancy.

Although several systematic reviews have assessed the literature on stimulant use during pregnancy (20, 21), this literature has important limitations. Notably, stimulants often represent drugs of abuse rather than prescribed treatment for a specific indication. The lack of comprehensive data on use or misuse and associated variables greatly constrains our ability to derive a reproductive safety profile for stimulants.

The data pertaining to stimulants suggest a potential impact on fetal growth rather than a risk of teratogenicity (22–24). In one study, pregnancy and neonatal outcomes were reported for women who had a diagnosis of ADHD (N=153) (24). The use of concomitant medications was common, reflecting the comorbidity that has been consistently reported. The medications most commonly used in this group were methylphenidate (82.4%), risperidone (29.4%), selective serotonin reuptake inhibitors (16.4%), and imipramine (4.6%). The most frequent delivery complication was neonatal hypoxia (15.6%). The most frequent side effect occurring during pregnancy was decreased maternal appetite (34.9%). It is difficult to discern whether neonatal effects such as hypoxia are attributable to stimulant use, but this result warrants further study. The report of low appetite is consistent with the side effect profile of stimulants, as well as with the observation of decreased body weight among pregnant animals exposed to methylphenidate (25). Other studies also suggest that first-trimester exposure to methylphenidate does not increase the risk of congenital abnormalities beyond the rate in the general population. In a recent report, Dideriksen et al. (22) reported congenital anomalies occurring in four of 180 exposed pregnancies, or 2.2%. In a study of 39 mothers who used methylphenidate as a substance of abuse (23), there were relatively high rates of prematurity, growth retardation, and withdrawal. There was no control group, and exposures also included alcohol, cigarettes, and other drugs of abuse.

The timing of stimulant exposure may determine the impact on fetal growth. In a large prospective study (N=42,101) in which 237 pregnant women were treated with dextroamphetamine to prevent excessive weight gain (26), birth weights were not significantly affected when the drug was discontinued before week 28 of gestation but were 4% lower on average when the drug was discontinued after week 28. Neonatal length and head circumference were not affected, and there was no association with any type of malformation.

Bupropion may be a reasonable option for women who have had a good response to it, for those with comorbid depression, and for those seeking a pharmacological treatment for smoking cessation. Compared with the number of reports regarding other antidepressants (especially the selective serotonin reuptake inhibitors), fewer studies are available regarding its reproductive safety; however, the amount of data available for bupropion exceeds that for other medications used in the treatment of ADHD. Published reports regarding its safety during pregnancy are relatively reassuring, but as noted above, bupropion is not as efficacious as stimulants in the treatment of ADHD (17–19).

Prospective birth outcome data from the Bupropion Pregnancy Registry suggest that birth defect rates with bupropion exposure are similar to the general population rate (34). In the registry, 3.6% (24/675) of the cohort experienced a congenital anomaly after first-trimester exposure. The rate of birth defects with second-trimester exposure was 2.1%. There was no clear pattern of type of birth defects.

In one prospective study of 136 women who used bupropion in the first trimester (35), there was no evidence of higher rates of malformations compared with a group of women who used other antidepressants and a group who had no exposure to teratogens. In an epidemiological study of women who used antidepressants in pregnancy (36), outcomes were compared for women who used bupropion in the first trimester (N=1,213), women who used other antidepressants in the first trimester (N=4,743), and women who used bupropion after the first trimester (N=1,049). Results did not support teratogenic effects of first-trimester bupropion exposure. A small increase in the risk of cardiovascular left outflow defects was reported in a retrospective case-control study from a birth defect registry (37). The absolute risk was approximately 2 out of 1,000 pregnancies.

The literature on bupropion use during breastfeeding is limited to small case reports. In a report of two infants whose mothers breastfed while using bupropion (38), neither had detectable levels of bupropion or metabolites in their serum. In the case of a 14-month-old infant who was breastfed while the mother was treated with bupropion (39), milk-to-maternal-plasma ratios were reported as low, and bupropion and its metabolites were undetectable in the baby’s plasma. In a third report (40), urine levels of bupropion were assessed in four infants who were breastfed while their mothers were treated with bupropion. One of the infants had detectable levels of urinary bupropion, and had also been premature. The estimated bupropion dose that the infants were exposed to was 5.7% of the weight-adjusted maternal dose, which is considered compatible with breastfeeding. There is also a case report (41) of a baby who was breastfed while the mother was using bupropion and had a possible seizure as reported by the mother.

No systematic studies in human pregnancy have been conducted for these two agents. In a report on the use of guanfacine to treat hypertension associated with preeclampsia (42), 23 of 30 women experienced a good response to the drug as an antihypertensive, and six of 30 infants were reported to have been small for gestational age, although it is not possible to discern a potential risk of guanfacine in this context.

Psychotherapeutic approaches for ADHD have been investigated. Cognitive behavioral therapy (CBT) has been demonstrated to have a significant impact on symptoms. CBT and “coaching” strategies can help improve functioning and assist patients in tailoring their routines in ways to cope with ADHD (43–46). For some women, such strategies may be adequate to sustain functioning during pregnancy.