The impact of melatonin on the sleep patterns of women undergoing IVF

a double blind RCT

Shavi Fernando, Sarah Nichole Biggs, Rosemary Sylvia Claire Horne, Beverley Vollenhoven, Nicholas Lolatgis, Nicole Hope, Melissa Wong, Mark Lawrence, Anthony Lawrence, Chris Russell, Kenneth Leong, Philip Thomas, Luk Rombauts, Euan Morrison Wallace

Research output: Contribution to journalArticleResearchpeer-review

Abstract

STUDY QUESTIONDoes melatonin result in a dose–response effect on sleep quality and daytime sleepiness in women undergoing IVF?
SUMMARY ANSWERMelatonin, 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 ALREADYMelatonin 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, DURATIONThe study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016.
PARTICIPANTS/MATERIALS, SETTING, METHODWomen 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 CHANCEIn 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 CAUTIONAs 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 FINDINGSWhile 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 INTERESTSThis 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 NUMBERThis trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785).
TRIAL REGISTRATION DATE27/11/2013
DATE OF FIRST PATIENT’S ENROLMENT1/9/2014
Original languageEnglish
Article numberhox027
Number of pages10
JournalHuman Reproduction Open
Volume4
Issue number1
DOIs
Publication statusPublished - Dec 2017

Cite this

@article{20e44daa73dd47ce8abc3185c49c9de0,
title = "The impact of melatonin on the sleep patterns of women undergoing IVF: a double blind RCT",
abstract = "STUDY QUESTIONDoes melatonin result in a dose–response effect on sleep quality and daytime sleepiness in women undergoing IVF?SUMMARY ANSWERMelatonin, 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 ALREADYMelatonin 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, DURATIONThe study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016.PARTICIPANTS/MATERIALS, SETTING, METHODWomen 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 CHANCEIn 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 CAUTIONAs 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 FINDINGSWhile 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 INTERESTSThis 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{\circledR}, Merck-Serono{\circledR} and Ferring{\circledR} and receives consulting fees from Ferring{\circledR}. S.N.B. reports consulting fees from Johnson & Johnson Consumer Inc{\circledR}, outside the submitted work.TRIAL REGISTRATION NUMBERThis trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785).TRIAL REGISTRATION DATE27/11/2013DATE OF FIRST PATIENT’S ENROLMENT1/9/2014",
author = "Shavi Fernando and Biggs, {Sarah Nichole} and Horne, {Rosemary Sylvia Claire} and Beverley Vollenhoven and Nicholas Lolatgis and Nicole Hope and Melissa Wong and Mark Lawrence and Anthony Lawrence and Chris Russell and Kenneth Leong and Philip Thomas and Luk Rombauts and Wallace, {Euan Morrison}",
year = "2017",
month = "12",
doi = "10.1093/hropen/hox027",
language = "English",
volume = "4",
journal = "Human Reproduction Open",
issn = "2399-3529",
publisher = "Oxford University Press",
number = "1",

}

The impact of melatonin on the sleep patterns of women undergoing IVF : a double blind RCT. / Fernando, Shavi; Biggs, Sarah Nichole; Horne, Rosemary Sylvia Claire; Vollenhoven, Beverley; Lolatgis, Nicholas; Hope, Nicole; Wong, Melissa; Lawrence, Mark; Lawrence, Anthony; Russell, Chris; Leong, Kenneth; Thomas, Philip; Rombauts, Luk; Wallace, Euan Morrison.

In: Human Reproduction Open, Vol. 4, No. 1, hox027, 12.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The impact of melatonin on the sleep patterns of women undergoing IVF

T2 - a double blind RCT

AU - Fernando, Shavi

AU - Biggs, Sarah Nichole

AU - Horne, Rosemary Sylvia Claire

AU - Vollenhoven, Beverley

AU - Lolatgis, Nicholas

AU - Hope, Nicole

AU - Wong, Melissa

AU - Lawrence, Mark

AU - Lawrence, Anthony

AU - Russell, Chris

AU - Leong, Kenneth

AU - Thomas, Philip

AU - Rombauts, Luk

AU - Wallace, Euan Morrison

PY - 2017/12

Y1 - 2017/12

N2 - STUDY QUESTIONDoes melatonin result in a dose–response effect on sleep quality and daytime sleepiness in women undergoing IVF?SUMMARY ANSWERMelatonin, 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 ALREADYMelatonin 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, DURATIONThe study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016.PARTICIPANTS/MATERIALS, SETTING, METHODWomen 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 CHANCEIn 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 CAUTIONAs 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 FINDINGSWhile 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 INTERESTSThis 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 NUMBERThis trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785).TRIAL REGISTRATION DATE27/11/2013DATE OF FIRST PATIENT’S ENROLMENT1/9/2014

AB - STUDY QUESTIONDoes melatonin result in a dose–response effect on sleep quality and daytime sleepiness in women undergoing IVF?SUMMARY ANSWERMelatonin, 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 ALREADYMelatonin 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, DURATIONThe study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016.PARTICIPANTS/MATERIALS, SETTING, METHODWomen 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 CHANCEIn 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 CAUTIONAs 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 FINDINGSWhile 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 INTERESTSThis 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 NUMBERThis trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785).TRIAL REGISTRATION DATE27/11/2013DATE OF FIRST PATIENT’S ENROLMENT1/9/2014

U2 - 10.1093/hropen/hox027

DO - 10.1093/hropen/hox027

M3 - Article

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JO - Human Reproduction Open

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SN - 2399-3529

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