Abstract
Metformin is used worldwide in the treatment of type 2 diabetes and has been used in the treatment of diabetes in pregnancy since the 1970s. It is highly acceptable to patients due to its ease of administration, cost and adverse effect profile. It is effective in reducing macrosomia, large-for-gestational-age infants and reduces maternal weight gain. Despite its many advantages, metformin has been associated with reductions in foetal size and has been associated with an increase in infants born small-for-gestational-age in certain cohorts. In this article, we review its efficacy, adverse effects and long-term follow-up before, during and after pregnancy for both mother and infant. We also evaluate the other forms of treatment for gestational diabetes, including oral therapies, insulin therapy and emerging treatments.
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Metformin has been used in the treatment of hyperglycaemia in pregnancy since the 1970s, however, more recently, concerns have been raised over offspring size and the long-term implications of its use. |
To date, there is conflicting evidence regarding the safety of metformin in different cohorts and its use should be evaluated in each individual patient. |
Long-term follow-up of infants who are exposed to metformin during pregnancy is essential to ensure long-term safety is evaluated. |
1 Introduction
Gestational diabetes mellitus (GDM) is defined as hyperglycaemia that is first identified during pregnancy and that does not meet the criteria for overt diabetes. While a number of different definitions of GDM exist, a comprehensive definition by the World Health Organization (WHO) distinctly differentiates GDM from other forms of diabetes mellitus in pregnancy [1].
GDM often reflects a state of previous insulin resistance that is exacerbated by the physiological stress of pregnancy. In the early stages of normal pregnancy, women become more sensitive to the action of insulin. This allows glucose to be readily taken up by adipose cells in preparation for the future physiological demands of pregnancy [2]. This, combined with a drop in growth hormone levels and the dilutional effect of increased blood volume results in a decrease in fasting blood glucose levels [3]. From week 9 onwards, levels of human placental lactogen, cortisol, prolactin and placentally derived growth hormone begin to rise, resulting in increased insulin resistance. This process is progressive throughout pregnancy and reaches its peak in the third trimester, when insulin sensitivity is 80% less than the pre-pregnant state [4]. In pregnancies unaffected by GDM, this glucose travels freely across the placenta to fuel the growing foetus and is compensated for by a physiological increase in pancreatic β-cell mass and subsequent insulin secretion [5]. Women who develop GDM most often have a predisposition to insulin resistance, β-cell dysfunction, or both, and the additional physiological stress of pregnancy unmasks these deficits and results in maternal hyperglycaemia.
Women and infants who are exposed to hyperglycaemia face a number of complications including pre-eclampsia and pregnancy-induced hypertension, Caesarean delivery, neonatal intensive care unit admission and long-term complications including obesity, hypertension, dysglycaemia and cardiometabolic disease.
To prevent such complications, tight glucose control is required throughout pregnancy from diagnosis to delivery. GDM treatments need to consider multiple aspects. Potential treatments should be cost effective, acceptable to patients, have relatively few adverse effects and, given the global nature of this problem, should be easily transported. Treatments should substantially reduce maternal glucose levels, limit maternal weight gain and reduce complications, including hypertensive disorders, and should not impact the foetus. Currently, no such treatment exits. Insulin and sulphonylureas cause maternal hypoglycaemia and weight gain [6, 7], while concern regarding metformin’s impact on foetal size and infant adiposity has limited its use in parts of Europe and the United States [8]. Given the need for effective treatments for GDM, an extension for metformin for use throughout pregnancy was announced in a European work-sharing partnership. The aims of this article are firstly to highlight the importance of maintaining good glycaemic control in pregnancy, and secondly, to evaluate the evidence supporting the use of metformin from preconception to birth.
2 Rationale for Treating Gestational Diabetes Mellitus (GDM)
2.1 Maternal Complications of GDM
2.1.1 Short-Term Maternal Complications of GDM
GDM infers a number or risks to both mother and infant, during and after pregnancy. Some of the most common complications of GDM are pregnancy-induced hypertension and pre-eclampsia. Hypertensive disorders and pre-eclampsia are already some of the most common complications of pregnancy and affect up to 10% of pregnancies [9]. Women with GDM have an additional risk of pre-eclampsia (adjusted odds ratio [aOR] 1.29, 95% confidence interval [CI] 1.19–1.41) [10]. Although this risk is well established, it was initially less clear whether GDM was a cause of pre-eclampsia or if this cohort shared many risk factors, including advanced maternal age and obesity. Studies identifying oxidative stress and nitric oxide reduction in response to hyperglycaemia have demonstrated that pre-eclampsia is increased in GDM independent of obesity and other factors [11]. Furthermore, pre-eclampsia can be reduced by improved glycaemic control, providing further evidence to the importance of treatment [12].
Pre-eclampsia is additionally important to treat as it contributes significantly to many of the other complications observed in GDM, including preterm delivery (seen in up to 20% of pregnancies) and operative delivery (seen in up to one-third of pregnancies) [13, 14]. Rates of polyhydramnios and maternal infection are also higher in women with GDM compared with women with normal glucose tolerance [15].
2.1.2 Long-Term Maternal Complications
Long-term effects of GDM include a complement of cardiometabolic complications. This includes dyslipidaemia, obesity, prediabetes, metabolic syndrome and overt type 2 diabetes mellitus (T2DM). T2DM is one of the most common complications of GDM and will affect up to 50–60% of women 10 years after their pregnancy [16, 17]. This effect appears to plateau after 10 years, however long-term screening is recommended [18]. Much like T2DM in other populations, the development of T2DM after GDM is dependent on a combination of genetic and environmental factors. Exercise, reduced dietary intake, weight loss and lactation can all reduce the risk of T2DM and should all be encouraged as part of post-partum care [19, 20].
Multiple markers of cardiovascular disease (CVD) are increased after GDM, and in women with GDM the CVD risk is two to three times the background population. This risk tends to cluster in the first 10 years after pregnancy and is not restricted to women who develop T2DM (women who do not develop T2DM have a relative risk (RR) of 1.56, 95% CI 1.04–2.32) [21]. This CVD risk is a culmination of obesity, adverse lipid profiles (consistent across triglycerides, total cholesterol, low- and high-density lipoprotein) and hypertension, and translates into higher coronary artery calcification [22,23,24].
Another CVD risk factor more recently identified is chronic kidney disease (CKD). A follow-up of nearly 10,000 women with GDM from a single centre found an OR of 2.3 (95% CI 1.4–3.7; p < 0.001) for a composite endpoint of hypertensive renal disease (with and without renal failure), chronic renal failure and other renal disease [25].
With this increased understanding of CVD post-GDM, some authors have suggested that this period offers a crucial opportunity to instigate interventions to reduce both future T2DM and CVD risk. The barriers to this intervention include appropriate diagnosis of GDM, engaging women in long-term follow-up and practical factors, including childcare, time constraints and financial implications, all of which can reduce access to meaningful healthcare interventions [26].
2.2 Offspring Complications
2.2.1 Short-Term Offspring Complications
Many of the offspring complications stem from issues arising in pregnancy, including polyhydramnios, birth by Caesarean delivery, macrosomia and large-for-gestational-age (LGA) delivery (OR 2.33, 95% CI 1.31–4.14; OR 1.67, 95% CI 1.25-2.23; 22.2% vs. 12.7% [p < 0.01] and 19.7 vs. 12.5% [p < 0.01], respectively). These issues are all caused or exacerbated by hyperglycaemia (see Sect. 3.3 on foetal hyperinsulinemia) [15].
Other complications faced by infants of women with diabetes include trauma due to increased foetal size and shoulder dystocia [27]; neonatal hypoglycaemia (seen in up to one-third of infants regardless of maternal treatment [28]); neonatal jaundice, respiratory distress syndrome (aOR 1.5, 95% CI 1.3–1.7) [29] and a cumulative increase in neonatal intensive care unit admissions (aOR 4.88, 95% CI 3.54–6.73) [15].
2.2.2 Long-Term Offspring Complications
There are numerous cardiometabolic and neurocognitive complications of exposure to maternal diabetes. Follow-up data from the landmark Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study that tracked the outcomes of offspring at 10–14 years showed that just under 40% were overweight or obese and 19.1% were obese [30]. This association was further explored in other follow-on studies that compared different measures of childhood adiposity. This elaborated that exposure to maternal hyperglycaemia did not just result in dichotomous outcomes of either being obese or non-obese, but that there was a linear relationship and that each increase by one standard deviation (SD) in maternal glucose resulted in a further increase in offspring adiposity scores [31].
Follow-on studies from the same population found that rising maternal glucose levels are significantly associated with elevated childhood glucose levels and insulin resistance, independent of the child’s body mass index (BMI) [32]. Studies from adolescents with obesity showed that up to one-third of adolescents in the GDM-exposed cohort developed impaired glucose tolerance compared with 17.7% of the non-exposed groups [33]. This rate fell to 21% in normal-weight adult offspring of mothers with diet-treated GDM, however the risk remains very elevated compared with offspring of mothers from the background population (7.76, 95% CI 2.58–23.39) [34].
Elevated rates of obesity and glucose intolerance feed into offspring cardiovascular disease, an increasingly recognized complication of maternal GDM. Even at a young age, children exposed to maternal hyperglycaemia demonstrate systolic hypertension which increases the lifelong risk of cardiovascular disease [35, 36].
Lastly, infants exposed to GDM appear to be at a higher risk of neurocognitive disorders, including autism and reduced neurocognitive function. Large observational cohort studies have found a risk of 1.42 (95% CI 1.16–1.75) for autism [37] and 1.64 (95% CI 1.25–5.56) for attention-deficit hyperactivity disorder [38], and infants exposed to hypoglycaemia within 24 h of birth showed lower adaptability neurocognitive skills at 2 years [39].
3 Pharmacological Treatment Options
Although dietary changes and increased physical activity are the cornerstones of GDM treatment, up to 30–50% of women will require pharmacotherapy. Insulin, which is the first-line therapy in a number of countries, is outside of the scope of this review. Sulphonylureas that are associated with foetal macrosomia and maternal hypoglycaemia are only suggested when other therapies are not available or acceptable to the patient. Given its recent licence extension, the remainder of this article will focus on metformin.
3.1 Pharmacodynamics
The pharmacodynamic profile of metformin is complex and its precise mechanism of action is incompletely understood. It is known to lower basal and postprandial blood glucose in patients with type 2 diabetes.
However, its effects include activation of monophosphate-protein-kinase (AMPK); increased functional activity of glucose transporters; reduced hepatic glucose output; increased peripheral glucose utilization; decreased fatty acid oxidation, reduced appetite and weight gain; sensitization of peripheral tissues to insulin; and increased insulin-mediated receptor tyrosine kinase expression [40].
Moreover, some of the therapeutic effects of metformin are mediated via glucagon-like peptide 1 (GLP-1), possibly by increasing GLP-1 secretions [41]. Its clinical efficacy requires the presence of insulin, however metformin does not increase pancreatic insulin secretion and does not induce hypoglycaemia [42]. The features and properties of metformin are summarized in Table 1.
3.2 Pharmacokinetics
Metformin is orally administered. Gastrointestinal absorption is apparently complete within 6 h of ingestion [42]. The mean (SD) fractional oral bioavailability (F) is 55% (16%), while higher oral doses are proportionately less bioavailable than lower doses [43]. Metformin is not protein bound and has a large volume of distribution (Vd), indicating considerable tissue uptake. As demonstrated by Graham et al. [43], the apparent Vd after oral administration (Vd/F) during dosage with metformin 2000 mg daily is approximately 600 L. Given approximately 50% absorption, the actual Vd during multiple dosage is about 300 L [43]. This Vd has been shown to be greater in early- and mid-pregnancy when compared with post-partum women [44].
No metabolites or conjugates have been identified and metformin is excreted unchanged in urine. The elimination half-life (t½) of metformin during multiple dosages in patients with good renal function is approximately 5 h [43]. However, pregnancy-related increases in glomerular filtration rate result in lower plasma metformin concentrations in pregnant versus non-pregnant patients when administered the same dose, reflected in higher renal clearance and apparent oral clearance and lower serum maximal concentrations in pregnant subjects compared with post-partum subjects [44,45,46]. One study of seven women with type 2 diabetes taking metformin demonstrated mean (95% CI) area under the curve (AUC)4 metformin concentrations in pregnancy that were 69% (53.6–84.8) of the postpartum value [45].
Taken together, this suggests that there is evidence that metformin exposures are reduced in pregnancy (compared with non-pregnant individuals), suggesting that dosing strategies established for non-pregnant populations may not be appropriate [47].
As a small molecule (129 Dalton), weak base, highly polar positively charged hydrophilic compound, metformin readily crosses the placenta, and foetal serum levels approximate maternal concentrations [48].
Ex vivo placental studies have shown that placental transfer seems to be carrier-mediated, in a dose-dependent manner, rather than occurring by passive diffusion. Organic cation transporters (OCTs) have been postulated as the likely transporters for metformin across the placenta, with higher transfer rates in the maternal-to-foetal direction compared with the foetal-to-maternal direction, which may provide some reduction in relative foetal exposure to metformin in pregnancy [48].
No evidence exists to date from animal or human studies of teratogenicity or developmental toxicity [49]. One meta-analysis (limited by the heterogeneity of included studies) revealed no differences in the rates of major congenital malformations, suggesting that metformin has low teratogenic potential [50].
3.3 Safety in Lactation
Metformin is excreted into breast milk. One small study demonstrated higher metformin milk concentrations compared with maternal serum concentrations, and a flat concentration-time profile of metformin in breastmilk, suggesting that some of the breastmilk transfer may be carrier-mediated rather than occurring by passive diffusion. However, estimated infant dose is < 0.3% of the mother’s weight-adjusted dose, with no metformin detected in breastfed infants’ plasma, and no adverse effects noted on breastfed infants [46]. Accordingly, metformin use is not contraindicated in lactation. It should be noted that the effect of ongoing exposure to small amounts of metformin is unknown.
3.4 Efficacy
The use of metformin has been studied in the pre-, ante- and post-natal periods and as an insulin-sensitizing and glucose-lowering therapy. It has been used in lower income countries since the 1970s as an alternative to insulin in pregnancy and is often preferred due to its lower cost and ease of administration. Its recent approval by the European work-sharing procedure means it is the first oral antidiabetic agent to be licensed during pregnancy. In this review, we evaluate its efficacy from conception to the post-partum period.
3.4.1 Pre-pregnancy
Metformin has a modest effect on weight loss [51] and may be prescribed to obese women with impaired glucose tolerance or polycystic ovary syndrome (PCOS). The use of metformin is particularly important in this cohort as it may restore ovulation and patients may unintentionally be exposed to metformin in early pregnancy [52, 53]. The consequences of exposure to metformin in early pregnancy are discussed in more detail below.
For women with PCOS, metformin may increase the rate of ovulatory menses [52], however it is probably only moderately effective in increasing live birth rates when compared with no treatment at all, and is almost certainly less effective than clomiphene, particularly in women with a BMI of ≤30 kg/m2 [54]. However, it should be noted that studies in this area are of low–moderate quality and other therapies are much more effective for those who desire pregnancy. Outside of this area, there is little information on fertility rates for obese women without either diabetes or PCOS treated with metformin [55].
3.4.2 Pregnancy
Obesity Obesity has been linked to complications in pregnancy, including pre-eclampsia, macrosomia and long-term complications such as childhood obesity and cardiovascular disease. As such, treatments that can prevent or reduce potential complications are of importance to healthcare providers. One Australian study evaluated metformin added to lifestyle advice at 10–20 weeks’ gestation in overweight women [56]. This study did not identify any difference in gestational weight gain (GWG) or infant size at birth in the intervention arm. The effect of Metformin on Foetal Outcomes in Obese Pregnant Women (EMPOWAR) study included women at 10–15 weeks’ gestation with a BMI ≥ 30 kg/m2 and similarly found no differences in meaningful outcomes such as rates of GDM or infant size. A temporary improvement in insulin resistances did not last until later in pregnancy [57]. Lastly, one study of more than 200 women with a BMI of ≥ 35 kg/m2 found reduced GWG in the metformin group and lower rates of pre-eclampsia, but no difference in foetal size or GDM rates [58].
Polycystic ovary syndrome PCOS affects between 5 and 15% of women of reproductive age [59]. It also increases the risk of pre-eclampsia, infertility, large foetal size and pre-term birth [60, 61]. Given these complications, as well as metformin’s use as an insulin sensitiser, it has been extensively studied during pregnancies complicated by PCOS. While observational and non-randomized studies have shown a substantial reduction in GDM, these findings have not been replicated in randomized controlled trials (RCTs) [62,63,64]. Studies from northern Europe have shown less GWG but no changes in foetal or other maternal outcomes [65]. Others have found a reduction in pre-term birth but no reduction in GDM rates [66]. Other studies have also found no change on markers of insulin resistance in women with PCOS [67]. A number of smaller studies have evaluated maternal androgens in response to metformin and found lower rates of certain complications (pre-term birth and infections) [68]; improved uterine artery flow (however these studies were underpowered to comment on maternal outcomes) [69] and an improvement in live birth rates in women with PCOS [70]. Although the evidence from large RCTs is lacking, a recent systematic review and meta-analysis of metformin use in PCOS demonstrated improvements in a number of parameters, including GDM, pre-eclampsia and weight gain, when data from RCTs and observational studies were combined [71].
Gestational diabetes mellitus A summary of the recent evidence evaluating the use of metformin in GDM is available in Tables 2 and 3. Table 2 details the RCTs evaluating metformin in GDM from 2008 to 2022, and Table 3 details the systematic reviews of metformin in pregnancies complicated by GDM.
Type 2 diabetes Due to the rising prevalence of pre-gestational diabetes, non-insulin therapies are of increasing interest in this group. Similar to GDM, metformin has been used to treat diabetes in pregnancy since the 1970s due to its lower cost and oral route of administration. Until 2009, many of the studies that evaluated metformin use were extremely small, recruiting between 20 and 60 patients [72,73,74,75,76]. The largest of such early studies included 150 patients assigned to either metformin or insulin. In total, 40% of women needed additional insulin, however the metformin group had lower rates of GWG, pregnancy-induced hypertension and neonatal hypoglycaemia. This group also noted a difference in the mean birth weight, with metformin-exposed infants being, on average, 0.5 kg lighter [77]. Other smaller studies mentioned above also found higher rates of small-for-gestational-age infants, and this along with other studies prompted further evaluation of metformin’s role [72, 74, 78] in effecting foetal size or fat composition, and its ability to reduce the need for, or dose of, insulin (nearly half of women taking metformin ultimately required insulin).
To answer these questions, the landmark Metformin in Women with Type 2 Diabetes in Pregnancy trial (MiTy) was launched [79]. This multicentre, international, randomized, placebo-controlled trial randomized over 500 insulin-treated women with T2DM to either 2000 g of metformin daily, or placebo. The majority of women entering this trial were obese. The results of this study convincingly demonstrated metformin’s ability to lower third trimester HbA1c (41 vs. 43 mmoL/moL), reduce the use of short-acting insulin and reduce the total daily dose of insulin, reduce GWG by 1.8 kg on average, and reduce the risk of Caesarean section by 10%.
This study also evaluated infant outcomes and found that infants exposed to metformin had lower birth weights and were less likely to have macrosomia (7 vs. 13%). There was also an increase in the number of infants born small for gestational age (SGA; from 7 to 13%). This decrease in overall foetal size was observed regardless of maternal BMI. These findings prompted some concern in the clinical community, as the benefits in reduced macrosomia must be balanced against the risk of SGA births, which are also associated with long-term complications [80].
It is also worth noting that although SGA has been a concern in women with T2DM, the risk of SGA infants was not increased in metformin-treated GDM women in a number of systematic reviews [81, 82], although it was noted that there was a trend for lower birth weights and a reduced lean mass in metformin-exposed infants [83].
3.4.3 Post-partum
Metformin has been studied in this population to establish its effects in reducing the incidence of type 2 diabetes post GDM. Although the risk of type 2 diabetes is directly related to the diagnostic criteria used, rates of 60% are quoted and the risk is 8–10 times that of an age-matched population [16]. Given this substantial risk, preventative strategies are of particular interest in this group. The pivotal study in this area was the Diabetes Prevention Programme, which randomized 350 women with previous GDM and current impaired glucose tolerance to receive either a combination of standard lifestyle measures and placebo or metformin, or to intensive lifestyle intervention (ILS) alone. The two cohorts in this study were well matched in terms of BMI, parity and ethnicity, however women with a previous history of GDM were younger than those without. In women without a history of GDM, the ILS intervention outperformed metformin initially and continued to show benefit at 3 years. In the cohort with previous GDM, the average weight loss at 6 months in the ILS group was >5 kg, however weight regain was noted and at 3 years there was no significant difference between ILS and metformin.
ILS reduced the risk of T2DM by 53% and metformin reduced the risk of progression by 50% at 3 years. At 3 years, the number needed to treat to prevent one case of T2DM was 6.1 in the metformin group versus 5.3 in the ILS group [84].
This same cohort were followed up a number of years later, and at 10 years, metformin reduced the risk of T2DM by 40% versus 35% for ILS (number needed to treat = 7.2 for metformin and 11.3 for ILS). Once again, the benefit of metformin was only observed in those with previous GDM, and women without previous GDM benefitted most from ILS [85]. Finally, the 15-year follow-up from this cohort found that women with a previous history of GDM had a hazard ratio of 0.59 for the development of type 2 diabetes [86].
While metformin does have considerable efficacy in this group, its efficacy may be enhanced by the combination of other medications, including liraglutide and dapagliflozin, although these are short-term studies and require further long-term follow-up [87, 88].
3.5 Long-Term Safety
The long-term follow-up of the infants of mothers with diabetes has become increasingly recognized and is increasingly important in light of increased rates of SGA in some metformin-exposed infants. The follow-up studies in this area can be categorized as follows.
3.5.1 Observational Studies
This risk of complications such as congenital anomaly, obesity and diabetes have been followed using observational data. A large case-control study over 50,000 infants with congenital anomalies found that the use of metformin in pregnancy increased the risk of pulmonary valve atresia (OR 3.54, 1.05–12.00) only [53]. A follow-up of over 3000 infants exposed to metformin (up to an average of 3.5 years of age) did not show any increase in obesity, hyperglycaemia or diabetes compared with infants treated with insulin alone. Although these large observational studies are reassuring, further studies have followed infants for up to 9 years and have found conflicting results in terms of childhood obesity and glucose tolerance [89].
3.5.2 Obesity
A follow-up of one study of over 500 women with obesity in pregnancy followed 426 children at 6 months, 382 children at 18 months and 304 children at 3 years and did not find any evidence of increased rates of obesity between the metformin and placebo arms [56] [90]. There were some statistically significant differences, including a larger head and arm circumference and higher z scores at 6 months (p = 0.037, 0.005 and 0.021, respectively). None of these differences persisted after the 6-month follow up.
3.5.3 Polycystic Ovary Syndrome
The majority of the follow-up data in PCOS comes from the combination of the PregMet and PregMet2 studies. These studies evaluated a total of 487 women with PCOS who were randomized to receive either metformin or placebo by week 23. At 4 years, the infants in the metformin group had a higher BMI and weight z scores and had higher rates of obesity (OR 2.17, 1.04–4.61; p = 0.038) [91]. At further follow-up at between 5 and 10 years, 144 children were studied. Those exposed to metformin had a higher BMI (difference between the means 0.41, 95% CI 0.03–0.78; p = 0.03) [92]. Smaller studies of 25 infants of mothers with PCOS were evaluated at 7–9 years and were found to have higher fasting glucose readings and systolic blood pressure [93]. Smaller 1-year follow-on studies confirmed higher mean weights and BMIs in the infants in the metformin group in women with PCOS (mean weight 10.2 ± 1.2 vs. 9.7 ± 1.1 kg) [94].
3.5.4 Gestational Diabetes Mellitus
Studies in this area have shown that infants exposed to metformin are consistently heavier at 12, 18 and 24 months, however it is worth noting that these changes were found in only one cohort of the MIG trial and studies examining body composition and fat deposition differ [8, 95]. The largest long-term follow-up studies come from the MIG study, which showed improved GWG and insulin doses and reduced neonatal hypoglycaemia in the metformin group without any differences in mean weight, macrosomia or SGA births [7]. A 2-year follow-up of 323 infants in this study identified larger arm circumference, subscapular thickness and free-fat mass in the metformin group [8]. The authors suggested that this may lead to the infants being more insulin-sensitive as more subcutaneous versus ectopic or visceral fat in these infants may reduce inflammatory responses to calorie excel. In this same cohort, systolic blood pressure was examined and no mean difference was found [96]. The complex interplay between maternal BMI, glycaemic control and nutritional intake was further highlighted by the 9-year MIG follow-up, which looked in detail at the Adelaide and Auckland cohorts [97]. This follow-up included 109 infants followed for 7 years in the Adelaide group. At birth, these infants were more likely to be LGA and mothers had a higher fasting glucose level. No difference in body composition was identified between the metformin and placebo groups. In contrast, at 9 years the 99 children from the Auckland group were heavier (37.0 ± 12.6 kg vs. 32.7 ± 7.7 kg; p = 0.049) and had larger mid-upper arm and waist circumferences and slightly higher BMIs. On dual x-ray absorptiometry (DXA) measurements of fat composition, the metformin-exposed children had higher fat mass in the upper arm. However, total abdominal fat and liver fat were similar between the metformin and placebo groups.
Although these groups were initially analysed together for the primary maternal and neonatal outcomes, the differences in the childhood outcomes have prompted further investigation. The authors’ theory is that as the infants in the Adelaide group had a higher birth weight and maternal glucose levels, this limited the action of metformin; however, the Auckland group had less GWG and their slightly better glycaemic control may have resulted in an environment that has been described in animal models. In mouse models, lean mice who are fed a calorie neutral diet and treated with metformin have smaller offspring, similar to those who are exposed to undernutrition. The offspring then go on to be exposed to a high-fat diet and are more insulin-resistant in childhood. In obese mice exposed to metformin, the male (but not female) offspring is leaner and more insulin-sensitive [98]. In summary, maternal nutrition plays a significant role in long-term offspring health.
3.5.5 Type 2 Diabetes Mellitus
The largest follow-up of the infants of women with T2DM comes from the MiTy study. Although the full results are not yet available, a preliminary report of 283 children at 2 years found that males exposed to metformin had a higher BMI growth trajectory at 8–24 months. The only other significant finding was a higher z score at 2 years, which was related to increased screen time and reduced hours of sleep [99].
3.5.6 Neurocognitive Development
A number of studies have evaluated the frequency of neurocognitive abnormalities in children exposed to metformin. GDM has been found to be associated with an increased risk of autism spectrum disorders and neurodevelopmental changes in both animal and human offspring [100, 101]. Although there is a complex genetic and environmental aetiology, glucose exposure is undoubtedly a contributor as women with type 1 diabetes have higher risks than those with T2DM and GDM. Follow-up studies examining the frequency of neurocognitive changes in metformin-exposed infants have found no changes in linguistic skills or overall cognitive function [90, 95, 102]. Assessment of specific developmental scores (Bayley Scales of Infant Development, Mental Development Index and Psychomotor Development Index [PDI]) were similar across metformin- and placebo-exposed infants in the MIG study [103]. Follow-up from the PregMet study (CogMet) found no statistically significant difference in the mean IQ scores between the two groups, however they did find that more children in the metformin group had borderline intellectual function (IQ < 85) than those in the placebo group [104]. The authors suggested that this finding was not replicated in other studies and did not suggest a causative relationship.
4 Conclusion
In summary, the treatment of GDM has many components. Not only do treatment decisions have immediate consequences for the woman with GDM, but there are short- and long-term implications for mother and infants. Cardiometabolic, glycaemic and neurocognitive health can all be impacted into adulthood and metformin use can alter the risk of maternal type 2 diabetes in the future. Careful consideration should be given to the best treatment option for each individual patient, and long-term follow-up studies are essential to ensure that treatment options secure the long-term health of those treated during their pregnancy, and their offspring.
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Newman, C., Rabbitt, L., Ero, A. et al. Focus on Metformin: Its Role and Safety in Pregnancy and Beyond. Drugs 83, 985–999 (2023). https://doi.org/10.1007/s40265-023-01899-0
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DOI: https://doi.org/10.1007/s40265-023-01899-0