Metformin in Obese Non-diabetic Pregnant Women
Condition: Pregnancy Complications; Obesity
MeSH terms: Pregnancy Complications
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

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.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; 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 intervention name(s): Glucophage; Dummy tablet
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Metformin, obese, pregnancy, gestational diabetes