Inge M. Evers

Macrosomia despite good glycaemic control in Type I diabetic pregnancy; results of a nationwide study in The Netherlands.

Abstract Aims/hypothesis. To investigate the incidence of foetal macrosomia (i.e. birth weight >90th percentile) in a non-selected nationwide cohort of women with Type I (insulin-dependent) diabetes mellitus in The Netherlands and to identify risk indicators predictive for macrosomia. Methods. We conducted a prospective nationwide cohort based survey regarding the outcome of Type I diabetic pregnancy in The Netherlands. Data of 289 women who gave birth to a live singleton infant without major congenital malformations at more than or equal to 28 weeks of gestation are shown. Results. The incidence of foetal macrosomia was very high (48.8%), with 26.6% of infants weighing more than 97.7th percentile. Glycaemic control during pregnancy was good (i.e. mean HbA1c ≤7.0%), in almost all (84%) women. Multiple logistic regression analysis resulted in a predictive model for macrosomia that incorporated five variables: third trimester HbA1c (Odds Ratio [95% Confidence Interval]: (1.6[1.1–2.4]), absence of third trimester severe hypoglycaemia (3.0[1.2–7.3]), the use of insulin lispro (3.1[0.9–10.4]), weight gain during pregnancy (1.1[1.0–1.2]) and non-smoking (2.8[0.9–9.3]). Third trimester HbA1c was the most powerful predictor for the occurrence of macrosomia, but its predictive capacity was weak (explained variance <5%). Conclusion/interpretation. Despite apparent good glycaemic control, the incidence of foetal macrosomia in this non-selected prospective nationwide cohort of 289 Type I diabetic women was very high. Third trimester HbA1c was the most powerful predictor, but its predictive capacity was weak. Thus, future research should focus on new more detailed glucose monitoring techniques (such as a continuous glucose monitoring system) as well as to alternative factors to reduce macrosomia.

Maternal hypoglycemia during pregnancy in type 1 diabetes: maternal and fetal consequences.

There is strong evidence that the avoidance of hyperglycemia is essential inoptimizing pregnancy outcome in type 1 diabetes. The price to pay is a striking increase in severe hypoglycemia (SH), defined as episodes requiring help from another person. During type 1 diabetic pregnancy, occurrence rates of SH up to 15 times higher as in the intensively treated group of the Diabetes Control and Complications Trial (DCCT) are reported. Blood glucose (BG) treatment targets differ considerably between clinics; some authors advocate lower limits as low as 3.3 mmol/l. Improved glycemic control and/or recurrent hypoglycemia (i.e. BG <3.9 mmol/l) may result in impairment of glucose counterregulatory responses. Also, glucose counterregulation may be altered by pregnancy itself. Short‐acting insulin analogs may help reduce hypoglycemia with preservation of good glycemic control, but their use during pregnancy has yet to be proven safe.

Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels

OBJECTIVE The primary aim of this study was to investigate the correlation between pregnancy outcome and bile acid (BA) levels in pregnancies that were affected by intrahepatic cholestasis of pregnancy (ICP). In addition, correlations between maternal and fetal BA levels were explored. STUDY DESIGN We conducted a retrospective study that included women with pruritus and BA levels ≥10 μmol/L between January 2005 and August 2012 in 3 large hospitals in the Netherlands. The study group was divided in mild (10-39 μmol/L), moderate (40-99 μmol/L), and severe (≥100 μmol/L) ICP. Main outcome measures were spontaneous preterm birth, meconium-stained amniotic fluid, asphyxia, and perinatal death. Univariate and multivariate logistic regression analysis was used to study associations between BA levels and adverse outcome. RESULTS A total of 215 women were included. Gestational age at diagnosis and gestational age at delivery were significantly lower in the severe, as compared with the mild, ICP group (P < .001). Spontaneous preterm birth (19.0%), meconium-stained fluid (47.6%), and perinatal death (9.5%) occurred significantly more often in cases with severe ICP. Higher BA levels were associated significantly with spontaneous preterm birth (adjusted odds ratio [aOR], 1.15; 95% confidence interval [CI], 1.03-1.28), meconium-stained amniotic fluid (aOR, 1.15; 95% CI, 1.06-1.25), and perinatal death (aOR, 1.26; 95% CI, 1.01-1.57). Maternal BA levels at diagnosis and at delivery were correlated positively with umbilical cord blood BA levels (P = .006 and .012, respectively). CONCLUSION Severe ICP is associated with adverse pregnancy outcome. Levels of BA correlate between mother and fetus.

Poor glucose control in women with type 1 diabetes mellitus and 'safe' hemoglobin A1c values in the first trimester of pregnancy

Objective: To observe glycemic excursions, measured continuously over 24 h, in relation to hemoglobin A1c values in the first trimester of pregnancy of women with type 1 diabetes mellitus. Methods: The MiniMed Continuous Glucose Monitoring System (CGMS) was used to obtain glucose values every 5 min during 24 h. Hemoglobin A1c was determined at the end of the continuous glucose recording and 6-12 weeks after the continuous glucose recording. Results: Continuous glucose recordings were obtained in 13 women between 7 and 15 weeks of gestation. Nine patients had hemoglobin A1c levels of ≤ 7.0% (< 1% above the upper limit of normal range) while up to 41.3% of the readings had values of < 3.9 mmol/l (70 mg/dl) and up to 52.8% of the readings had values of > 7.8 mmol/l (140 mg/dl). Conclusions: Hemoglobin A1c does not reflect the complexities of glycemic control in women with type 1 diabetes who are considered to have accomplished tight glycemic control in the first trimester of pregnancy.

Effect of breast milk of diabetic mothers on bodyweight of the offspring in the first year of life

Objective: There is increasing evidence that in healthy populations, breast-fed infants are leaner than formula-fed infants. It is of interest to know the effects of breast-feeding on infant weight in case of maternal diabetes, given the high incidence of fetal macrosomia and risk of childhood obesity in this population.Design and Subjects: As part of a nation-wide study in the Netherlands on diabetes and pregnancy, 229 women with Type 1 diabetes were sent a questionnaire on weight and height of their infant, the type of nutrition given during the first 6 weeks of life, the duration of lactation and intercurrent diseases during the first year of life.Results and conclusion: Our data show no significant difference between breast-,formula-, and mixed-fed infants in weight and body mass index (BMI) at 1 y of age, which is not in accordance with the findings in nondiabetic populations.Sponsorship: Novo Nordisk Farma BV, Alphen aan de Rijn, the Netherlands and the Cornelis Visser Foundation.

The efficacy and effectiveness of continuous glucose monitoring during pregnancy: a systematic review

Objective Diabetic pregnancies carry a high risk for both mother and child, especially when glycemic control is poor. A novel technique that aims to improve glycemic control is the continuous glucose monitor (CGM). This tool is already in use to improve pregnancy outcome. This review presents the available evidence on the efficacy of CGM use in pregnancy and the effectiveness on pregnancy outcome. Methods A systematic search was conducted using PubMed, EMBASE, and the Cochrane Libraries for articles on CGM in pregnancy. We evaluated the selected articles with particular attention for clinical and cost-effectiveness of CGM to improve pregnancy outcome. Results We retrieved 5032 articles, 11 of which remained as relevant after selection according to predefined criteria. Most studies were limited to the evaluation of the role of CGM on clinical decision making. Only 2 studies were randomized controlled trials (RCTs) evaluating the effect on pregnancy outcome. One small RCT on retrospective CGM showed a significant reduction in third-trimester HbA1c and a significant reduction in neonatal macrosomia. A second RCT on real-time CGM did not show any effect on either glycemic control or on pregnancy outcome. Conclusions Current evidence on the efficacy of CGM on improving glycemic control during pregnancy as well as on the effectiveness on pregnancy outcome is limited to 2 RCTs with contradicting results. Evidence on the cost-effectiveness is lacking. Further proper RCTs on the effectiveness and cost-effectiveness of CGM in pregnancy are required before wide implementation in practice. Target Audience: Obstetricians and gynecologists, family physicians and internists Learning Objectives: After completing this CME activity, physicians should be better able to compare the results of the 2 major trials on the efficacy and effectiveness of the continuous glucose monitoring system (CGM) in treating pregnant women with diabetes and evaluate the evidence on the cost-effectiveness of CGMS use in pregnant women with diabetes.

Male predominance of congenital malformations in infants of women with type 1 diabetes.

OBJECTIVE To investigate sex-related differences in maternal, perinatal, and neonatal outcome in type 1 diabetic pregnancies in the Netherlands. RESEARCH DESIGN AND METHODS This was a nationwide prospective cohort-based study. Logistic regression analysis was used to identify sex-specific risk factors for adverse pregnancy outcome. RESULTS A total of 323 type 1 diabetic pregnancies were included; 314 were ongoing after 24 weeks of gestation. There were eight twin pregnancies and one triplet, resulting in 324 infants born after 24 weeks of gestation. Multiple logistic regression analysis showed that the occurrence of congenital malformations was independently associated with male newborns (OR 3.5 [95% CI 1.3–10.0]; P = 0.02). CONCLUSIONS The higher incidence of congenital malformations in infants of women with type 1 diabetes appears to be restricted to male infants only.

External validation of prognostic models to predict risk of gestational diabetes mellitus in one Dutch cohort: prospective multicentre cohort study

Objective To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first trimester of pregnancy. Design External validation of all published prognostic models in large scale, prospective, multicentre cohort study. Setting 31 independent midwifery practices and six hospitals in the Netherlands. Participants Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded. Main outcome measures Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots. Results 3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit. Conclusions In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact.

Effectiveness of continuous glucose monitoring during diabetic pregnancy (GlucoMOMS trial); a randomised controlled trial

BackgroundHyperglycemia in pregnancy is associated with poor perinatal outcome. Even if pregnant women with diabetes are monitored according to current guidelines, they do much worse than their normoglycaemic counterparts, marked by increased risks of pre-eclampsia, macrosomia, and caesarean section amongst others. Continuous Glucose Monitoring (CGM) is a new method providing detailed information on daily fluctuations, used to optimize glucose control. Whether this tool improves pregnancy outcome remains unclear. In the present protocol, we aim to assess the effect of CGM use in diabetic pregnancies on pregnancy outcome.Methods/designThe GlucoMOMS trial is a multicenter open label randomized clinical trial with a decision and cost-effectiveness study alongside. Pregnant women aged 18 and over with either diabetes mellitus type 1 or 2 on insulin therapy or with gestational diabetes requiring insulin therapy before 30 weeks of gestation will be asked to participate. Consenting women will be randomly allocated to either usual care or complementary CGM. All women will determine their glycaemic control by self-monitoring of blood glucose levels and HbA1c. In addition, women allocated to CGM will use it for 5–7 days every six weeks. Based on their CGM profiles they receive dietary advice and insulin therapy adjustments if necessary. The primary outcome measure is rate of macrosomia, defined as a birth weight above the 90th centile. Secondary outcome measures will be birth weight, composite neonatal morbidity, maternal outcome and costs. The analyses will be according to the intention to treat principle.DiscussionWith this trial we aim at clarifying whether the CGM improves pregnancy outcome when used during diabetic pregnancies.Trial registrationNederlands Trial Register: NTR2996

Economic analysis of use of pessary to prevent preterm birth in women with multiple pregnancy (ProTWIN trial)

To assess the cost‐effectiveness of a cervical pessary to prevent preterm delivery in women with a multiple pregnancy.