William M. Hague

Metformin versus Insulin for the Treatment of Gestational Diabetes

BACKGROUND Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking. METHODS We randomly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin (with supplemental insulin if required) or insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity. The trial was designed to rule out a 33% increase (from 30% to 40%) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin. Secondary outcomes included neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment. RESULTS Of the 363 women assigned to metformin, 92.6% continued to receive metformin until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32.0% in the group assigned to metformin and 32.2% in the insulin group (relative risk, 0.99 [corrected]; 95% confidence interval, 0.80 [corrected] to 1.23 [corrected]). More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P<0.001). The rates of other secondary outcomes did not differ significantly between the groups. There were no serious adverse events associated with the use of metformin. CONCLUSIONS In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment. (Australian New Zealand Clinical Trials Registry number, 12605000311651.).

Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU): Body composition at 2 years of age

OBJECTIVE In women with gestational diabetes mellitus, who were randomized to metformin or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on growth of the children. RESEARCH DESIGN AND METHODS In Auckland, New Zealand, and Adelaide, Australia, women who had participated in the MiG trial were reviewed when their children were 2 years old. Body composition was measured in 154 and 164 children whose mothers had been randomized to metformin and insulin, respectively. Children were assessed with anthropometry, bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods. RESULTS The children were similar for baseline maternal characteristics and pregnancy outcomes. In the metformin group, compared with the insulin group, children had larger mid-upper arm circumferences (17.2 ± 1.5 vs. 16.7 ± 1.5 cm; P = 0.002) and subscapular (6.3 ± 1.9 vs. 6.0 ± 1.7 mm; P = 0.02) and biceps skinfolds (6.03 ± 1.9 vs. 5.6 ± 1.7 mm; P = 0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = 114) were not different. CONCLUSIONS Children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone. Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive. If so, this would have significant implications for the current pandemic of diabetes.

Hyperinsulinemia is common in family members of women with polycystic ovary syndrome

OBJECTIVE To determine whether disorders of insulin secretion are common in male and female family members of subjects with polycystic ovary syndrome (PCOS). DESIGN Family study of siblings and parents of PCOS subjects (five families). All proband cases met the criteria of polycystic ovaries (PCO) by ultrasound (US) and hyperandrogenism. SETTING University Reproductive Medicine Unit. PATIENT(S) Family members of PCOS subjects. INTERVENTION(S) Oral glucose tolerance testing (OGTT), insulin, and lipids were measured. Clinical examination including assessment of premature baldness in men and US of ovaries in female members. MAIN OUTCOME MEASURE(S) Insulin, lipids, and clinical parameters. RESULT(S) Hyperinsulinemia (69%) and hypertriglyceridemia (56%) was common in family members as were PCO in 79% of 24 females and premature baldness in men in 88% of eight subjects. CONCLUSION(S) Hyperinsulinemia is a potential metabolic and genetic marker for subjects who may be carriers of a familial tendency for PCO.

Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT

Summary.  Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.

Inherited thrombophilia and pregnancy complications revisited.

Inherited thrombophilias are not yet established as a cause of placenta-mediated pregnancy complications, such as fetal growth restriction, preeclampsia, abruption, and pregnancy loss. An inherited thrombophilia is only one of many factors that lead to development of these diseases and is unlikely to be the unique factor that should drive management in subsequent pregnancies. The paucity of evidence for benefit, coupled with a small potential for harm, suggests that low molecular weight heparin should be considered an experimental drug for these indications until data from controlled trials are published. At present, women with a history of placenta-mediated pregnancy complications, with or without a thrombophilia, should be followed closely without routine prophylactic low molecular weight heparin other than for prevention of venous thromboembolism in limited circumstances.

Homocysteine and pregnancy

Homocysteine is an amino acid that is involved in several key metabolic processes, including the methylation and sulphuration pathways. Blood concentrations of homocysteine are determined by various dietary factors, including folic acid and vitamin B(12), by alteration in physiology, such as renal impairment, and by variation in the activity of enzymes in the various pathways as a result of genetic polymorphisms, some of which are commonly found in the population. Hyperhomocysteinaemia has been associated with vascular disease, although whether it is cause or effect is still a matter of debate. In normal pregnancy, homocysteine concentrations fall. Disturbance of maternal and fetal homocysteine metabolism has been associated with fetal neural tube defects, with various conditions characterized by placental vasculopathy, such as pre-eclampsia and abruption, and with recurrent pregnancy loss. Apart from folate supplementation, which has been clearly shown to halve the risk of fetal neural tube defects, no other strategies have been identified in relation to homocysteine metabolism that will reliably reduce the frequency of these other common obstetric pathologies.

Transient diabetes insipidus and acute fatty liver of pregnancy

Objective To review the association of transient diabetes insipidus and acute fatty liver of pregnancy.

Glycemia and Its Relationship to Outcomes in the Metformin in Gestational Diabetes Trial

OBJECTIVE To determine how glucose control in women with GDM treated with metformin and/or insulin influenced pregnancy outcomes. RESEARCH DESIGN AND METHODS Women randomly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes (MiG) trial had baseline glucose tolerance test (OGTT) results and A1C documented, together with all capillary glucose measurements during treatment. In the 724 women who had glucose data for analysis, tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated. The relationships between maternal factors, glucose values, and outcomes (including a composite of neonatal complications, preeclampsia, and large-for-gestational-age [LGA] and small-for-gestational-age infants) were examined with bivariable and multivariate models. RESULTS Baseline OGTT did not predict outcomes, but A1C predicted LGA infants (P = 0.003). During treatment, fasting capillary glucose predicted neonatal complications (P < 0.001) and postprandial glucose predicted preeclampsia (P = 0.016) and LGA infants (P = 0.001). Obesity did not influence outcomes, and there was no interaction between glycemic control, randomized treatment, or maternal BMI in predicting outcomes. The lowest risk of complications was seen when fasting capillary glucose was <4.9 mmol/l (mean ± SD 4.6 ± 0.3 mmol/l) compared with 4.9–5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9–6.4 mmol/l (6.2 ± 0.2 mmol/l) or lower. CONCLUSIONS Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin is strongly related to outcomes. Obesity is not related to outcomes in this group. Targets for fasting and postprandial capillary glucose may need to be lower than currently recommended.

Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial

Summary.  Background: The risk of decreased bone mineral density (BMD) with prophylactic dose long‐term low‐molecular‐weight heparin (LMWH) is unknown. Objectives: We sought to determine whether long‐term prophylactic dalteparin in pregnancy leads to loss of BMD. Patients/methods: Patients in a substudy of an ongoing multicenter randomized trial investigating the effect of antepartum dalteparin prophylaxis on pregnancy outcomes in thrombophilic pregnant women were randomized to either dalteparin 5000 U s.c. daily until 20 weeks and then 5,000 U s.c. q12 h until >37 weeks or to the control group. The primary outcome was absolute spine BMD at six weeks postpartum. Results: Of 77 patients eligible for the BMD substudy, 62 were analyzed. 33 patients received a mean of 212 days of dalteparin in the intervention group. 29 patients received a mean of 38 days of postpartum dalteparin in the control group. There was no difference in mean BMD between the intervention (1.11 g cm−2) and the control groups (1.14 g cm−2). Similarly, there was no difference in T‐scores; the difference of −0.34 (95% confidence interval −0.93 to +0.25) in favor of the control group excludes a clinically important increase in fracture risk. Conclusions: Our results suggest that the use of long‐term prophylactic dalteparin in pregnancy is not associated with a significant decrease in BMD.

The placenta in maternal hyperhomocysteinaemia

It is becoming increasingly apparent that mild or moderate hyperhomocysteinaemia may be associated with adverse perinatal complications and outcomes. The placental pathology in 14 pregnancies from 11 women diagnosed retrospectively to have hyperhomocysteinaemia, following a recent history of intrauterine fetal growth restriction, abruption or of thromboembolic disease, were reviewed. Most of the placental findings indicated abnormal placentation but these were not specific to maternal hyperhomocysteinaemia nor found in every placenta. Features observed included absence of trophoblast‐induced physiological vascular changes, acute atherosis, intraluminal endovascular trophoblast in the third trimester, infarction, retroplacental haematoma formation and accelerated villous maturity. Uteroplacental vascular thrombosis was also seen. Three of the women had a subsequent pregnancy where they were treated empirically with folic acid, and these resulted in improved perinatal outcomes. The finding of placental pathology warrants investigation of the woman for hyper‐ homocysteinaemia. Further randomised controlled trials of folic acid supplementation in preventing pregnancy complications associated with hyperhomocysteinaemia should be conducted.