OBJECTIVE: Restless legs syndrome (RLS) affects approximately one in five pregnant individuals and has been associated with adverse pregnancy outcomes and a fourfold increased risk of developing chronic RLS in later life.1,2 First-generation antihistamines (FGAs), commonly used during pregnancy to treat nausea, sleep disturbance, and allergy symptoms, have been shown to trigger or exacerbate RLS in non-pregnant adults.3 Because FGAs readily cross the blood-brain barrier and may interfere with dopaminergic signaling, they could plausibly increase susceptibility to RLS.2 However, whether initiation of FGAs during pregnancy is associated with gestational RLS is unknown. We therefore examined the association between FGA initiation during pregnancy and the prevalence of gestational RLS. STUDY DESIGN: We conducted a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b), a prospective cohort of 10,038 nulliparous individuals with singleton pregnancies enrolled at 8 U.S. sites (10/1/2010-9/30/2013).4 Study visits occurred at 60-136 weeks (Visit 1), 160-216 weeks (Visit 2), and 220-296 weeks of gestation (Visit 3). At each visit, participants reported all prescription and overthe-counter medications taken either within the two months before conception (Visit 1) or since the preceding study visit (Visits 2 and 3), including medication name, start and stop dates, and reasons for use. We excluded individuals with a history of RLS diagnosis (n=178), missing medication data (n=381), or FGA use within 2 months before conception (n=170) (Figure S1). Early-pregnancy exposure was defined as initiating any FGA between conception and Visit 1. Mid-pregnancy exposure was defined as FGA use between Visits 2 and 3, the period immediately preceding RLS assessment. RLS symptoms were ascertained at early (after Visit 1) and mid-pregnancy (after Visit 3) using the International RLS Study Group diagnostic criteria;5 participants meeting all four criteria were classified as having RLS symptoms. Poisson regression with robust standard errors estimated relative risks for RLS symptoms by FGA exposure, adjusting for maternal age, gestational age at RLS assessment, early-pregnancy body mass index, iron supplementation, and tobacco use within one month. Sensitivity analyses further adjusted for nausea and vomiting severity and included comparator models evaluating second-generation antihistamine exposure. RESULTS: The early-pregnancy analysis included 6,641 participants (median age, 28 years [IQR, 23-31]; gestational age at assessment, 130 [116-136] weeks; Table 1). FGAs were initiated in 5.1% (339/6,641). The most commonly used FGAs were promethazine (41.3%), doxylamine (35.1%), and diphenhydramine (22.7%), most frequently taken for nausea or vomiting (66.4%) and sleep problems (18.0%). RLS symptoms were reported by 20.9% (71/339) of exposed and 16.4% (1,034/6,302) of unexposed participants. After adjustment, FGA initiation was associated with a higher prevalence of early-pregnancy RLS symptoms (RR=1.29; 95% CI, 1.04-1.59), corresponding to 4.5 additional cases per 100 exposed pregnancies (Table 2). The mid-pregnancy analysis included 6,585 participants, of whom 4.2% (275/6,585) reported FGA use between Visits 2 and 3. The most frequently used FGAs were diphenhydramine (40.0%), promethazine (32.4%), and doxylamine (28.4%), primarily used for nausea (44.7%) and sleep problems (26.5%). RLS symptoms, assessed at a median gestational age of 280 [266-290] weeks, were reported by 34.9% (96/275) of exposed and 29. 0% (1,830/6,310) of unexposed participants. Adjusted analyses showed a similar association (RR=1.20; 95% CI, 1.01-1.42), corresponding to 5.9 additional cases per 100 exposed pregnancies. Associations remained statistically significant after additional adjustment for nausea and vomiting severity (Table 2). In contrast, second-generation antihistamines were not statistically associated with RLS symptoms in adjusted models at either time point (Figure S2). CONCLUSION: In this prospective cohort of nulliparous pregnant individuals without prior RLS or preconception antihistamine use, initiation of first-generation antihistamines during pregnancy was associated with a higher prevalence of RLS symptoms in both early and mid-pregnancy, corresponding to approximately 4-6 additional cases per 100 exposed pregnancies. Second-generation antihistamines, which have less central nervous system penetration, were not statistically associated with RLS symptoms after adjusting for potential confounders; however, point estimates were similar in magnitude to those for first-generation antihistamines, and the null finding may represent type II error.
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