Melatonin May Offer a New Line of Defense Against Dangerous Pregnancy Complications

Melatonin, the hormone most famous for its role in lulling the brain to sleep, is emerging as one of the most intriguing candidates for treating some of the most dangerous complications of pregnancy. A comprehensive review published in Reproductive Sciences by researchers at West China Second University Hospital of Sichuan University synthesizes decades of evidence showing that this small, versatile molecule acts as a potent antioxidant, anti-inflammatory agent, and mitochondrial guardian at the maternal-fetal interface. Led by first author Shanza Waseem and senior author Xue Xiao, the analysis moves beyond melatonin’s circadian credentials to argue that supplementation could one day help protect mothers and babies from preeclampsia, fetal growth restriction, gestational diabetes mellitus, and preterm birth, four conditions that together account for a substantial share of pregnancy-related illness and death worldwide.

The scientific foundation for this idea rests on a surprising biological fact: the placenta is not merely a passive recipient of maternal melatonin but an active producer of the hormone itself. Human placental trophoblasts synthesize melatonin and express its receptors, MT1 and MT2, throughout gestation. During pregnancy, maternal serum melatonin levels rise steadily, and they plummet immediately after delivery, implicating the placenta as a major source of the hormone in late pregnancy. This dual origin, maternal pineal and placental, means the developing fetus is bathed in melatonin signaling that likely helps coordinate circadian rhythms across mother, placenta, and fetus, a kind of three-part harmony that studies suggest is essential for normal fetal development and programming. Disrupting this rhythm, through shift work or other forms of gestational chronodisruption, has been linked to lasting deficits in offspring brain function, including impaired spatial memory and altered expression of NMDA receptor subunits in the hippocampus.

Mechanistically, melatonin’s appeal as a therapeutic agent lies in its chemistry and its receptor biology. The molecule is both water- and fat-soluble, allowing it to cross cell membranes and the placenta freely, and it accumulates in mitochondria, the energy factories that are among the first casualties of placental disease. Melatonin directly scavenges reactive oxygen species and, more powerfully, stimulates the activity of antioxidant enzymes while suppressing pro-oxidant pathways. It also operates through receptor-mediated signaling: MT1 and MT2 receptors couple to Gi and Gs proteins, modulating pathways such as extracellular signal-regulated kinase, and nuclear receptors for melatonin, including ROR family members, can repress inflammatory gene expression. Through these routes, melatonin reduces inflammation, curbs endoplasmic reticulum stress, regulates autophagy, and protects trophoblasts from the hypoxia-reoxygenation cycles that batter the placenta in complicated pregnancies.

Preeclampsia, the sudden onset of hypertension and organ dysfunction in pregnancy, features prominently in the review. The condition is driven by defective placentation, oxidative stress, antiangiogenic signaling, and systemic endothelial and immune dysfunction. Several human studies have found that circulating melatonin levels are significantly lower in women who develop preeclampsia, and a meta-analysis confirmed the association between reduced melatonin concentrations and disease development. Preclinical work has been compelling: in rat models of L-NAME-induced gestational hypertension, melatonin attenuated hypertension and oxidative stress, and in pinealectomized rats subjected to reduced uterine perfusion pressure, melatonin supplementation normalized oxidative stress and apoptosis in fetal hearts. In vitro, melatonin improved endothelial function, reduced the secretion of the antiangiogenic factor sFLT1 from primary trophoblasts, and diminished the release of toxic extracellular vesicles from preeclamptic placentae. Notably, melatonin also appears to regulate trophoblast proliferation, apoptosis, and invasion by inhibiting endoplasmic reticulum stress, addressing one of the earliest defects in the disease.

Translational evidence in preeclampsia is still early but suggestive. A phase I pilot clinical trial protocol, PAMPR, was designed to test antenatal maternal melatonin in pregnancies affected by early-onset preeclampsia, and a related in vitro and clinical study reported that melatonin improved endothelial function in laboratory assays and prolonged pregnancy in women with early-onset disease. The review is candid about the limits of the evidence: melatonin enhances placental antioxidant defenses and reduces sFLT1 secretion, but it does not fully rescue endothelial dysfunction in all experimental settings, meaning supplementation is more likely to be preventive or stabilizing than a standalone cure once severe disease is established. That nuance shapes the authors’ argument for carefully designed trials rather than reflexive adoption.

Fetal growth restriction receives a similarly rigorous treatment. In placentas from affected pregnancies, expression of melatonin MT1 and MT1B receptors is decreased, and animal studies suggest the receptor pathway is functionally important: deletion of Mtnr1b in mice disrupts placental angiogenesis through the VEGF pathway and produces fetal growth restriction. Supplementation experiments in undernourished rodents showed that melatonin improved placental efficiency, increased birth weight, and boosted placental antioxidant enzyme expression, while other work demonstrated protection against ischemia-reperfusion-induced mitochondrial damage in the placenta. In models of environmental stress, melatonin suppressed ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts, preserving fetal growth. Human trials are underway: a phase I pilot trial of antenatal melatonin in growth-restricted pregnancies has been conducted, and the triple-blinded, placebo-controlled Protect-Me randomized trial is assessing whether maternal melatonin supplementation provides fetal neuroprotection in early-onset fetal growth restriction. Sheep studies add encouraging neurodevelopmental data, with maternal melatonin reducing newborn neurodevelopmental deficits and brain injury in placental insufficiency models.

Gestational diabetes presents a more complicated picture, one in which melatonin biology can cut both ways. Large genetic studies have repeatedly linked the MTNR1B locus, which encodes the MT2 melatonin receptor, to glucose homeostasis and diabetes risk. A functional polymorphism, rs10830963, is associated with the risk of gestational diabetes mellitus, abnormal insulin and C-peptide kinetics, and interactions with lifestyle interventions and pre-pregnancy body mass index. Human experimental work shows that acute melatonin administration can impair glucose tolerance, and increased melatonin signaling in certain genetic contexts is a risk factor for type 2 diabetes. Yet in diabetic models, melatonin supplementation improves insulin resistance, oxidative stress, and lipid peroxidation through pathways including Nrf2 signaling, and systematic reviews and meta-analyses of randomized trials report favorable effects on insulin levels and resistance. The review’s authors read this duality as a caution: melatonin therapy for gestational diabetes cannot be prescribed generically, and pharmacological optimization must account for chronobiology, genotype, and timing.

Preterm birth is the fourth major disorder examined, and here melatonin’s anti-inflammatory profile is central. Preterm parturition involves inflammatory cytokines, prostaglandin signaling, cervical ripening, and activation of inflammasomes such as NLRP3. In experimental models, melatonin prevented inflammation-induced preterm labor and increased offspring survival, and prenatal melatonin therapy enhanced postnatal lung development in a mouse model of inflammation-induced preterm birth. Mouse studies also showed that melatonin administration prevented placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress, and protected against fetal brain injury in premature birth models. The neuroprotective theme extends to the newborn: melatonin has been tested as an adjunct to hypothermia therapy in asphyxiated infants, with pilot randomized trials and a systematic review and meta-analysis of clinical trials reporting safety and preliminary signals of benefit, likely reflecting the drug’s ability to blunt excitotoxicity, glutamate release, NADPH-oxidase-derived radical production, and neuroinflammation through AMPK/mTOR and Nrf2/ARE pathways.

The review’s most valuable contribution may be its framing of what comes next. The authors stress that compelling preclinical data and emerging clinical studies support melatonin as a potentially safe and effective strategy to mitigate oxidative stress and inflammation at the maternal-fetal interface, but they identify critical gaps: standardized dosing informed by clinical pharmacokinetics, biomarker-driven trial design using measures such as angiogenic factors and pro-inflammatory markers, pharmacogenomic stratification of metabolic disorders, and long-term developmental safety follow-up of exposed children. Melatonin crosses the placenta freely, so any intervention must consider fetal exposure and circadian programming effects, including the hormone’s known influence on uterine contraction timing in late pregnancy. As the Protect-Me and other trials mature, melatonin, a molecule long dismissed as a simple sleep aid, may find its most consequential role not in the pharmacy’s sleep aisle but in the delivery suite, shielding the most vulnerable patients in medicine.

Subject of Research: Melatonin's protective mechanisms and therapeutic potential in pregnancy-related disorders such as preeclampsia, fetal growth restriction, gestational diabetes, and preterm birth

Article Title: Melatonin in Pregnancy-Related Disorders: A Review of Protective Mechanisms and Therapeutic Potential

Article References: Waseem, S., Zhan, J., Yu, L., & Xiao, X. (2026). Melatonin in Pregnancy-Related Disorders: A Review of Protective Mechanisms and Therapeutic Potential. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02196-3

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02196-3

Keywords: melatonin, pregnancy, preeclampsia, fetal growth restriction, gestational diabetes, preterm birth, placenta, oxidative stress, antioxidant, inflammation, MTNR1B, neuroprotection