Melatonin in Pregnancy
Condition: Pregnancy
Study type: Observational

Summary: 
      Melatonin is well known for its role in the sleep-wake cycle and is synthesised in response
      to low light levels from the pineal gland. In our previous study it was found that serum
      melatonin levels increased dramatically during pregnancy, such that levels were up to 100
      fold higher in the third trimester compared to healthy non-pregnant women. The placenta
      contains the enzymes which are involved in synthesising melatonin but it is unclear if this
      is the source of the high levels in pregnancy. Severe pre-eclampsia has been reported to be
      associated with low levels of melatonin. In this study its is proposed to measure serum
      melatonin immediately before and after delivery and in cord blood and relate the levels to
      those in the placenta itself. This will contribute to the potential role for melatonin as a
      biomarker for obstetric disease and potentially as a therapeutic agent in future. This
      observational pilot study aims to measure serum and placental melatonin levels (as the major
      metabolite 6-hydroxymelatonin sulphate) in pregnant women undergoing elective Caesarean
      section.
    

Detailed description: 
      Background Melatonin, a substance produced by the pineal gland, is well known for its role in
      the sleep-wake cycle but it is less well known as an effective antioxidant. It is able to
      access all parts of the cell, and can cross the blood-brain and placental barrier.

      Melatonin has been reported to be synthesised in the placenta and may have both receptor
      mediated and non-receptor mediated protective functions during pregnancy. Severe
      pre-eclampsia has been reported to be associated with low levels of melatonin in the placenta
      although it is not known if the placental melatonin contributes to circulating levels.1,2
      Despite this, melatonin levels have been proposed as a biomarker of pre-eclampsia. More
      information on the role of melatonin and metabolism of melatonin in pregnancy would inform
      planning of larger research studies to investigate the potential role for melatonin as a
      bio-marker for obstetric disease and potentially as a therapeutic agent in future.

      Melatonin is synthesized endogenously from serotonin via two steps; the first, rate limiting
      step is arylalkylamine N-acetyltransferase mediated acetylation of serotonin to N-acetyl
      serotonin. The second step is methylation of N-acetyl serotonin via the enzyme hydroxyindole
      O-methyltransferase (also called N-acetylserotonin O-methyl-transferase).3,4 Interrogation of
      our database of next generation sequencing analysis of 80 human foetal livers revealed that
      the genes encoding these enzymes were not present although those encoding related
      acetyltransferases were. We can conclude that the human foetal liver is not a site of
      melatonin synthesis.

      Our previous work found melatonin levels do however increase markedly during pregnancy and
      are up to 50-100 times higher than non-pregnant women in the third trimester (Figure). The
      physiological role of these elevated melatonin levels remains a supposition and the
      relationship of melatonin levels in the placenta with the maternal and foetal circulations at
      different stages of pregnancy are unclear. Melatonin synthesizing enzymes have been found in
      human placental tissue, however it is not clear whether placental production of melatonin is
      directly related to the elevated circulating maternal melatonin levels.

      The production of melatonin is catalysed by specific enzymes and although these enzymes have
      been found in placental tissue, it is not known if the high melatonin levels in pregnancy
      come from the placenta and what the role of this melatonin is. It is proposed to measure
      melatonin in placentas and maternal/cord blood from women undergoing planned Caesarean
      section. The results should enable defining as to whether the placenta is a major source of
      melatonin and how the pattern of production changes in pregnancy. The blood samples taken
      from women having a Caesarean section and the umbilical cord will provide information about
      the role of melatonin at delivery.

      If melatonin levels in the maternal circulation falls after delivery and placental tissue
      melatonin levels are well above limits of detection, then a firm conclusion that the placenta
      is the source of elevated maternal melatonin would be justified. This observational pilot
      study aims to measure 6-hydroxymelatonin sulphate levels in blood from women undergoing
      Caesarean section and umbilical cords, and from placental tissue.

      This is an observational pilot study to investigate 6-hydroxymelatonin sulphate levels in
      blood from pregnant women immediately before and after delivery, from umbilical cord blood at
      the time of delivery and in samples of placental tissue.

      Healthy pregnant women will be recruited at the pre-Caesarean section pre-assessment clinic.
    

Intervention name(s): Melatonin analysis
Intervention type(s): Other
Intervention description(s): Measurement of 6-hydroxymelatonin
Intervention MeSH terms: Melatonin
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy pregnant women scheduled for elective Caesarean section
      
Biospecimen description: 
      Serum and placenta