Women's views on postpartum testing for type 2 diabetes after gestational diabetes: Six month follow-up to the DIAMIND randomised controlled trial.

BACKGROUND: This study assessed the views of the women who participated in the DIAMIND randomised trial of postpartum SMS reminders to test for type 2 diabetes after gestational diabetes (GDM) on their preferred type of postpartum reminder system and barriers and facilitators to completion of postpartum diabetes testing. METHOD: A written questionnaire was sent to women with recent GDM who participated in the DIAMIND trial (n=276) via post or email at six months after the birth of their baby. RESULTS: 208 women (75%) returned the study questionnaires. Preferred postpartum reminder types were: SMS (67%), email (17%), postal (12%) and voice call (1%). Women who had not yet completed an OGTT indicated that they planned to undertake one in the future (61%). Common barriers to postpartum OGTT completion included: not having enough time (73%), inadequate childcare (30%), and a need to focus on the health of the baby (30%). The most common facilitator was having a shorter test (33%). CONCLUSIONS: Improved childcare quality and access as well as more research into a shorter, more convenient test procedure for type 2 diabetes screening are needed. Reminder systems for postpartum diabetes screening should be electronic where possible.

Does low-molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomised controlled trial results.

OBJECTIVE: Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency? DESIGN: Secondary outcomes of the FRUIT-RCT. SETTING: Multicentre, international. POPULATION: The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia. METHODS: After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi-square test. MAIN OUTCOME MEASURES: Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries. RESULTS: No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. CONCLUSION: The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity. TWEETABLE ABSTRACT: LMWH does not influence fetal growth or uterine or umbilical flow velocities.

Postpartum SMS reminders to women who have experienced gestational diabetes to test for Type 2 diabetes: the DIAMIND randomized trial.

AIMS: This parallel group randomized controlled trial assessed whether an SMS reminder system for women, after gestational diabetes, would increase their attendance for an oral glucose tolerance test (OGTT) by six months postpartum. METHODS: Women were eligible for inclusion if they were diagnosed with gestational diabetes in their recent pregnancy, had a mobile phone and normal blood glucose profile prior to postnatal discharge from the Women's and Children's Hospital, Adelaide. A computer-generated random number sequence and telephone randomization were used. Two hundred and seventy-six women were randomized. Women in the six-week group (n = 140) were sent a text reminder to attend for an OGTT at six weeks postpartum, with further reminders at three and six months if required. Women in the control group (n = 136) received one text reminder at six months postpartum. Blinding was not feasible. The primary outcome was OGTT attendance within six months postpartum. RESULTS: Women in the six-week group did not increase their attendance for an OGTT within six months postpartum compared with women in the control group, 104 (77.6% of 134) versus 103 (76.8% of 134), relative risk (RR) 1.01, 95% confidence interval (CI) 0.89-1.15. CONCLUSIONS: The SMS reminder system did not increase postpartum OGTT, fasting plasma glucose or HbA1c completion, although high rates of test completion were measured in both groups. Further research is required into factors influencing attendance for postpartum testing from the perspective of women, and into optimal counselling relating to Type 2 diabetes risk in the postpartum period for increasing postpartum glucose testing rates.

Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment.

AIM: The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. METHODS: Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. RESULTS: Circulating TB12, HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p < 0.001), but not in insulin-treated women. CONCLUSIONS: Total, but not bioavailable, vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation.

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

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. 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 1.9­15.5%; 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.

Increased lymphocyte micronucleus frequency in early pregnancy is associated prospectively with pre-eclampsia and/or intrauterine growth restriction.

Genome stability is essential for normal foetal growth and development. To date, genome stability in human lymphocytes has not been studied in relation to late pregnancy diseases, such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR), which can be life-threatening to mother and baby and together affect >10% of pregnancies. We performed a prospective cohort study investigating the association of maternal chromosomal damage in mid-pregnancy (20 weeks gestation) with pregnancy outcomes. Chromosome damage was measured using the cytokinesis-block micronucleus cytome (CBMNcyt) assay in peripheral blood lymphocytes. The odds ratio for PE and/or IUGR in a mixed cohort of low- and high-risk pregnancies (N = 136) and a cohort of only high-risk pregnancies (N = 91) was 15.97 (P = 0.001) and 17.85 (P = 0.007), respectively, if the frequency of lymphocytes with micronuclei (MN) at 20 weeks gestation was greater than the mean + 2 SDs of the cohort. These results suggest that the presence of lymphocyte MN is significantly increased in women who develop PE and/or IUGR before the clinical signs or symptoms appear relative to women with normal pregnancy outcomes. The CBMNcyt assay may provide a new approach for the early detection of women at risk of developing these late pregnancy diseases and for biomonitoring the efficacy of interventions to reduce DNA damage, which may in turn ameliorate pregnancy outcome.

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

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. CLINICAL TRIAL REGISTRATION: ISRCTN87441504 at http://www.controlled-trials.com.

Anticoagulation in pregnancy and the puerperium.

For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain.

Biparental contribution to fetal thrombophilia in discordant twin intrauterine growth restriction.

Poor pregnancy outcomes have been reported to be associated with maternal thrombophilia. We present a case where 1 dizygotic twin inherited thrombophilic genes from both the father and mother, resulting in placental fetal thrombotic vasculopathy and intrauterine growth restriction, whereas its co-twin inherited only 1 such gene from its mother and was unaffected.

Drugs in pregnancy. Endocrine disease (including diabetes).

This chapter reviews the treatment of endocrine disease in pregnancy, including diabetes mellitus, hypo- and hyperthyroidism, adrenal and pituitary disorders, and hyper- and hypoparathyroidism. Pregnancy in some of these disorders is relatively rare, so that management is often based on limited information and clinical judgement rather than on strong evidence-based criteria.

Pulmonary alveolar proteinosis: two contrasting cases.

Pulmonary alveolar proteinosis is a rare condition characterized by the abnormal accumulation of surfactant-like material within the alveolar spaces and distal bronchioles. Two cases with contrasting modes of presentation, course, and response to therapeutic whole lung lavage are described. Both cases were in hypoxaemic respiratory failure at the time the definitive diagnosis was made, and in both cases the diagnosis was made by segmental bronchoalveolar lavage following negative open lung biopsy. In neither was an underlying causative organism or agent identified. In one case the alveolar proteinosis developed in late pregnancy, a presentation that is previously unreported. Clinical improvement in this case required repeated whole lung lavages and was accompanied by a trend towards normalization of the ratios of surfactant protein-A and surfactant protein-B to disaturated phospholipid, ratios which may be useful as prognostic indicators. The response to therapeutic lavage was markedly different in the two cases, and it is postulated that this may relate to the fact that alveolar proteinosis is a heterogeneous disease and that the course and response to treatment may relate in part to the specific composition of the abnormal proteinaceous fluid.

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 hyperhomocysteinaemia. Further randomised controlled trials of folic acid supplementation in preventing pregnancy complications associated with hyperhomocysteinaemia should be conducted.

Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: an Australian randomized trial. FRACOG and the ACT Study Group.

A multicentre, randomized controlled double-blind trial in 5 maternity hospitals in Australia assessed the effect of a daily supplement of calcium (1.8g oral calcium or an oral placebo) taken daily until delivery, from less than 24 weeks' gestation, on the frequency of pregnancy-induced hypertension, preeclampsia and preterm birth (< 37 weeks' gestation) in 456 nulliparas with a singleton pregnancy. Treatment with calcium reduced the risk of preeclampsia (relative risk 0.44 [95% CI, 0.21-0.90], p = 0.02) and the risk of preterm birth (relative risk 0.44 [95% CI, 0.21-0.90], p = 0.02). No significant differences were seen between the 2 groups in the frequency of pregnancy-induced hypertension, although the study only had statistical power to detect large differences in this outcome. An updated systematic review of the 9 randomized trials of calcium supplementation in pregnancy shows a significant reduction in the risk of hypertension and preeclampsia although no effect on preterm birth. Calcium supplementation during pregnancy reduced the risk of preeclampsia and preterm birth in this nulliparous population. The available evidence for systematic review of all the randomized trials of calcium supplementation shows benefit in reducing the risk of hypertension and preeclampsia.