Study design and population
This retrospective observational cohort study of women with GDM was conducted in two hospitals in the North of the Netherlands, University Medical Center Groningen and non-university Martini Hospital Groningen. Those centers adopted a joint protocol on screening and treatment of GDM in January 2011 after revision of the Dutch guideline in 2010 [11]. The electronic medical files of all women with a diagnosis of GDM, who visited the outpatient clinic of both hospitals between January 2011 and September 2014, were eligible for inclusion in the study.
Pregnant women were tested for GDM if they had risk factors for GDM according to the Dutch guideline or signs suggestive of GDM (like foetal macrosomia and/or polyhydramnion). These GDM risk factors were: previous GDM, pre-gestational body mass index (BMI) ≥30 kg/m2, previous infant weighing ≥4500 g at birth, first-degree relative with type 2 diabetes, ethnic origin (South-Asian, Hindu, Afro-Caribbean, Middle-Eastern, Morocco, and Egypt), history of intrauterine fetal death, and history of polycystic ovary syndrome. Pregnant women with GDM risk factors were routinely screened for GDM at 24–28 weeks of gestation by their midwife’s office care, or by their gynaecologist in secondary care. Women with previous GDM were screened at 16–18 weeks of gestation and when the results were negative, this was repeated in week 24–28 of gestation.
A 75-g OGTT was used for the screening of GDM. GDM was diagnosed when fasting plasma glucose was ≥7.0 mmol/l and/or 2-h value ≥7.8 mmol/l after the 75-g glucose load, according to the diagnostic criteria of the WHO (1999) [12]. In addition, GDM was diagnosed without an OGTT if fasting glucose was >7.0 mmol/l or a random glucose was >11.1 mmol/l.
In total 839 women were diagnosed with GDM and referred to the diabetes outpatient clinic for treatment. For the present analysis, women with twin pregnancy (n = 15) or missing pregnancy outcomes (n = 4) were excluded (Fig. 1). This study is conducted in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice. The study has been exempted for approval according to the Medical Research Involving Human Subjects Act [19]. This report is based on patient data acquired during care-as-usual, the data has been analyzed retrospectively and all the requirements for patient anonymity are in agreement to the regulations of the ethical committee of both hospitals for publication of patient data. According to this and the Dutch law Medical Research with Human Subjects, no approval from an ethics committee is necessary.
GDM management
The first step in the management of women with GDM was dietary advice by a dietician, which included advice about carbohydrate intake and carbohydrate distribution. Women were also instructed to measure fasting and 1-h postprandial blood glucose levels every day. Blood glucose levels were reviewed after 1–2 weeks. Women with fasting blood glucose level >5.3 mmol/l and/or post prandial blood glucose level >7.8 mmol/l received additional insulin therapy to obtain blood glucose values below these treatment goals. Insulin was commenced when two blood glucose results at the same moment of the day were elevated despite dietary intervention. Insulin treatment regimens were: long-acting insulin only, prandial short-acting insulin or a combination of both (basal-bolus regimen), depending on the individual glycaemic profile. In both centres short-acting insulin analogues and Neutral Protamine Hagedorn (NPH) insulin were used in GDM treatment.
Women were intensively followed with regular e-mail and/or telephone contact, at least weekly, in order to assist them to achieve and maintain the glycaemic targets. Every 3–4 weeks or on request if indicated, women visited the diabetes and obstetric outpatient clinics. If applicable based on self-monitoring of the blood glucose values, diet was adjusted and insulin dose increased to maintain blood glucose levels within the target range.
Fetal growth was evaluated by ultrasonography, performed every 4 weeks by trained obstetricians. In both centres labour was induced at or around 38 weeks in women on insulin therapy with taking blood glucose control as well as fetal growth into consideration. Labour was also induced for non-GDM related maternal or fetal indications, for instance gestational hypertension or preeclampsia. The diet- and insulin-treated women were both followed to the date of delivery and were discussed every 3 weeks in a multidisciplinary consultation in the University Medical Center Groningen. In the Martini Hospital multidisciplinary consultation occurred immediately after the outpatient clinic visit.
Clinical data collection
All data were collected from electronic medical- and birth records. Ethnicity was labeled in five categories: Caucasian, Asian (Indian or South-East Asian), African-American, Mediterranean (Hispanic, Middle-Eastern, North-African or South-American), and unknown. Chronic hypertension was defined as a systolic blood pressure (SBP) ≥140 mmHg, a diastolic blood pressure (DBP) ≥90 mmHg on two occasions at least 4 h apart or the use of blood-pressure lowering drugs, before pregnancy. Family history of diabetes was defined as having a first degree relative who had type 2 diabetes. HbA1c values were measured by standardized HPLC method on a Tosoh G8 system (Tosoh, Tokyo, Japan), considering 22–42 mmol/mol (4.2–6.0 %) as normal. The HbA1c values were measured at the time of GDM diagnosis within 1 week after the OGTT.
Neonatal outcomes
Neonatal outcomes were a composite outcome of perinatal complications (still birth/neonatal death, birth trauma (shoulder dystocia, fracture of humerus or clavicle, brachial plexus injury), neonatal hypoglycaemia and neonatal hyperbilirubinaemia), gestational age at birth, birth weight, neonate weighing >4000–4499 g, neonate weighing >4200 g, neonate weighing ≥4500 g, large for gestational age (LGA) (defined as birth weight above the 90th percentile, adjusted for gestational age, gender, parity, and ethnicity [20]), small for gestational age (SGA) (defined as birth weight below the 10th percentile, adjusted for gestational age, gender, parity, and ethnicity [20]), Apgar score <7 at 5 min, need for respiratory support, preterm delivery (defined as delivery before 37 completed weeks of gestation), and admission to the neonatology department.
The presence of neonatal hypoglycaemia (occurring >2 h after birth) was defined as a blood glucose level <2.6 mmol/l or treatment with a glucose infusion [11]. Neonatal hyperbilirubinaemia was recorded when the infant was treated with phototherapy after birth or admission at the neonatology department for this reason. Respiratory support was defined as the need for supplemental oxygen or continuous positive airway pressure after birth.
Obstetric outcomes
The obstetric outcomes were: induction of labour, delivery type (spontaneous, instrumental (forceps or vacuum extraction), planned caesarean section and secondary caesarean section), gestational hypertension, and preeclampsia.
Gestational hypertension was defined as a SBP ≥140 mmHg and/or a DBP ≥90 mmHg, with no evidence of pre-existing hypertension and the absence of proteinuria. Preeclampsia was defined as a combination of gestational hypertension and proteinuria (≥300 mg/24-h) and included eclampsia and ‘Hemolysis Elevated Liver enzymes and Low Platelets’ (HELLP)-syndrome.
For comparison, the general obstetric population in the Northern region of the Netherlands and their registered neonatal and obstetric outcomes during the period 2011–2013 served as a reference population screened with the same guidelines, these data were provided from the Dutch Perinatal Registry and the Municipal Health Service Groningen. Data of the general obstetric population were available for the following outcomes: still birth/neonatal death, neonate weighing >4000–4499 g, neonate weighing ≥4500 g, LGA, SGA, and Apgar score <7 at 5 min.
Statistical analyses
Continuous data are presented as mean ± standard deviation (SD) or as median and inter quartile range [IQR] in case of skewed distribution. Categorical data are presented as number and percentage. Differences between the groups were tested using Student’s unpaired t-test for continuous data or Mann-Whitney U Test in case of skewed distribution. For categorical data Chi-square or Fisher’s exact test were used.
All P-values are two-tailed, and P-values <0.05 were considered statistically significant. All analyses were conducted with the use of the statistical package IBM SPSS (version 22.0. Armonk, NY: IBM Corp).