Is melatonin safe for use in pregnancy? I know that there is some evidence that “low doses of melatonin (1 to 3 milligrams) are considered safe for the short term,” but what does that mean? Once a week? Once a month? The studies published online also seem to suggest that melatonin may even help lower the likelihood of having complications like preeclampsia and preterm birth.
—Sleepy mom of one anticipating adding one more
This type of vague statement — “low doses,” “short term” — is often a sign of limited data. It often means that we have no strong reason to be concerned but also no compelling direct evidence for safety. I would prefer in these situations that guidelines would say some version of that directly, instead of making vague statements about limiting consumption, but that’s rarely the case.
The case of melatonin in pregnancy is interesting, in part for the reasons you say at the end of your question. Melatonin is a hormone that occurs naturally in humans and that supports your circadian rhythms. Basically, it’s what tells you to fall asleep at night and wake up in the morning. There is a growing body of evidence that suggests that melatonin is important in pregnancy. In particular, genetic issues with melatonin production may be a cause of higher-risk pregnancy.
Gestational diabetes, preeclampsia, and preterm birth have all been associated with issues around melatonin. This has led some to argue that melatonin supplements may help with these issues, but we do not have any good evidence yet that they do.
This set of data alone is all very positive — not only does melatonin appear safe but also that it might be beneficial. However: what we do not have is any direct evidence on the use of melatonin supplements for insomnia in people. We know that melatonin in supplements is transferred to the fetus (just like naturally occurring melatonin is). We also know there is good safety data in rats, but also maybe some evidence of minor fetal growth issues in sheep.
People are not rats or sheep, and it is hard to be sure how the doses translate.
With all this — where can we possibly land? There is nothing in the data that would provide any strong reason for concern, and melatonin is therefore the first-line prescription when people face pregnancy insomnia. For someone who wants more airtight randomized controlled trial evidence, you’ll have to wait.
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What gives me pause in the absence of robust safety data is the plausible mechanism linking placental melatonin concentration (which, as was mentioned in the post, has been demonstrated to increase from exogenous (supplemental) melatonin) with uterine contraction and induction of labor. Melatonin is being considered for its potential role in labor induction.
See the following paper and its citations: https://www.mdpi.com/2227-9059/10/12/3252#B9-biomedicines-10-03252:
“6. Melatonin and Labor Uterine contraction is essential to progress into active labor for vaginal birth (Figure 2). In the last decade, induction of labor has been a common practice performed with the intent of reducing risks to the mother and/or baby by simply calling an end to the pregnancy. Ideally, induced labor progresses to vaginal delivery, but most induced labors fail and become a caesarean delivery [45–47]. Caesarean section increases the fetal and mother mobility, such as postpartum hemorrhage and venous thrombosis [48,49]. Maternal melatonin levels increase with advancing gestation, peaking during labor and then falling rapidly after birth [50]. The myometrium (uterine muscle) expresses the melatonin receptor MT2, and it is more highly expressed in laboring myometrium, collected at intrapartum caesarean section, than in myometrium from non-laboring women [51]. It has been proposed that melatonin receptor 1B (hMTNR1B) synergizes with oxytocin to promote nocturnal uterine contractions [7]. In fact, in humans, spontaneous labor in term pregnancies is more often initiated and more babies are born at night [52], a time when the pineal gland secretes the hormone melatonin into circulation. Melatonin receptor expression in the human pregnant uterus has been reported only during labor. In late-term pregnancy, circulating melatonin is of fundamental importance to induce timing and degree of contractions; conversely, its acute inhibition with light suppresses myometrial contractions [53]. In the same study, melatonin was also shown to increase the expression of the protein connexin, a gap-junction protein necessary for myometrial cell communication and the synchronization of uterine contractions. In addition, another study underlined that as melatonin increases, so does the sensitivity of the myometrium to oxytocin-induced contractions [7]. Taken together, these in vivo and in vitro observations suggest that melatonin plays a biological role in the timing of the onset of spontaneous labor and the effectiveness of spontaneous uterine contractions in labor [52]. The manuscript by Rahman SA et al., 2019, evaluated the impact of light-induced modulation of melatonin secretion on uterine contractions in women during the late third trimester (~36–39 weeks) of pregnancy in two inpatient protocols. The result of this study confirmed that there is a positive relationship between melatonin concentrations and uterine contractions in women after ~35 weeks of pregnancy. Moreover, there are many potential applications of this discovery to provide a newmechanism for therapeutically influencing the timing of labor and childbirth, since endogenous melatonin levels can be suppressed by both light and pharmacologic agents, and melatonin receptors can be activated by melatonin. Regarding this interesting topic, there is a work in progress, a double-blind randomized placebo-controlled trial MILO (Melatonin as an adjuvant agent in the induction of labor), by Swarnamani K et al., 2021, that aims to test the hypothesis that the inclusion of melatonin will reduce the need for the caesarian section in induced labor delivery [9].”