Restless Legs in Pregnancy Triples Risk of Perinatal Depression, Study Finds

For millions of expectant mothers, the final months of pregnancy bring an unwelcome companion: an irresistible, often maddening urge to move the legs, typically worse at night and only relieved by motion. Restless legs syndrome, or RLS, has long been dismissed as a nuisance symptom of pregnancy, but a new prospective study from Japan suggests it may be far more consequential than previously appreciated. Researchers at the University of Tokyo report that pregnant women whose RLS status changes over the course of gestation face roughly three times the risk of developing a full-blown major depressive episode before their baby’s first months of life, a finding that could reshape how clinicians screen and intervene during one of medicine’s most vulnerable windows.

The study, published in the Journal of Clinical Sleep Medicine, is the first to combine a validated diagnostic instrument for RLS with a formal diagnostic interview for depression, while also tracking how RLS status shifts between the second and third trimesters. Earlier research had hinted at a connection, but most of it relied on screening questionnaires such as the Edinburgh Postnatal Depression Scale, which flag elevated risk rather than establish clinical diagnoses, and most assessed RLS at only a single point in pregnancy. Because RLS prevalence is known to climb steadily from the first trimester onward, a one-time snapshot risks misclassifying women whose symptoms wax and wane, potentially diluting or distorting the true association with depression.

To overcome these limitations, the team led by Kazuhide Tezuka and Daisuke Nishi analyzed data from 2,435 Japanese pregnant women who had served as controls in a large randomized controlled trial of a web-based cognitive behavioral therapy program designed to prevent perinatal depression. That trial, known as iPDP, recruited more than 5,000 users of a popular pregnancy smartphone application between November 2019 and March 2020, inviting women aged 20 or older at 16 to 20 weeks of gestation. After excluding those with lifetime bipolar disorder or a major depressive episode in the previous month, the remaining participants were randomized, and the control group, which received only general antenatal mental health information, became the cohort for the present analysis.

RLS was assessed twice, at 16 to 20 weeks and again at 32 weeks of gestation, using the short form of the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, a 13-item instrument that probes not only the core features of RLS but also the mimicking conditions, such as muscle cramps and positional discomfort, that plague simpler four-criterion screens. Women were classified as RLS cases only if they reported symptoms on at least two to three days per week over the preceding year, a stricter threshold than many prior studies applied. The questionnaire itself has strong credentials: the original English version showed 87.2 percent sensitivity and 94.4 percent specificity against a telephone diagnostic interview, while the validated Japanese version achieved 88.9 percent sensitivity and perfect specificity against specialist clinical diagnoses.

Depression, meanwhile, was measured with unusual rigor for this field. The primary outcome was the incidence of a major depressive episode between the second trimester and three months postpartum, ascertained with the self-administered Japanese version of the World Health Organization Composite International Diagnostic Interview 3.0, which applies DSM-IV-TR criteria and asks participants when each episode began. A secondary outcome, perinatal depressive symptoms, was tracked with the Edinburgh Postnatal Depression Scale at 32 weeks, one week postpartum, and three months postpartum, using cutoff scores of 13, 11, and 9 to span the range of thresholds used internationally. The statistical approach was equally deliberate: Cox proportional hazards models treated RLS as a time-varying covariate, meaning a woman who developed RLS between the second and third trimesters contributed person-time to the unexposed category until her diagnosis and to the exposed category thereafter, and vice versa for women whose symptoms remitted.

The results were striking. RLS was diagnosed in 40 women, or 1.6 percent, in the second trimester and 60 women, or 3.5 percent, in the third, and 92 participants, 3.8 percent overall, met criteria at either time point. Over a mean follow-up of 6.5 months, 69 women developed perinatal depression, corresponding to 4.3 cases per 1,000 person-months among women without RLS but 13.2 per 1,000 person-months among those with the syndrome. Time-varying RLS status was associated with a hazard ratio of 3.04 for incident perinatal depression, with a 95 percent confidence interval of 1.22 to 7.58, and the estimate barely budged after adjustment for age, education, partner status, employment, number of children, and pregnancy planning. The association with depressive symptoms at the strict EPDS cutoff of 13 was also significant, with a hazard ratio of 2.12, though it weakened and lost statistical significance at the more permissive cutoffs of 11 and 9.

Perhaps the most clinically revealing detail lies in the timing. No excess depression was observed among women with RLS identified in the second trimester, but RLS diagnosed at 32 weeks carried a hazard ratio of 3.30, and the depressive episodes among affected women emerged only from the third trimester onward. The authors point to iron deficiency as a plausible common driver. Iron stores commonly plummet in the third trimester as fetal demands surge, and iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, making iron depletion a well-established trigger of the dopaminergic dysfunction implicated in RLS. The same deficiency has been independently linked to maternal depression, suggesting that late-pregnancy iron depletion may simultaneously fuel restless legs and precipitate depressive episodes, with fragmented sleep acting as an additional conduit between the two conditions.

The study is not without caveats, and the authors are candid about them. Participants were self-selected volunteers recruited through a smartphone app, likely a healthier and more digitally literate group than the general pregnant population, which may explain why the observed RLS prevalence of 1.6 to 3.5 percent sits well below the roughly 21 percent pooled estimate from meta-analyses of pregnancy worldwide, and such healthy volunteer bias would tend to attenuate rather than inflate the reported association. All measures were self-reported, leaving room for recall bias about depression onset, RLS was not assessed after delivery, only five depression cases occurred among women with RLS so the hazard ratio rests on thin numbers, and potential confounders such as iron status, hypothyroidism, and RLS treatments were not captured. The researchers also note that screening instruments inevitably include false positives, which is precisely why the diagnostic-interview approach matters: hazard ratios for EPDS-defined symptoms fell steadily as the cutoff loosened, consistent with the scale capturing transient or subclinical distress at lower thresholds.

Even with those limitations, the implications are concrete. Perinatal depression affects approximately 11.9 percent of pregnant and postpartum individuals globally and is associated with preterm birth, low birth weight, maternal suicidal behavior, and even mortality, yet it often goes undetected until after delivery. The authors argue that a simple RLS screen, particularly in the third trimester when both the syndrome and the depression risk peak, could flag women who warrant closer mental health monitoring, timely RLS treatment, and evaluation of iron status. What remains unproven is the crucial causal question: whether treating RLS, with iron supplementation or other therapies, would actually lower the incidence of perinatal depression. Until trials answer that, the study’s message is one of heightened vigilance, urging obstetricians and midwives to stop treating restless legs as a trivial complaint and start treating it as a potential early warning sign for one of pregnancy’s most serious complications.

The biological plausibility of a link between restless legs syndrome and depression rests largely on the shared role of iron in both conditions. Iron is not only essential for oxygen transport but also serves as a required cofactor for tyrosine hydroxylase, the enzyme that controls the rate of dopamine production in the brain. When maternal iron stores fall during pregnancy, particularly as fetal demands intensify in the later months of gestation, dopaminergic signaling can be disrupted. This same dopaminergic pathway is central to current models of restless legs syndrome, and iron depletion has also been implicated in mood regulation, offering a mechanism by which a single nutritional deficit might contribute to both conditions simultaneously.

Sleep disruption provides a second plausible conduit. The uncomfortable sensations and irresistible urge to move that define RLS typically worsen in the evening and at night, delaying sleep onset and fragmenting rest. Chronic sleep insufficiency during pregnancy is itself associated with poorer mood outcomes, and the resulting daytime fatigue can compound the emotional burden of gestation. In this way, RLS may act both as a direct physiological stressor and as an amplifier of the ordinary sleep difficulties that accompany late pregnancy, when hormonal shifts, fetal movement, and physical discomfort already conspire against restorative sleep.

The design choices of the new study strengthen confidence in its findings. By modeling RLS as a time-varying exposure rather than a fixed baseline characteristic, the investigators allowed women to contribute unexposed follow-up time before developing symptoms and exposed time afterward, or to move in the opposite direction if symptoms remitted. This approach respects the natural fluctuation of the condition across gestation and reduces the misclassification that a single assessment would introduce. Pairing a validated diagnostic questionnaire for RLS with a structured diagnostic interview for depression, rather than relying solely on screening scores, further distinguishes the work from earlier cross-sectional and symptom-based studies in the field.

The findings also align with a broader clinical picture. Restless legs syndrome occurs in the general population far less frequently than in pregnancy, where its prevalence has been estimated at roughly 21 percent across pooled international studies, and it is known to increase progressively from the first trimester toward term. That trajectory parallels the timing of depressive episodes observed among affected women in this cohort, which emerged from the third trimester onward, and echoes the observation that iron demands peak in the same period. Together, these converging lines of evidence suggest that the third trimester represents a window in which both conditions are most likely to arise in tandem, and in which a targeted inquiry about leg sensations could yield clinically meaningful information for maternity care providers monitoring maternal mental health.

Subject of Research: The association between time-varying restless legs syndrome during pregnancy and the risk of incident perinatal depression.

Article Title: Time-varying restless legs syndrome and risk of incident perinatal depression

Article References: Tezuka, K., Ito, Y., Sasaki, N., & Nishi, D. (2026). Time-varying restless legs syndrome and risk of incident perinatal depression. Journal of Clinical Sleep Medicine, 22(1), Article 154. https://doi.org/10.1007/s44470-026-00168-7

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00168-7

Keywords: restless legs syndrome, perinatal depression, pregnancy, major depressive episodes, sleep disorders, iron deficiency, Edinburgh Postnatal Depression Scale, Cox proportional hazards model, third trimester, postpartum, longitudinal study, mental health screening