Diabetes drug linked to health benefits in pregnancy

Anastasia Tsirtsakis

18/09/2020 3:44:36 PM

Metformin has been found to help women with type 2 diabetes throughout pregnancy. But are there long-term implications for the child?

Pregnant woman taking medication
Benefits from metformin included better glucose control, lower insulin requirements, less gestational weight gain, and fewer caesarean births.

A new study, published in The Lancet Diabetes and Endocrinology, tested the effects of metformin in women with type 2 diabetes during pregnancy, investigating its effects on neonatal morbidity and mortality.
The multicentre randomised control trial involved 502 women from 25 centres in Canada and four in Australia.
Participants were given either 1000 mg of metformin twice daily or a placebo, in addition to their usual insulin.
Researchers found no significant difference between groups in the primary composite outcome of neonatal mortality and serious morbidity; however, several health benefits were noted for women in the metformin group, including:

  • better glucose control
  • lower insulin requirements
  • less gestational weight gain
  • fewer caesarean births.
Professor David Simmons from the School of Medicine at Western Sydney University led the Australian component of the study that tracked 24 women.
He said while metformin – a first-line treatment used to optimise blood glucose levels – has been known to be safe for use in pre-conception, there has previously been little evidence to help guide clinicians over use of the drug once a woman is pregnant.
‘Many women become pregnant while being treated with metformin and we have reasonable evidence to say that it’s safe up to 12 weeks, but some women don’t even know that they are pregnant, even at 12 weeks,’ Professor Simmons told newsGP.
‘This study provides good news for Australian women, who can be comfortable that metformin has now been shown to be a helpful drug during the pregnancy.
‘Lower insulin requirements also mean that women can sometimes avoid extra daily injections, which is another positive.’
Diabetes in the mother is a common cause of babies being born large for gestational age, yet the trial noted that infants born to women in the metformin group were less likely to be large for gestational age, weighing an average of 210 g less, and had reduced adiposity measures.
This is a result of metformin diverting glucose away.
‘We do know that if we didn’t divert that fuel, if we had the babies bigger as is happening with the insulin treated ones, for example, then there is certainly a long-term risk of the baby being fatter and potentially even of increased risk of having more diabetes,’ Professor Simmons said.
The trial did note that more infants – around one in eight – were small for gestational age in the metformin group. Professor Simmons says it is a fine line to tread.
‘It’s very difficult to find that sweet spot where you don’t want the baby to have too little food in utero, but we certainly don’t want the baby to have too much,’ he said.
‘We have scans to help guide us and then you look at the pattern. If we are looking at a tailing off of a baby’s growth, then we usually stop the metformin and then we would have to increase the insulin.
‘What you don’t want to do is stop the metformin, up goes the glucose, and then the baby starts metabolising this increased glucose. It then needs more oxygen, and if there are problems with the baby getting a good oxygen supply, it will not have enough oxygen to metabolise the glucose properly and that’s where you can have stillbirths.
‘So you have to manage this really proactively, and it needs a lot of intensive management by those who are skilled in diabetes and pregnancy management.’
But could there be long-term implications of metformin use on infants in the future?
Dr Gary Deed, a GP and Chair of the RACGP Specific Interests Diabetes network, welcomed the study’s insights, but said it provides little clarity.
‘When we’re treating pregnancy we’re not just treating the mother, we’re treating the baby and the mother – I think that’s the guiding principle,’ he told newsGP. ‘The implications of pregnancy do not end at the delivery of the child.
‘We do know that metformin crosses the placental barrier, and so the foetus is exposed to metformin … we’re not absolutely certain that the effects have been fully elucidated.
‘There are previous studies which showed that the metformin babies that were born with small gestational weight actually did gain weight after the pregnancy. However, there is some evidence that some of those children then developed later on with being overweight and obese at the age of nine.
‘If the baby may become small for gestational age, what are the long term effects on that baby into their adolescent years? It’s an unknown.’
To be eligible for the study, women had to be between six and 22 weeks plus six days’ gestation. Given the variances between each participant, Dr Deed says there are a number of unanswered questions.
‘What dose of metformin is correct for benefit versus harm? What’s the length of exposure? There were different times when the women were given the metformin during the study, and so is it best only to give the metformin later on in pregnancy, or during a [specific] time of pregnancy rather than all of pregnancy?’ he said.
‘That sort of detail is still not available to us. So for me as a clinician, it still leaves uncertainty.’
Professor Simmons acknowledges that more research is needed to understand the impact of the diversion of fuel from the baby and a smaller gestational weight. That will be the focus of the next phase of the study – MiTy Kids.
In the meantime, Dr Deed has concerns over how many women are being properly informed of the potential long-term risks.
‘The impact may take a decade or more to emerge. So in that interim, do we wait another decade and look back and say, “Oh, actually, some of those children could have been harmed”?’ he said.
‘We need to communicate with women who are exposed to or offered the use of metformin that there is still unknown risks to their babies in the long-term, and if that risk is acceptable or not acceptable to themselves.
‘Remember, type 2 diabetes and people who get pregnant do cluster in people with lower health literacy, so there are issues of communicating the message effectively.’
As is suggested in Management of type 2 diabetes: A handbook for general practice, Professor Simmons says there needs to be a focus on women with diabetes receiving treatment prior to conception, given the complications that can arise.
‘GPs will usually be managing the women with type 2 diabetes of reproductive age before they become pregnant. So pre-pregnancy planning is really crucial,’ he said.
‘Most women with type 2 diabetes are not having properly planned pregnancies, they’re not having their contraception reviewed, they don’t have Implanon or Mirena in place. We are still having many women who have become pregnant on medications which are not proven to be safe in pregnancy and in the first trimester.
‘These are very, very high-risk pregnancies. There is increased stillbirth rates, there’s increased malformation rates, there is an increase of every single adverse outcome.
‘We very much would [also] like GPs to make sure that they’re managing the cardiovascular disease risk factors if women need statins or anti-hypertensives.’
Dr Deed agrees.
‘The management of pregnancy with diabetes commences well before conception occurs, six months at least before, where attention and normalisation of glucose as best you can, without causing harm, reduces mothers and future foetal risks,’ he said.
‘Short-term studies like this are great in that they say that there are measurable outcomes during pregnancy and at the end of pregnancy to the mother and some of the babies – not all.
‘But we have to look at pregnancy beyond just markers of metabolic change. We are trying to help people who are pregnant with diabetes, but in trying to help are we also possibly creating harm, especially when the harm is not yet quantified? So it’s a balance risk.’
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