Background
Melatonin is a potent oxygen scavenger and is capable of altering blood flow in various vascular beds.
Aims
We aimed to determine the effect of melatonin on ovarian vascular indices during ...ovarian stimulation for in vitro fertilisation (IVF).
Materials and Methods
This is a pilot double‐blind placebo‐controlled randomised trial. Sixty‐nine women (mean age 35.8 ± 4.3 years) undergoing their first cycle of IVF were randomised to receive either placebo, 2, 4 or 8 mg of melatonin, twice a day. Each participant underwent a transvaginal ultrasound at days 6–10 assessing follicular number and size. The vascularisation index (VI), flow index (FI) and vascularisation‐flow index (VFI) were measured. These indices were then correlated with embryological outcomes. Informed consent was obtained from participants. This trial was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12613001317785).
Results
The number of follicles did not differ between groups (P = 0.4). There were no differences in the VI (P = 0.4), FI (P = 0.1) or VFI (P = 0.3) in the right ovary or the FI (P = 0.3) or VFI (P = 0.3) in the left ovary between groups. When comparing placebo to any dose of melatonin, there were no differences in any measured parameter. While there was correlation between the number of follicles on ultrasound and all measured embryological outcomes, there was no correlation between ovarian vascular indices and these important clinical outcomes.
Conclusions
Melatonin does not appear to change ovarian vascular indices during ovarian stimulation. In addition, such vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle. These findings require confirmation in future larger studies.
The transition from a fetus to a neonate at birth represents a critical phase in our life. Most infants make this transition without complications, but preterm infants usually require some form of ...assistance due to immature cardiopulmonary systems that predispose them to lifelong sequelae. As the incidence of preterm birth is increasing, there is now an urgent need for the development of management strategies that facilitate this transition, which will likely include improved strategies for the management of the maternal third stage of labor. For instance, recent studies on the physiological transition at birth have led to the discovery that establishing ventilation in the infant before the umbilical cord is clamped greatly stabilizes the cardiovascular transition at birth. While most benefits of delayed clamping previously have been attributed to an increase in placenta to infant blood transfusion, clearly there are other significant benefits for the infant, which are not well understood. Nevertheless, if ventilation can be established before cord clamping in a preterm infant, the large adverse changes in cardiac function that normally accompanies umbilical cord clamping can be avoided. As preterm infants have an immature cerebral vascular bed, large swings in cardiovascular function places them at high risk of cerebral vascular rupture and the associated increased risk of mortality and morbidity. In view of the impact that cord clamping has on the cardiovascular transition at birth, it is also time to re-examine some of the strategies used in the management of the third stage of labor. These include the appropriate timing of uterotonic administration in relation to delivery of the infant and placenta. As there is a lack of evidence on the effects these individual practices have on the infant, there is a necessity to improve our understanding of their impact in order to develop strategies that facilitate the transition to newborn life.
Abstract
STUDY QUESTION
Does melatonin result in a dose–response effect on sleep quality and daytime sleepiness in women undergoing IVF?
SUMMARY ANSWER
Melatonin, even when given at high doses twice ...per day, does not cause significant daytime sleepiness or change night time sleep quantity or quality.
WHAT IS KNOWN ALREADY
Melatonin is being increasingly used as an adjuvant therapy for women undergoing IVF owing to its antioxidative effects. It is widely considered to be sedative but there are scant objective data on the effects of melatonin on sleep in the setting of IVF.
STUDY DESIGN SIZE, DURATION
The study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016.
PARTICIPANTS/MATERIALS, SETTING, METHOD
Women who were undergoing their first cycle of IVF at private IVF centers were recruited into the RCT and randomized to receive either placebo, 2 mg, 4 mg or 8 mg of melatonin, twice per day (BD) from Day 2 of their cycle until the day before oocyte retrieval. Each participant wore an accelerometer that provides an estimate of sleep and wake activity for up to 1 week of baseline and throughout treatment (up to 2 weeks). They also kept sleep diaries and completed a Karolinska sleepiness score detailing their night time sleep activity and daytime sleepiness, respectively.
MAIN RESULTS AND THE ROLE OF CHANCE
In total, 116 women were included in the intention-to-treat analysis (placebo BD (n = 32), melatonin 2 mg BD (n = 29), melatonin 4 mg BD (n = 26), melatonin 8 mg BD (n = 29)). There were no significant differences in daytime Karolinska sleepiness score between groups (P = 0.4), nor was there a significant dose–response trend (β=0.05, 95% CI −0.22–0.31, P = 0.7). There were no differences in objective measures of sleep quantity or quality, including wake after sleep onset time, sleep onset latency, and sleep efficiency before and after treatment or between groups. There was an improvement in subjective sleep quality scores from baseline to during treatment in all groups, except 8 mg BD melatonin: placebo (percentage change −13.3%, P = 0.01), 2 mg (−14.1%, P = 0.03), 4 mg (−8.6%, P = 0.01) and 8 mg (−7.8%, P = 0.07).
LIMITATIONS, REASONS FOR CAUTION
As this was a subset of a larger trial, the melatonin in ART (MIART) trial, it is possible that the sample size was too small to detect statistically significant differences between the groups.
WIDER IMPLICATIONS OF THE FINDINGS
While this study suggests that melatonin can be used twice per day at high doses to achieve sustained antioxidation effects, with the reassurance that this will not negatively impact daytime sleepiness or night time sleep habits, the sample size is small and may have missed a clinically significant difference. Nevertheless, our findings may have implications not only for future studies of fertility treatments (including meta-analyses), but also in other medical fields where sustained antioxidation is desired.
STUDY FUNDING/COMPETING INTERESTS
This study was funded by the Monash IVF Research and Education Foundation (PY12_15). S.F. is supported by the National Health and Medical Research Council (Postgraduate Scholarship APP1074342) and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists Ella Macknight Memorial Scholarship. E.W. is supported by an National Health and Medical Research Council Program Grant (APP1113902). S.F., E.W., R.H., B.V., N.L., N.H., M.W., M.L., A.L., P.T., K.L. have nothing to declare. L.R. is a Minority shareholder in Monash IVF Group, has unrestricted grants from MSD®, Merck-Serono® and Ferring® and receives consulting fees from Ferring®. S.N.B. reports consulting fees from Johnson & Johnson Consumer Inc®, outside the submitted work.
TRIAL REGISTRATION NUMBER
This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785).
TRIAL REGISTRATION DATE
27/11/2013
DATE OF FIRST PATIENT’S ENROLMENT
1/9/2014
This thesis describes a series of clinical and laboratory studies examining the value of inhibins as novel prenatal markers of Down's syndrome. Inhibins are a family of glycoprotein proteins ...identified in gonadal tissue but known to be secreted by the placenta in pregnancy. The ontogeny of inhibin secretion in early pregnancy is described in detail comparing various pregnancy compartments in both normal and Down's syndrome pregnancies. It is shown that maternal serum levels of inhibin-A, one of two possible full processed inhibin dimers, are significantly elevated in Down's syndrome in both the first and second trimesters of pregnancy. Furthermore, mathematical modelling studies with other established prenatal markers (maternal age, human chorionic gonadotrophin and alpha fetoprotein) suggests that inhibin-A could increase second trimester detection rates by as much as 20%. Studies on amniotic fluid revealed that, unlike maternal serum in which only inhibin-A is detectable, both dimers, inhibin-A and inhibin-B, were present raising the possibility that the fetal membranes secrete significant amounts of inhibin. The lack of relationship between inhibin-A levels in paired serum and amniotic fluid samples supported this hypothesis, representing a significant re-appraisal of the previous understanding of inhibin biology in pregnancy. Studies of the amniotic fluid inhibin levels in Down's syndrome showed that inhibin-A levels are significantly lower than normal, the opposite of serum. This suggests that the fetal membranes not only secrete different inhibins from the placenta but that the secretion is differentially controlled. These studies have therefore described, in detail, the biology of specific inhibin forms in normal and aneuploid pregnancy demonstrating inhibin-A to be the second most valuable serum marker of Down's syndrome. Novel insights into normal placental endocrinology have also been afforded by the studies with the promise of new initiatives in Down's syndrome screening and conditions with related endocrinology.
This thesis describes a series of clinical and laboratory studies examining the value of inhibins as novel prenatal markers of Down's syndrome. Inhibins are a family of glycoprotein proteins ...identified in gonadal tissue but known to be secreted by the placenta in pregnancy. The ontogeny of inhibin secretion in early pregnancy is described in detail comparing various pregnancy compartments in both normal and Down's syndrome pregnancies. It is shown that maternal serum levels of inhibin-A, one of two possible full processed inhibin dimers, are significantly elevated in Down's syndrome in both the first and second trimesters of pregnancy. Furthermore, mathematical modelling studies with other established prenatal markers (maternal age, human chorionic gonadotrophin and alpha fetoprotein) suggests that inhibin-A could increase second trimester detection rates by as much as 20%. Studies on amniotic fluid revealed that, unlike maternal serum in which only inhibin-A is detectable, both dimers, inhibin-A and inhibin-B, were present raising the possibility that the fetal membranes secrete significant amounts of inhibin. The lack of relationship between inhibin-A levels in paired serum and amniotic fluid samples supported this hypothesis, representing a significant re-appraisal of the previous understanding of inhibin biology in pregnancy. Studies of the amniotic fluid inhibin levels in Down's syndrome showed that inhibin-A levels are significantly lower than normal, the opposite of serum. This suggests that the fetal membranes not only secrete different inhibins from the placenta but that the secretion is differentially controlled. These studies have therefore described, in detail, the biology of specific inhibin forms in normal and aneuploid pregnancy demonstrating inhibin-A to be the second most valuable serum marker of Down's syndrome. Novel insights into normal placental endocrinology have also been afforded by the studies with the promise of new initiatives in Down's syndrome screening and conditions with related endocrinology.
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