Metformin in Obese Non-diabetic Pregnant Women (MOP)
Obesity is on the rise in all developed countries. Of particular concern is that more young people including children are being recognised as being overweight or obese. We know from a recent large national enquiry into all maternal and child deaths in the UK, known as CEMACH, that obesity is a major risk both for the mother and her child. When all deaths in women during pregnancy are analysed, obesity comes out as the most common risk factor. Babies of obese mothers are more than 3 times as likely to need admission to the Neonatal Intensive Care Unit.
Traditionally, obesity is treated by lifestyle measures encouraging healthy eating and increasing physical activity. Unfortunately these measures are often insufficient to produce significant improvements in weight. If obese women gain little or even no weight during pregnancy, the outcome of the pregnancy is known to be improved. This was shown in a very large study of more than 120, 000 obese women.
The drug metformin has been used for years in the treatment of diabetes and more recently for polycystic ovary syndrome (PCOS). Studies in pregnant PCOS women and women with diabetes in pregnancy have shown it to be safe and effective. Fortunately it is relatively cheap and taken as a tablet with meals.
Metformin has the great advantage of not causing weight gain and often leads to a small amount of weight loss. It works by improving the body's sensitivity to insulin which is important as resistance to insulin is common in obesity.
We have a lot of experience using metformin to treat women with diabetes in pregnancy where it is greatly beneficial. We now wish to examine its potential for obese women who do not have diabetes. We are hoping to show that it will benefit these women by causing less weight gain, less high blood pressure, and less diabetes. We anticipate babies will also have better birth weights, will be easier to deliver naturally, will not need to go to special care baby units and will be healthier.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
|Official Title:||Does Metformin Improve Pregnancy Outcomes (Incidence of LGA (≥90% Birth Weight Centile) Babies, Onset of Maternal GDM, Hypertension, PET, Macrosomia, Shoulder Dystocia, Admission to SCBU) in Obese Non-diabetic Women?|
- Birth Weight centile (z-score) [ Time Frame: At Birth ] [ Designated as safety issue: No ]
- Maternal Weight gain [ Time Frame: Weight at recruitment and at end of pregnancy ] [ Designated as safety issue: No ]
- Development of Gestational Diabetes [ Time Frame: 28 weeks of pregnancy ] [ Designated as safety issue: No ]A Glucose Tolerance Test would be conducted at 28 wks of pregnancy to diagonose diabetes
- Development of hypertension/Preeclampsia [ Time Frame: Throughout pregnancy ] [ Designated as safety issue: No ]Blood Pressure and urinary proteins would be monitored at each visit to diagonose hypertension/Preeclampsia
- Caesarian Section [ Time Frame: delivery ] [ Designated as safety issue: No ]
- Postpartum haemorrhage [ Time Frame: Delivery ] [ Designated as safety issue: No ]
- Neonatal Hypoglycemia [ Time Frame: within 2 hours after birth and immediate post birth ] [ Designated as safety issue: No ]
Blood glucose is checked within 2 hours after birth and before each feeding until consecutive glucose values of 2.6 mmol per liter (46.8 mg per deciliter) or greater were achieved.
Neonatal hypoglycemia was defined as 2 capillary plasma glucose levels< 2.6 mmol/l at least 30 minutes apart.
- Prematurity [ Time Frame: Delivery ] [ Designated as safety issue: No ]Born < 37 weeks gestation
- Hyperbilirubinemia [ Time Frame: at birth and after ] [ Designated as safety issue: No ]Hyperbilirubinemia requiring phototherapy
- Polycythaemia [ Time Frame: At birth ] [ Designated as safety issue: No ]Cord blood hematocrit > 0.6
- Respiratory Distress [ Time Frame: At birth and within 24 hours ] [ Designated as safety issue: No ]4 or more hours of respiratory suppory or oxygen with associated diagnosis
- Macrosomia/Large for Gestational Age [ Time Frame: At birth ] [ Designated as safety issue: No ]Birth weight>90th centile based on appropriate growth standards
- Birth Trauma [ Time Frame: At birth ] [ Designated as safety issue: No ]Shoulder dystocia, brachial plexus injury
- Apgar score <6 [ Time Frame: 5 minutes after birth ] [ Designated as safety issue: No ]
- Admission to level 2 or greater neonatal unit [ Time Frame: at birth and immediately after ] [ Designated as safety issue: No ]If yes, then length of stay
- Stillbirth/Intrauterine deaths [ Time Frame: Throughout pregnancy ] [ Designated as safety issue: No ]
- 2nd trimester miscarriages [ Time Frame: in 2nd trimester of pregnancy ] [ Designated as safety issue: No ]
|Study Start Date:||October 2010|
|Estimated Study Completion Date:||September 2014|
|Estimated Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
|Active Comparator: Metformin||
Maximum dosage 500 mg 2 tablets 3 times a day (with each meal) start with 1 tablet twice a day and gradually titrate upwards to maximum dose
Other Name: Glucophage
|Placebo Comparator: Placebo||
Placebo maximum dosage 2 tablets 3 times a day ( with meals) start with 1 tablet twice a day and gradually titrate upwards to maximum dose
Other Name: Dummy tablet
Hide Detailed Description
Obesity in Pregnancy has been identified by the Confidential Enquiry into Maternal and Child Health [CEMACH] report (2007) as a major health risk to mother and baby:
- 35% of women who died were obese
- 30% of the mothers who had a stillbirth or a neonatal death were obese
Obesity increases the risk of miscarriages, GDM, pregnancy-induced hypertension/PET, Caesarean sections, deep venous thrombosis, puerperal sepsis and LGA babies. There is a 5-fold increase in costs of antenatal care. Results from various studies have concluded that limited or no weight gain during pregnancy in obese women results in more favourable pregnancy outcomes. By improving insulin sensitivity and enhancing GLP-1 release, metformin is associated with weight reduction by approximately 5.8% with no serious adverse events.
The aim of this study is to test the hypothesis that management of obese non-diabetic pregnant women with standardised life-style intervention (diet and physical activity) plus metformin will lead to improved maternal and perinatal outcomes compared with life-style intervention alone.
The study will also seek to determine whether metformin will improve body fat distribution as measured by bioimpedance during pregnancy with particular emphasis on metabolic active visceral fat.
Genetic studies will investigate whether patients with polymorphisms of the candidate fat gene, FTO gene, differ in their response to metformin and whether this is associated with favourable pregnancy outcomes.
This is a randomised, multicentre, double blind, placebo-controlled trial.Assuming power 90%, significance level 5% and 2-sided testing, we will recruit 425 subjects per arm of the trial.This will allow the detection of a difference in mean centile (z-score) of 0.21 standard deviations.
All women will undergo oral glucose tolerance testing at booking and at 28 wks; those found to have GDM at 28 weeks will commence home glucose monitoring and will receive metformin if glucose values are outside target range.
The primary outcome will be the birth weight centile (z score). Secondary outcomes include maternal and neonatal outcomes, body composition scores, patient satisfaction and infant development at 2 years. The relation between FTO gene variants and pregnancy outcomes will be examined. Parametric and non-parametric tests will be used as appropriate.
This is a multicentre trial to be undertaken in 7 centres in the UK over a period of 3 years in order to reach the required sample size. Mr Hassan Shehata, Clinical lead and Consultant Obstetrician and Gynecologist is the Chief Investigator of the trial and the trial will be centrally coordinated by Dr Jyoti Balani at Epsom and St Helier University Hospital. In the first phase of the research, we would be recruiting a total of 546 pregnant women into the trial. 200 women would be recruited at Epsom and St Helier Hospital, 200 women at kings college Hospital under the supervision of Professor Kypros Nicolaides and 146 at Royal Surrey County Hospital under the supervision of Dr Lesley Roberts.
Given the low cost of metformin and the potentially high impact on health for both mother and baby, we anticipate the study will show metformin to be highly cost-effective. We anticipate improved patient satisfaction scores in those taking metformin as they gain less weight and develop fewer complications. Improvements in the metabolic milieu during interuterine growth is expected to improve long term outcome for the infants of mothers treated with metformin.
Benefits to patients will be immediate from the time the project's findings are presented. Implementation into clinical practice is expected to greatly benefit the NHS.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01273584
|Contact: Dr Jyoti Balani, MD||00 44 firstname.lastname@example.org|
|Contact: Dr Steve Hyer, MD,FRCP||00 44 email@example.com|
|Epsom and St Helier University Hospitals NHS Trust||Recruiting|
|Carshalton, Surrey, United Kingdom, SM5 1AA|
|Contact: Dr Jyoti Balani, MD 00 44 2082962140 firstname.lastname@example.org|
|Contact: Dr Steve Hyer, MD, FRCP 00 44 2082962119 email@example.com|
|Principal Investigator: Mr Hassan Shehata, MD, MRCOG,|
|Sub-Investigator: Dr Steve Hyer, MD, FRCP|
|Sub-Investigator: Dr Jyoti Balani, MD|
|Sub-Investigator: Dr Antoinette Johnson, MRCOG|
|Kings College, London||Not yet recruiting|
|London, United Kingdom, SE5 8RX|
|Principal Investigator: Professor Kypros Nicolaides, PhD, MRCOG|
|Principal Investigator:||Mr Hassan Shehata, MD MRCOG||Epsom and St Helier University Hospitals NHS Trust|
|Study Director:||Dr Steve Hyer, MD, FRCP||Epsom and St Helier University Hospitals NHS Trust|
|Principal Investigator:||Prof Kypros Nicolaides, PhD, MRCOG||King's College London|