Our group has noted that we are seeing an increase in the number of consultations for women treated with psychostimulants in combination with an antidepressant. The reasons vary. Some women have depression and comorbid attention-deficit/hyperactivity disorder (ADHD). Sometimes a psychostimulant is used to manage residual symptoms and side effects, such as fatigue and cognitive deficits. In other situations, stimulants are used to enhance the effects of the antidepressant.
Historically we have recommended that patients stop treatment with psychostimulants during pregnancy for women with mild to moderate ADHD. This recommendation was motivated in part by the limited information regarding the reproductive safety of these medications, as well as the belief that in the majority of these cases, discontinuation of stimulants for the treatment of ADHD — and the potential increase in levels of ADHD symptoms — would not compromise the health and well-being of the mother and the fetus. There are, of course, exceptions to this approach. One example would be a patient with such severe ADHD that, without medication, she would be at increased risk of accidental injury, including car accidents.
Over time, information regarding the reproductive safety of stimulants has increased. (We last reviewed this topic in June 2016.) Most of the studies have focused on risk for major malformations. The findings have not demonstrated any increase in risk of major malformations in children with first trimester exposure to methylphenidate, the active ingredient of Concerta, Ritalin, Metadate, and other preparations. There is less available data on dextroamphetamine and amphetamine, which are contained in Adderall, but still no evidence of teratogenesis.
While these reports are reassuring with regard to the risk of malformations, most studies have not included information on other outcomes, such as gestational age or birth weight. Some studies of stimulants, including women who abuse stimulants, have suggested higher rates of preterm birth, lower birth weight, and other adverse outcomes in infants exposed to stimulants during pregnancy.
A more recent study has taken a look at the use of stimulants and risk of gestational hypertension. This was a prospective, longitudinal observational study of pregnant women. Women with histories of psychiatric illness were enrolled before conception or during early gestation (no later than 16 weeks estimated gestational age). ACOG guidelines were used to define gestational hypertension as two blood pressure measurements equal to or greater than 140/90 mmHg or a single reading equal to or exceeding 160/110 mmHg after 20 weeks of gestation. Women with hypertension predating conception or arising before the 20th week of pregnancy were excluded from the analysis.
A total of 686 women were included in the analysis. Eighty-six (12.5%) of the participants were diagnosed with gestational hypertension. After adjusting for confounders, gestational hypertension was significantly associated with the use of psychostimulants (odds ratio [OR] = 6.11; 95% CI, 1.79-20.9) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (OR = 2.57; 95%, 1.34-4.93) after 20 weeks of gestation. Use of serotonin reuptake inhibitors was not associated with increased risk for hypertension. In women taking the SNRI venlafaxine or amphetamine stimulants, risk for gestational hypertension was seen more commonly at higher medication doses.
This finding is not so surprising, given that the SNRI, venlafaxine, and psychostimulants have been associated with increased blood pressure in non-pregnant patients. More difficult to explain is the finding that hypertension was also associated with a lifetime history of cocaine dependence (OR = 2.99; 95% CI, 1.12-7.98) and panic disorder (OR = 1.78; 95% CI, 1.06-2.98). Hypertension risk was not associated with other psychiatric disorders.
The authors speculate that sensitization to noradrenergic rather than serotonergic activity may modulate risk for hypertension among women with psychiatric illness. Psychostimulants, cocaine, and SNRIs all increase norepinephrine signaling. But why do women with a history of cocaine dependence (with no current use of cocaine) also have an increased risk of hypertension. This could be explained by heightened vascular reactivity to sympathetic/noradrenergic stimulation which is triggered during a period of cocaine use and persists during subsequent periods of abstinence, a finding which has been documented in animal models. Panic disorder has also been associated with sympathetic dysregulation and heightened vasoreactivity, which may explain the elevated risk for gestational hypertension in women with panic disorder.
While the total number of women exposed to stimulants and SNRIs in this study was relatively small, these findings raise concerns regarding the use of these medications during pregnancy given the observed increase in risk for gestational hypertension. The authors suggest that alternatives to SNRIs and psychostimulants should be considered, particularly for women with prior histories of gestational hypertension. In patients where no alternatives are available — and also in women with histories of panic disorder or cocaine dependence — more vigilant prenatal monitoring for gestational hypertension is warranted.
Ruta Nonacs, MD PhD
Newport DJ, Hostetter AL, Juul SH, Porterfield SM, Knight BT, Stowe ZN. Prenatal Psychostimulant and Antidepressant Exposure and Risk of Hypertensive Disorders of Pregnancy. J Clin Psychiatry. 2016 Nov;77(11):1538-1545.