Research Article: Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis

Date Published: August 6, 2019

Publisher: Public Library of Science

Author(s): Jane L. Tarry-Adkins, Catherine E. Aiken, Susan E. Ozanne, Huixia Yang

Abstract: BackgroundMetformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown.Methods and findingsPubMed, Ovid Embase, Medline, Web of Science,, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference −107.7 g, 95% CI −182.3 to −32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference −0.13 kg/m3, 95% CI −0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18–24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5–9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes.ConclusionsFollowing intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503.

Partial Text: Gestational diabetes mellitus (GDM) currently affects 3%–25% of pregnancies worldwide [1], constituting a significant global healthcare burden. The continuing increase in the global incidence of GDM may relate to new screening approaches, decreasing threshold values for diagnosis, or increases in population risk factors, particularly obesity [2,3]. GDM poses significant risks to the immediate and long-term health of the mother and fetus. For the fetus, a key risk is accelerated intrauterine growth, resulting in macrosomic or large for gestational age (LGA) neonates [4,5]. At delivery, macrosomic and LGA neonates are at significantly elevated risk of adverse perinatal outcomes, including shoulder dystocia, birth trauma, neonatal hypoglycaemia, and admission to neonatal intensive care [6,7]. Hence it is essential to implement effective clinical interventions to maintain glycaemic control and limit fetal growth to within normal parameters during GDM-affected pregnancies [8].

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [33]. The PRISMA checklist is detailed in S1 PRISMA Checklist. The systematic review protocol was registered in PROSPERO (CRD42018117503) (S1 Text). Ethical approval was not required.

In this study of randomised evidence, we found that neonates exposed to metformin in utero weighed less at birth than neonates whose mothers were exposed to insulin, in the context of treatment for GDM. The risk of macrosomia is substantially lower, by 40%, when GDM is treated with metformin compared to insulin, without a concomitant increase in the risk of being born SGA. The limited number of studies that have addressed neonatal anthropometry suggest that metformin-exposed neonates have lower lean mass compared to neonates whose mothers were treated with insulin, in terms of lower ponderal index, head circumference, and chest circumference with no change in abdominal circumference.



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