Melatonin for Uterine Contractions in Pregnancy

(MelPreg Trial)

Overseen By Shadab A Rahman, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Brigham and Women's Hospital

Must not be taking: Beta blockers, NSAIDs, CNS depressants, others

Disqualifiers: Color blind, Diabetes, Immunosuppressants, others

Compensation: Varies

Number of Visits: 2

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The study will extend recent discoveries that have been made in basic human physiology related to responses melatonin and uterine contractions in late- or full-term pregnant women. The basic physiology work has been conducted in in vitro models of the human myometrium characterizing its responses to melatonin, and in pilot in vivo studies correlating the number of uterine contractions with melatonin concentrations that were manipulated by different types of light exposure. The planned experiments will test a causal link between circulating melatonin levels and uterine contractions in full-term pregnant women by manipulating melatonin levels using exogenous melatonin (i) during the day when endogenous levels of melatonin are very low (Experiment 1), and (ii) during the evening under conditions with lighting that would be expected to suppress the higher evening and nighttime levels of endogenous melatonin (Experiment 2).

Will I have to stop taking my current medications?

If you are taking prescription drugs that affect sleep, melatonin, or circadian rhythms, or medications that might interact with melatonin, you may need to stop them to participate in this trial. It's best to discuss your specific medications with the study team to determine eligibility.

Is melatonin safe for use in humans?

Melatonin is generally safe for use in humans, with most studies reporting minor and short-lived side effects like fatigue and mood changes. Some studies noted effects on reproductive and cardiovascular functions, which can be managed by proper dosing and timing. ^{1 2 3 4 5}

How does the drug melatonin differ from other treatments for uterine contractions in pregnancy?

Melatonin is unique because it is a hormone that naturally increases at night and may influence uterine contractions by interacting with melatonin receptors in the uterus, potentially affecting the timing of labor. Unlike other treatments, melatonin also acts as an antioxidant and can cross the placenta, providing benefits to both the mother and fetus. ^{1 3 5 6 7}

What evidence supports the effectiveness of the drug melatonin for uterine contractions in pregnancy?

Research suggests that melatonin may play a role in the timing of labor, as it can influence uterine contractions, especially when combined with another hormone, noradrenaline. Melatonin levels naturally rise at night, which is when labor often begins, indicating it might help regulate the timing of birth. ^{1 3 4 6 8}

Who Is on the Research Team?

Elizabeth B Klerman, MD PhD

Principal Investigator

MGH

Are You a Good Fit for This Trial?

This trial is for first-time pregnant women aged 18-35, with a BMI under 36 before pregnancy, and at least 40 weeks into a single-fetus pregnancy. They must be receiving care from MassGeneralBrigham and planning to deliver at an MGB-affiliated institution. Women taking certain medications or with conditions affecting sleep, melatonin levels, or uterine contractions are excluded.

Inclusion Criteria

Planned admission for delivery at a MGB affiliated institution

BMI<36 pre-pregnancy

Pregnancy-associated obstetrical care by nurse midwife or physician associated with MassGeneralBrigham (MGB) (including hospital and community health centers)

Exclusion Criteria

Color blind

I am not taking any medications that could interact badly with melatonin.

I have a condition that could affect my melatonin levels or uterine contractions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Daytime Treatment

Participants receive exogenous melatonin during the day when endogenous levels are low

10 hours

1 visit (in-person)

Nighttime Treatment

Participants receive exogenous melatonin during the evening under lighting conditions expected to suppress endogenous melatonin

4 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Melatonin
• Placebo

Trial Overview The study tests if melatonin affects uterine contractions in full-term pregnant women. It involves giving exogenous melatonin during the day when natural levels are low and in the evening under light that suppresses natural melatonin production. Participants will either receive actual melatonin or a placebo.

How Is the Trial Designed?

Group I: Nighttime melatonin 0.5 mg Experimental Treatment 1 Intervention

Nighttime melatonin 0.5 mg

Group II: Daytime melatonin 3.0 mg Experimental Treatment 1 Intervention

Daytime melatonin 3.0 mg

Group III: Daytime melatonin 0.5 mg Experimental Treatment 1 Intervention

Daytime melatonin 0.5 mg

Group IV: Nighttime melatonin 0.0 mg Placebo Group 1 Intervention

Nighttime melatonin 0.0 mg

Group V: Daytime melatonin 0.0 mg Placebo Group 1 Intervention

Daytime melatonin 0.0 mg

Melatonin is already approved in European Union, United States for the following indications:

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

A study involving women in the late third trimester of pregnancy found a significant positive relationship between circulating melatonin levels and the frequency of uterine contractions, suggesting that melatonin may play a role in initiating labor.

For every 10 pg/mL*h increase in melatonin concentration, there was an increase of 1.4 to 2.1 contractions per 30 minutes, indicating that melatonin levels can be influenced by light exposure and may have clinical implications for managing labor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between endogenous melatonin concentrations and uterine contractions in late third trimester of human pregnancy. Rahman, SA., Bibbo, C., Olcese, J., et al.[2023]

Melatonin does not directly affect uterine contractility on its own, but it enhances contractions when combined with noradrenaline, suggesting a potential role in modulating uterine activity.

The study, which involved uterine tissue samples from women at full term during caesarean sections, indicates that melatonin may influence the timing of labor, particularly since labor often starts in the evening when melatonin levels are higher.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin together with noradrenaline augments contractions of human myometrium. Mårtensson, LG., Andersson, RG., Berg, G.[2019]

Circadian rhythms, regulated by the suprachiasmatic nucleus and melatonin production, play a crucial role in pregnancy, influencing physiological processes and the timing of birth.

Melatonin may offer therapeutic benefits in improving pregnancy outcomes, potentially reducing risks of complications like preeclampsia and preterm birth by helping to align maternal and fetal circadian systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riding the Rhythm of Melatonin Through Pregnancy to Deliver on Time. McCarthy, R., Jungheim, ES., Fay, JC., et al.[2020]

Melatonin receptors (MT1 and MT2) are expressed in the myometrial tissues of both pregnant and nonpregnant women, suggesting that melatonin may play a role in regulating uterine contractions during childbirth.

The study found that melatonin can differentially affect cAMP signaling in myocytes based on the reproductive state, indicating its potential to modulate myometrial function and possibly lead to new treatments for childbirth-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The human myometrium as a target for melatonin. Schlabritz-Loutsevitch, N., Hellner, N., Middendorf, R., et al.[2015]

Melatonin receptors, specifically MTNR1B, are present in the human myometrium during late-term pregnancy and play a crucial role in enhancing uterine contractions by working together with oxytocin signaling.

Exposure to white light can inhibit melatonin levels, which in turn reversibly suppresses uterine contractions, highlighting the importance of melatonin in regulating labor timing and intensity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical significance of melatonin receptors in the human myometrium. Olcese, J., Beesley, S.[2014]

A systematic review of 50 studies on oral melatonin supplementation found that 26 studies reported no significant adverse events, indicating a generally favorable safety profile for melatonin, especially when used according to natural circadian rhythms.

While most adverse events were minor and manageable, some studies noted potential impacts on endocrine and cardiovascular functions, suggesting that dosage and timing are important factors to consider in melatonin use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Foley, HM., Steel, AE.[2019]

Melatonin is a crucial hormone during pregnancy, as it crosses the placenta easily and helps regulate biological rhythms, which may be essential for a successful pregnancy.

The hormone has multiple roles, including acting as an endocrine modulator and antioxidant, and it may help address complications such as abortion, pre-eclampsia, and fetal brain damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and pregnancy in the human. Tamura, H., Nakamura, Y., Terron, MP., et al.[2018]

Melatonin has demonstrated a tocolytic effect, meaning it can help inhibit uterine contractions, based on experiments conducted on isolated uterine horns in various animal models.

The research suggests that melatonin works by antagonizing the effects of oxytocin, which is known to induce uterine contractions, indicating a potential mechanism of action for its tocolytic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The tocolytic activity of melatonin]. Drogovoz, SM., Ryzhenko, IM.[2014]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Relationship between endogenous melatonin concentrations and uterine contractions in late third trimester of human pregnancy. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Melatonin together with noradrenaline augments contractions of human myometrium. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Riding the Rhythm of Melatonin Through Pregnancy to Deliver on Time. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

The human myometrium as a target for melatonin. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical significance of melatonin receptors in the human myometrium. [2014]

6. Scotland pubmed.ncbi.nlm.nih.gov

Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Melatonin and pregnancy in the human. [2018]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The tocolytic activity of melatonin]. [2014]