DIABETICMedicine DOI: 10.1111/dme.13076
Research: Care Delivery Twin pregnancies complicated by gestational diabetes mellitus: a single centre cohort study G. K. Dinham1, A. Henry1,2,3, S. A. Lowe1,2, N. Nassar4, K. Lui1,2, V. Spear2 and A. W. Shand1,2,4 1 School of Women’s and Children’s Health, University New South Wales Medicine, Kensington, NSW, 2Department of Obstetrics, Royal Hospital for Women, Randwick, NSW, 3Women’s and Children’s Health, St George Hospital, Kogarah, NSW, and 4Clinical and Population Perinatal Health Research, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
Accepted 19 January 2016
Abstract Aims In women with a twin pregnancy, to determine the incidence of, risk factors for and outcomes of women with gestational diabetes mellitus, and assess how these have changed with a change in gestational diabetes screening. Methods Retrospective cohort study of women with a twin pregnancy attending an Australian tertiary hospital, 2002– 2013. Information on gestational diabetes status, gestational diabetes risk factors and pregnancy outcomes was ascertained. Pregnancy outcomes included hypertensive disorders, twin birthweight centile and a composite adverse pregnancy outcome. Analysis was stratified pre/post screening protocol change (epoch 1: 2002–2009, epoch 2: 2010– 2013) and by gestational diabetes status.
Gestational diabetes was diagnosed in 86/982 (8.8%) women, increasing from 4.4% to 14.7% between epochs (P = 0.0001). The proportion of women with hypertensive disorders increased (11.7% vs. 13.4%, P = 0.009), but the proportion of infant’s birthweight > 90th centile decreased (11.0% vs. 7.6%, P = 0.02) between epochs. Overall, 33.6% of women had ≥ 1 risk factors for gestational diabetes. Three-quarters (73.7%) of women overall had an adverse pregnancy outcome, with a slightly higher proportion in women with gestational diabetes compared with those with no gestational diabetes (79.7% vs. 73.1%, P = 0.06). The rate of the adverse pregnancy outcome did not change by epoch, after adjusting for maternal and pregnancy risk factors (adjusted odds ratio = 0.96, 95% confidence interval 0.73–1.26). Results
Conclusions Almost 1 in 10 women with a twin pregnancy were diagnosed with gestational diabetes, with the incidence of gestational diabetes increasing threefold with a new screening protocol. The pregnancy outcomes of women with a twin pregnancy did not change with increased detection and treatment for gestational diabetes.
Diabet. Med. 00, 000–000 (2016)
Introduction Gestational diabetes mellitus is defined as carbohydrate intolerance resulting in hyperglycaemia of varying severity, with onset or first recognition during pregnancy [1]. The landmark observational Hyperglycaemia and Adverse Pregnancy Outcomes study found strong, linear associations between increasing maternal hyperglycaemia and adverse pregnancy outcomes, including Caesarean section, preeclampsia, perineal trauma, a large for gestational age infant and neonatal hypoglycaemia [2]. Recognition of these associations has led to a plethora of new screening guidelines for gestational diabetes, including the International Correspondence to: Antonia W. Shand. E-mail: [email protected]
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Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel, the Australasian Diabetes in Pregnancy Society (ADIPS) [4] and the World Health Organisation (WHO) [5]. The IADPSG and ADIPS guidelines recommend that women at increased risk of gestational diabetes should undergo blood testing for diabetes mellitus at the first antenatal visit [3,4]. ADIPS recommends fasting or random plasma glucose testing for ‘moderate risk’ women and a 75–g oral glucose tolerance test (75–g OGTT) for ‘high risk’ women, as defined in Appendix 1 [4]. In addition, both guidelines, recommend that all women not known to have diabetes mellitus have a 75–g OGTT at 24–28 weeks’ gestation [3,4]. Twin pregnancy is associated with adverse pregnancy outcomes, including an increased risk of gestational diabetes, pre-eclampsia and preterm birth [6]. Women with gestational
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Gestational diabetes mellitus in twin pregnancies G. K. Dinham et al.
What’s new? Rates of gestational diabetes in twin pregnancy increased threefold from 4.4% to 14.7% with a change towards universal early pregnancy glucose-tolerance testing. Adverse pregnancy outcomes in twin pregnancies did not change with increased screening and treatment of gestational diabetes, although there was a decrease in large for gestational age infants. Nearly half of women with a twin pregnancy had risk factors for gestational diabetes, apart from twin pregnancy.
diabetes and women with twin pregnancies frequently have shared risk factors, including older maternal age, obesity, polycystic ovarian syndrome, and the use of assisted reproductive technology [7–9]. It is uncertain how much gestational diabetes exacerbates the underlying maternal or fetal risks associated with a twin pregnancy. However, it is known that twin fetuses are at lower risk of macrosomia [11] than singletons, partly because of the very high rates of preterm birth [12], but also due to in utero placental size restrictions leading to higher rates of small for gestational age infants. In systematic reviews and meta-analyses, treatment of gestational diabetes compared with no treatment has been found to result in less pre-eclampsia and macrosomia [13] and lower rates of large for gestational age infants, shoulder dystocia and gestational hypertension [14]. However, of the two largest randomized controlled trials of treatment of gestational diabetes, one excluded twin pregnancies [15] and one included only small numbers of twin pregnancies [16]. Disappointingly, the Hyperglycaemia and Adverse Pregnancy Outcomes study also excluded women with twin pregnancies [2] and, hence, the IADPSG [3] and the ADIPS [4] guidelines, based on the Hyperglycaemia and Adverse Pregnancy Outcomes study, do not specifically mention twin pregnancy as a risk factor for gestational diabetes. Thus, clinicians have been left to use screening guidelines developed by observation or treatment of gestational diabetes in mostly singleton pregnancies, the appropriateness of which has not been investigated in twin pregnancies. The Royal Hospital for Women twins clinic, commenced in April 2009, recommended that all women with a twin pregnancy have screening for gestational diabetes twice during pregnancy, with a 75–g OGTT at 14–16 weeks and again at 26– 28 weeks’ gestation. Gestational diabetes was diagnosed if the blood glucose level was ≥ 5.5 mmol/l (99 mg/dl) at 0 h or ≥ 8.0 mmol/l (144 mg/dl) at 2 h. Prior to that time, women with a twin pregnancy received gestational diabetes screening, similar to women with a singleton pregnancy, in whom screening involved a two-step process: a 50–g glucose challenge test at 26–28 weeks (random, non-fasting),
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followed by a 75–g OGTT if the glucose challenge test was abnormal [blood glucose level ≥ 7.8 mmol/l (140 mg/dl) at 1 h]. The 75–g OGTT criteria for gestational diabetes diagnosis were the same in both epochs. The aim of this study was to assess in women with twin pregnancies, the pregnancy outcomes of women with gestational diabetes and the impact of changing gestational diabetes screening guidelines on gestational diabetes diagnoses, including whether this changed pregnancy outcomes. In addition we aimed to examine the proportion of women with a twin pregnancy with risk factors for gestational diabetes as defined by ADIPS.
Materials and methods The study was a 12-year retrospective cohort of all women with a twin pregnancy who delivered at the Royal Hospital for Women, Sydney, NSW, Australia between 1 January 2002 and 31 December 2013. The Royal Hospital for Women is a tertiary maternity hospital with over 4000 births per year and a neonatal intensive care unit. It is the also the main centre for laser for twin-to-twin transfusion syndrome in NSW [17]. Women were excluded if they had pre-existing diabetes mellitus. Where a woman had more than one twin pregnancy, only the first twin pregnancy was included. Demographic and pregnancy data were obtained from the electronic hospital records, Obstet and ObstetriX (Obstetrix Consortium, NSW Health). These databases contain information about all births of ≥ 20 weeks’ gestation (or 400 g birthweight where the gestational age is unknown), including maternal demographics, pregnancy, birth and infant outcomes, which are entered by a midwife at the point of care. More detailed information about women with gestational diabetes was also extracted from the Royal Hospital for Women Diabetes Clinic database and medical records. Maternal outcomes analysed included diagnosis of gestational diabetes, gestation at diagnosis and type of treatment for gestational diabetes. Pregnancy outcomes included mode of birth, induction of labour, maternal hypertensive disorders (pre-eclampsia, gestational hypertension and superimposed pre-eclampsia) classified according to the Society of Obstetric Medicine of Australia and New Zealand [18], prematurity < 37 weeks’ gestation, birthweight < 10th centile or birthweight > 90th centile (using twin birthweight centile charts [19]), congenital anomaly and perinatal death, a composite of stillbirth (birth with no signs of life ≥ 20 weeks’ gestation or birthweight > 400 g) and neonatal death (any infant death within 28 days of birth). A composite adverse pregnancy outcome comprising preterm birth, birthweight < 10th centile, birthweight > 90th centile, birth trauma, perinatal death, pre-eclampsia or gestational hypertension was also defined. Maternal characteristics that were assessed included age, BMI, parity and smoking. BMI (kg/m2) was calculated using a pre-pregnancy weight where known, or other pregnancy
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weight where pre-pregnancy weight was not known. Placental chorionicity was classified as dichorionic, monochorionic (monoamniotic or diamniotic) or unknown, based on placental histology, ultrasound findings or discordant sex where ultrasound or placental histology was not known. Nine broad ethnic groups were defined according to the Australian Standard Classification of Cultural and Ethnic Groups [20]. Six of the nine ethnic groups, Asian, Indian subcontinent, Middle Eastern, Aboriginal or Torres Strait Islander, Pacific Islander or Maori and non-white African, were classified as high-risk ethnicity according to the ADIPS criteria [4]. Where ethnicity was not known, country of birth was used as a surrogate. A family history of diabetes mellitus was defined as having a first-degree relative with diabetes mellitus or a sister with gestational diabetes. ADIPS risk status was defined based on ADIPS risk factors, and women were classified as having one or more medium risk, one or more high-risk factors or no risk factors (see Appendix 1). The cohort was divided into two epochs based on infant birth dates: epoch 1 (2002–2009) and epoch 2 (2010–2013). This was to account for the change in screening protocol for gestational diabetes after the commencement of the twins’ clinic in April 2009. Because of a lag time between commencement of the twins clinic, change in screening protocol and infant birth dates, the beginning of 2010 was chosen as reflective of a time when early pregnancy screening
would have been applied to all women with twin pregnancy at birth. Descriptive statistics were calculated to examine maternal characteristics and pregnancy outcomes by gestational diabetes status and epoch. The chi-squared test was used to assess the association between gestational diabetes, maternal characteristics including ADIPS risk factors, epoch of birth and pregnancy outcomes. Multivariate logistic regression analysis was then used to adjust for potential confounding by relevant maternal and pregnancy characteristics including maternal age, placental chorionicity, model of care and ADIPS risk factors and where P < 0.2 on univariate analysis. Given that chorionicity is one of the major risk factors for perinatal mortality we evaluated this specific factor in relation to perinatal mortality [21], to assess its contribution to overall adverse composite pregnancy outcome. Data were analysed using SAS 9.3 (SAS Inc., Cary, NC, USA) and a P-value < 0.05 was considered to be statistically significant. Ethics approval was obtained from the South Eastern Sydney Local Health District Human Research Ethics Committee, HREC Ref: 13/333 – LNR /13/POWH/718.
Results A flow chart of participants in the study is shown in Fig. 1. After exclusion of the women with pre-pregnancy diabetes
Women with a twin pregnancy who delivered at the Royal Hospital for Women, January 2002 – December 2013 n=995
Women with pre-GDM (n=9) and pregnancies where a woman had a second twin pregnancy (n=4) excluded n=982 women
No GDM n=896
Epoch 1 (January 2002December 2010) n=542
Epoch 2 (January 2010December 2013) n=354
GDM n=86
Epoch 1 (January 2002December 2010) n=25
Epoch 2 (January 2010December 2013) n=61
FIGURE 1 Flowchart of participants in the study.
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with rates of gestational diabetes continuing to rise to 26.0% in 2013 (data not shown). Almost one quarter (23.1%) were diagnosed with gestational diabetes prior to 20 weeks’ gestation and 76.9% diagnosed beyond 20 weeks. Gestational diabetes diagnoses also increased at both < 20 weeks’ and ≥ 20 weeks’ gestation in epoch 2 compared with epoch 1 (P < 0.001). Maternal and infant outcomes by epoch are presented in Table 2. The proportion of women with hypertensive disorders increased significantly between epochs (11.7% epoch 1 vs. 13.4% epoch 2, P = 0.009), whereas the proportion of infants large for gestational age decreased (11.0% epoch 1 vs. 7.6% epoch 2, P = 0.02). No infant had a birthweight > 4000 g. Compared with epoch 1, there was a higher rate of perinatal death in epoch 2 (2.6% vs. 5.4%, P = 0.002), however, there was no difference in the rate of composite adverse pregnancy outcome between epochs (74.4% vs.
mellitus and the second pregnancies of women who had two twin pregnancies during the study period, 982 women with a twin pregnancy (1964 fetuses) were included in the analysis. Overall, gestational diabetes was diagnosed in 86 (8.8%) women, with 567 women who delivered in epoch 1 and 415 who delivered in epoch 2. Demographic characteristics and gestational diabetes status by epoch are shown in Table 1. Compared to epoch 1, women in epoch 2 were more likely to be ≥ 35 years of age (35.8% in epoch 1 vs. 43.4% in epoch 2, P = 0.001), to have a known monochorionic twin pregnancy (16.9% vs. 34.5%, P = 0.001), and less likely to have a pregnancy of unknown chorionicity (28.9% vs. 4.8%, P < 0.001). One third (34.6%) of women had one or more ADIPS risk factors for gestational diabetes, and this increased over time (26.8% vs. 45.3%, P = 0.001). The proportion of women diagnosed with gestational diabetes also increased, from 4.4% in epoch 1 to 14.7% in epoch 2 (P = 0.001),
Table 1 Demographic characteristics and gestational diabetes mellitus status of 982 women with a twin pregnancy by screening epoch
Maternal age (years) < 20 20–34 35–39 ≥ 40 Booking BMI (kg/m2) (n = 549) < 25 25–29.9 ≥ 30–34.9 ≥ 35 Parity (n = 417) 0 1 ≥2 Smoker Chorionicity Monochorionic Dichorionic Unknown ADIPS risk status† None ≥ 1 Medium risk ≥ 1 High risk Gestational diabetes Gestational diabetes diagnosis (n=78) < 20 weeks ≥ 20 weeks Gestational diabetes treatment Diet Insulin Insulin/oral hypoglycaemic
All women
Epoch 1 2002–2009
Epoch 2 2010–2013
N = 982
N = 567
N = 415
n
%
n
%
n
%
P*
43 556 278 105
4.4 56.6 28.3 10.7
29 335 156 47
5.1 59.1 27.5 8.3
14 221 122 58
3.4 53.3 29.4 14
0.001
358 120 42 28
65.2 21.9 7.6 5.1
127 44 20 12
62.6 21.7 9.9 5.9
231 76 22 16
67 22 6.4 4.6
0.13
140 198 79 47
33.6 47.5 18.9 4.8
60 90 41 27
31.4 47.1 21.5 4.8
80 108 38 20
35.4 47.8 16.8 4.8
0.2
239 559 184
24.3 56.9 18.7
96 307 164
16.9 54.1 28.9
143 252 20
34.5 60.7 4.8
0.0001
642 210 130 86
65.4 21.4 13.2 8.8
415 100 52 25
73.2 17.6 9.2 4.4
227 110 78 61
54.7 26.5 18.8 14.7
0.0001
18 60
1.8 6.1
6 17
1.1 3
12 43
2.9 10.4
0.0001
5.6 2.5 0.6
16 9 0
2.8 1.6 0
39 16 6
9.4 3.9 1.4
0.0001
55 25 6
0.9
0.0001
ADIPS, Australasian Diabetes In Pregnancy Society. *P-values indicate difference between epoch 1 and 2. † ADIPS risk criteria. Medium risk – Ethnicity: Asian, Indian subcontinent, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African or BMI 25–35 kg/m2. High risk – Previous gestational diabetes, previously elevated blood glucose level, maternal age ≥ 40 years, family history of diabetes (first-degree relative with diabetes or a sister with gestational diabetes), BMI > 35 kg/m2, polycystic ovarian syndrome, corticosteroids, antipsychotics.
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Table 2 Maternal and neonatal outcomes of 982 women with a twin pregnancy and their 1964 infants by screening epochs
Overall n Women Mode of delivery Any Caesarean section Caesarean section both twins Vaginal both twins Vaginal/Caesarean Induction of labour Hypertensive disorder† Infants Gestational age at birth < 37 weeks Birthweight centile‡ < 10th 10–90th > 90th Congenital anomaly Perinatal death§ Stillbirth Neonatal death Adverse pregnancy outcome||
%
N = 982
Epoch 1: 2002– 2009
Epoch 2: 2010– 2013
n
n
%
N = 567
%
P*
N = 415 0.17
660 648 322 12 267 121 N = 1964
67.2 66 32.8 1.2 27.2 12.3
391 384 176 7 90 66 N = 1134
68.9 67.7 31 1.2 15.9 11.7
269 264 146 5 177 55 N = 830
64.8 63.6 35.2 1.2 30.6 13.4
1280
65.2
743
65.5
537
64.7
178 1576 185 34 74 42 32 1448
9.1 80.2 9.4 1.7 3.8 2.1 1.6 73.7
97 901 123 22 29 14 15 844
8.7 80.4 11 1.9 2.6 1.2 1.3 74.4
81 675 62 12 45 28 17 604
9.9 82.5 7.6 1.5 5.4 3.4 2.1 72.8
0.0001 0.009 0.62
0.49 REF 0.02 0.4 0.002
0.4
*P-values indicate difference between epoch 1 and 2. Gestational hypertension or pre-eclampsia. ‡ Using twin birthweight centile charts. § Stillbirth or neonatal death in hospital. || Defined as preterm birth < 37 weeks, perinatal death, birthweight < 10th centile, birthweight > 90th centile or 4500 g, birth trauma, preeclampsia, gestational hypertension or pre-eclampsia. †
72.8%, P = 0.4). Even after adjusting for maternal and pregnancy risk factors, there remained no association between the composite adverse pregnancy outcome and epoch [adjusted odds ratio (AOR) 0.96, 95% confidence interval (CI) 0.73–1.26]. Overall, women with a monochorionic twin pregnancy were almost four times more likely to have a composite adverse pregnancy outcome (including perinatal mortality) than women with a dichorionic twin pregnancy [odds ratio (OR) 3.8, 95% CI 2.8–5.3]. Maternal ADIPS risk status and maternal and infant outcomes, by maternal gestational diabetes status, are presented in Table 3. Two thirds of women (69.8%) with gestational diabetes had any ADIPS risk factors for gestational diabetes, compared with fewer than a third of women without gestational diabetes (31.2%) (P = 0.001). Women with gestational diabetes had a higher rate of hypertensive disorders (19.8% vs. 11.6%, P = 0.003), and a trend towards more adverse pregnancy outcomes (79.7% vs. 73.1%; P = 0.06) compared with women without gestational diabetes. After adjusting for maternal and pregnancy risk factors, women with gestational diabetes were almost 1.6 times more likely to have an adverse pregnancy outcome (AOR 1.58, 95% CI 1.02–2.47) than women without gestational diabetes. There were no differences in any pregnancy outcomes in women with gestational diabetes, if they were treated with diet alone compared to whether they
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were treated with insulin and/or oral hypoglycaemic therapy (P > 0.05).
Discussion This is one of the largest contemporary cohort studies of twin pregnancies with a well-defined screening policy for gestational diabetes applied in the study setting. The overall proportion of women with twin pregnancies diagnosed with gestational diabetes was 8.8%, which increased more than threefold with a change in screening from 4.4% to 14.7%. Women with gestational diabetes were more likely to have hypertensive disorders, late preterm birth and composite adverse pregnancy outcomes than those without gestational diabetes. Despite overall findings that about one third of women had risk factors for gestational diabetes and both these and pregnancy hypertension increased even with a change in gestational diabetes screening, there was a reduction in large for gestational age infants between epochs, but no change in composite adverse pregnancy outcomes. The incidence of gestational diabetes in this study was higher than that reported in the NSW population [9], a Canadian population-based study of twin pregnancies (7.3%) [11] and a single centre USA study of twin pregnancies (6.5%) [22], but lower than for Chinese twin pregnancies screened using the new IADPSG glucose thresholds (20.4%) [23]. However, the
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Table 3 Mother ADIPS risk status and mother and infant outcomes of women with a twin pregnancy by gestational diabetes mellitus status No gestational diabetes n Mother ADIPS risk status† No medium or high risk ≥ 1 Medium risk ≥ 1 High risk Mode of delivery Any Caesarean section Caesarean section both twins Vaginal both twins Vaginal/Caesarean Induction of Labour Hypertensive disorder‡ Infant Gestational age at birth < 37 weeks Birthweight centile§ < 10th 10th–90th > 90th Neonatal complication birth Hypoglycaemia Respiratory distress Congenital anomaly Perinatal Death|| Stillbirth Neonatal death Adverse pregnancy outcome¶
Gestational diabetes %
N = 896
n
%
P*
N = 86 0.001
616 185 95
68.8 20.6 10.6
26 25 35
30.2 29.1 40.7
597 586 299 11 194 104 N = 1792
66.6 65.4 33.4 1.2 21.6 11.6
63 62 23 1 23 17 N = 172
73.3 72.1 26.6 1.2 26.7 19.8
1157
64.6
123
71.5
164 1433 171
9.3 81.1 9.7
14 143 7
8.2 83.6 8.2
0.59 REF 0.5
20 277 33 71 41 30 1311
1.1 15.5 1.8 4.0 2.3 1.7 73.1
19 34 1 3 1 2 137
11.1 19.8 0.6 1.7 0.6 1.2 79.7
0.0001 0.13 0.2 0.3
0.2
0.1 0.0003 0.08
0.06
ADIPS, Australasian Diabetes In Pregnancy Society. *P-value indicates difference between women with and without gestational diabetes. ADIPS criteria. Medium risk – ethnicity: Asian, Indian subcontinent, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African or BMI 25–35 kg/m2. High risk – previous gestational diabetes, previously elevated blood glucose level, maternal age ≥ 40 years, family history of diabetes mellitus (first-degree relative with diabetes or a sister with gestational diabetes), BMI > 35 kg/m2, polycystic ovarian syndrome, corticosteroids, antipsychotics. ‡ Gestational hypertension or pre-eclampsia. § Using twin birthweight centile charts. || Stillbirth or neonatal death in hospital. ¶ Defined as preterm birth < 37 weeks, perinatal death, birthweight < 10th centile, birthweight > 90th centile or 4500 g, birth trauma, preeclampsia or gestational hypertension. †
increase in gestational diabetes diagnoses with a change in gestational diabetes screening seen in this study is consistent with other studies [11,24] and the recent increase seen in the overall NSW maternity population (4.8% in 2008 to 7.4% in 2012) [9], which may be explained by change in ADIPS screening guidelines. Evidence of the impact of changing gestational diabetes screening criteria was recently reported in a study that reported a twofold increase in the incidence of gestational diabetes in singleton pregnancies [25]. It is also possible that the change in incidence with a change in gestational diabetes screening may be explained by a real change in risk factors for gestational diabetes, such as maternal age and BMI, and/or improved identification and documentation of risk factors. Overall, we found that one third of all women with a twin pregnancy had at least one ADIPS risk factor, which almost doubled from 26.8% to 45.3% in the most recent epoch. This translates into about half of women with a twin pregnancy who would meet ADIPS criteria for early gestational diabetes
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screening. For the women who are ultimately diagnosed with gestational diabetes, but do not meet ADIPS criteria for early screening, screening at 26–28 weeks’ gestation may result in later detection and commencement of treatment than if all women with a twin pregnancy had screening for gestational diabetes in early pregnancy. The impact of earlier screening and subsequent treatment is difficult to predict, given that the randomized controlled trials of treatment for gestational diabetes [15,16,26] have been predominantly undertaken in singleton pregnancies, and the optimal timing of diagnosis in singleton pregnancies, let alone twin pregnancies, remains unclear [27]. The cost-effectiveness of universal early screening with the 75–g OGTT has not been evaluated; however, the procedure discomfort and inconvenience are well recognized. In addition, increased screening, higher rates of diagnosis and treatment generated an increase in clinic visits, laboratory tests and costs, as well as inconvenience to women who had to see both diabetes and twin clinics. Thus, our findings suggest that an assessment of risk factors for gestational diabetes should be
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undertaken for women with twin pregnancies as is recommended for singleton pregnancies, in order to determine whether early pregnancy screening for gestational diabetes should be undertaken. Women with twin pregnancies and gestational diabetes were found to have higher rates of hypertensive disorders, which is consistent with other studies [8,11,28,29]. However, despite increased rates of gestational diabetes diagnoses with a change in gestational diabetes screening, there was no decrease in hypertensive disorders. This contrasts with a recent study, which found decreased rates of pre-eclampsia in women with twin pregnancies following a change of gestational diabetes screening policy that resulted in increased diagnosis and treatment of gestational diabetes [23]. In terms of infant characteristics, the number of large for gestational age infants (using twin charts) decreased with a change in gestational diabetes screening, and there was no association found between gestational diabetes and large for gestational age. In some studies of twin pregnancies, women with gestational diabetes have been found to have higher rates of large for gestational age infants [8,11] and Caesarean section [11]. By contrast, an Israeli cohort study of twin pregnancies found no difference in Caesarean section rates in women with gestational diabetes compared with no gestational diabetes and a reduction in perinatal mortality in infants born to women with gestational diabetes [29], which is consistent with our study. Given that twins are smaller than singletons at all gestational ages, and therefore at lower risk of shoulder dystocia, birth trauma and significant maternal perineal trauma, and that no infant was > 4000 g, the clinical significance of this reduction in the rate of large for gestational age infants with a change in screening protocol is uncertain. Although the rate of perinatal death doubled between epochs, we found that maternal gestational diabetes status was not associated with an increased rate of perinatal death, which is in keeping with findings from other studies of twin pregnancies [6,8,29]. However, the increased mortality may be due to an increasing prevalence of known monochorionic twin pregnancies attending the hospital; the proportion of which doubled to one third of twin pregnancies from epoch 1 to epoch 2 (despite the larger proportion of unknown chorionicity in epoch 1), particularly with the establishment of the NSW Fetal Therapy Centre undertaking laser for twin-to-twin transfusion during this time [17]. We also found that women with a monochorionic pregnancy were up to four times more likely to have the composite adverse pregnancy outcome (including perinatal mortality) than women with a dichorionic twin pregnancy. This is consistent with other studies, which have shown that monochorionic pregnancies, especially those complicated by twin–twin transfusion syndrome or intrauterine growth restriction, carry an increased risk of perinatal death compared with dichorionic twin pregnancies [21]. The strength of this study was the ethnic diversity of the study population, which increases its external validity.
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However, it was limited by the single centre, retrospective study design and use of routinely collected data over a long period. In general, the ascertainment of demographic characteristics and perinatal outcomes was good and increased over time. But the large proportion of unknown placental chorionicity was a weakness, as this is a potential confounder of fetal and neonatal outcomes in twin pregnancies. The diagnostic blood glucose thresholds recommended in the new IADPSG and ADIPS guidelines were not used in this study, and the effect that these criteria would have on gestational diabetes diagnoses and the outcomes of twin pregnancies is not known, although other studies in twin and singleton pregnancies have found higher rates of gestational diabetes diagnoses after a change to new glucose thresholds [23,25,30]. In addition, the blood glucose levels or HbA1c levels of women with gestational diabetes were not known, nor whether women with gestational diabetes were diagnosed with diabetes mellitus post-partum. In conclusion, this study has shown that the rate of gestational diabetes diagnoses in women with a twin pregnancy increased threefold with a change in screening, and that women with gestational diabetes and their infants have poorer perinatal outcomes than those without gestational diabetes. With improved detection of gestational diabetes there has been a reduction in large for gestational age infants, however, it is debateable as to whether this is a meaningful clinical outcome in twin pregnancies. Overall, our findings suggest that for women with a twin pregnancy, ADIPS risk factors for gestational diabetes should be used to determine timing and type of screening for gestational diabetes. Further studies of gestational diabetes should include women with twin pregnancies, taking into account placental chorionicity and blood glucose levels at diagnosis and during pregnancy.
Funding sources
None.
Competing interests
None declared.
Acknowledgements
Natasha Nassar is supported by an NHMRC Career Development Fellowship (APP1067066). The authors wish to thank the diabetic educators who maintained the diabetes database and the midwives for data collection.
References 1 Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop–Conference on Gestational Diabetes Mellitus. Diabetes Care 1998; 21: B161–B167.
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2 Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991–2002. 3 Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PM, Damm P et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33: 676–682. 4 Nankervis A, Moses R, Ross G, Callaway L, Porter C, Jeffries W et al. Australasian Diabetes in Pregnancy Society (ADIPS) consensus guidelines for the testing and diagnosis of gestational diabetes mellitus in Australia. 2014. 5 World Health Organisation. Definition, diagnosis and classification of diabetes mellitus and its complications. Geneva: World Health Organisation, 2013. 6 Rauh-Hain JA, Rana S, Tamez H, Wang A, Cohen B, Cohen A et al. Risk for developing gestational diabetes in women with twin pregnancies. J Matern Fetal Neonat Med 2009; 22: 293– 299. 7 Wang YA, Chambers GM, Sullivan EA. Assisted reproductive technology in Australia and New Zealand 2008. Assisted reproduction technology series no. 14. Cat. no. PER 49. Canberra: AIHW, 2010. 8 Gonzalez Gonzalez NL, Goya M, Bellart J, Lopez J, Sancho MA, Mozas J et al. Obstetric and perinatal outcome in women with twin pregnancy and gestational diabetes. J Matern Fetal Neonat Med 2012; 25: 1084–1089. 9 Centre for Epidemiology and Evidence. New South Wales mothers and babies 2012. Sydney: NSW Ministry of Health, 2014. 10 McDonald S, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of in vitro fertilization twins: a systematic review and metaanalyses. Am J Obstet Gynecol 2005; 193: 141–152. 11 Lai FY, Johnson JA, Dover D, Kaul P. Outcomes of singleton and twin pregnancies complicated by preexisting diabetes and gestational diabetes: a population based study in Alberta, Canada, 2005–2011. J Diabetes 2014; epub ahead of print. 12 Algert CA, Morris JM, Bowen JR, Giles W, Roberts CL. Twin deliveries and place of birth in NSW 2001–2005. Aust NZ J Obstet Gynaecol 2009; 49: 461–466. 13 Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Aktary WM et al. Screening and diagnosing gestational diabetes mellitus. Evidence Report/Technology Assessment No. 210. Rockville, MD: Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021-I. AHRQ Publication No. 12(13)-E021-EF, 2012. 14 Poolsup N, Suksomboon N, Amin M. Effect of treatment of gestational diabetes mellitus: a systematic review and metaanalysis. PLoS One 2014; 9: e92485. 15 Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361: 1339–1348. 16 Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 2477– 2486. 17 Meriki N, Smoleniec J, Challis D, Welsh AW. Immediate outcome of twin–twin transfusion syndrome following selective laser photocoagulation of communicating vessels at the NSW Fetal Therapy Centre. Aust NZ J Obstet Gynaecol 2010; 50: 112–119. 18 Lowe S, Brown M, Dekker G, Gatt S, McLintock C, McMahon L et al. Guidelines for the management of hypertensive disorders of pregnancy. Sydney: Society of Obstetric Medicine of
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Australia and New Zealand, 2008. Available at https://somanz.org/pdfs/somanz_guidelines_2008.pdf Last accessed 1 March 2014. Roberts CL, Algert CS, Morris JM, Henderson-Smart DJ. Trends in twin births in New South Wales, Australia 1990–1999. Int J Gynecol Obstet 2002; 78: 213–219. Australian Bureau of Statistics. 1249.0 – Australian Standard Classification of Cultural and Ethnic Groups (ASCCEG). Sydney: Australian Bureau of Statistics, 2011 [updated 2012]. Available at http://www.abs.gov.au/ausstats/[email protected]/mf/1249.0 Last accessed 1 October 2014. Hack KE, Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. Br J Obstet Gynaecol 2008; 115: 58–67. Rebarber A, Dolin C, Fields JC, Saltzman DH, Klauser CK, Gupta S et al. Screening approach for gestational diabetes in twin pregnancies. Am J Obstet Gynecol 2014; 211: e1–e5. Liu X, Chen Y, Zhou Q, Shi H, Cheng WW. Utilization of International Association of Diabetes and Pregnancy Study Groups criteria vs. a two-step approach to screening for gestational diabetes mellitus in Chinese women with twin pregnancies. Diabet Med 2015; 32: 367–373. Shand AW, Bell JC, McElduff A, Morris J, Roberts CL. Outcomes of pregnancies in women with pre-gestational diabetes mellitus and gestational diabetes mellitus; a population-based study in New South Wales, Australia, 1998–2002. Diabet Med 2008; 25: 708– 715. Mayo K, Melamed N, Vandenberghe H, Berger H. The impact of adoption of the International Association of Diabetes in Pregnancy Study Group criteria for the screening and diagnosis of gestational diabetes. Am J Obstet Gynecol 2015; 212: e1–e9. Bonomo M, Corica D, Mion E, Goncalves D, Motta G, Merati R et al. Evaluating the therapeutic approach in pregnancies complicated by borderline glucose intolerance: a randomized clinical trial. Diabet Med 2005; 22: 1536–1541. Tieu J, McPhee AJ, Crowther CA, Middleton P. Screening and subsequent management for gestational diabetes for improving maternal and infant health. Cochrane Database Syst Rev 2014; 2: CD007222. Guillen MA, Herranz L, Barquiel B, Hillman N, Burgos MA, Pallardo LF. Influence of gestational diabetes mellitus on neonatal weight outcome in twin pregnancies. Diabet Med 2014; 31: 1651– 1656. Okby R, Weintraub AY, Sergienko R, Eyal S. Gestational diabetes mellitus in twin pregnancies is not associated with adverse perinatal outcomes. Arch Gynecol Obstet 2014; 290: 649–654. Moses RG, Morris GJ, Petocz P, San Gil F, Garg D. The impact of potential new diagnostic criteria on the prevalence of gestational diabetes mellitus in Australia. Med J Aust 2011; 194: 338–340.
Appendix 1 Australasian Diabetes in Pregnancy Society (ADIPS) risk factors for gestational diabetes in pregnancy
ADIPS recommends that women not known to have preexisting glucose abnormalities but with risk factors for gestational diabetes in pregnancy should be tested early in pregnancy.
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Moderate risk factors for gestational diabetes Ethnicity: Asian, Indian subcontinent, Aboriginal, Torres
Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African. BMI 25–35 kg/m2.
DIABETICMedicine Maternal age ≥ 40 years. Family history diabetes mellitus (first-degree relative with
diabetes mellitus or a sister with gestational diabetes). BMI > 35 kg/m2. Previous macrosomia (baby with birthweight > 4500 g
or > 90th centile). High risk factors for gestational diabetes Previous gestational diabetes. Previously elevated blood glucose level.
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Polycystic ovarian syndrome. Medications: corticosteroids, antipsychotics.
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Research: Care Delivery Twin pregnancies complicated by gestational diabetes mellitus: a single centre cohort study G. K. Dinham1, A. Henry1,2,3, S. A. Lowe1,2, N. Nassar4, K. Lui1,2, V. Spear2 and A. W. Shand1,2,4 1 School of Women’s and Children’s Health, University New South Wales Medicine, Kensington, NSW, 2Department of Obstetrics, Royal Hospital for Women, Randwick, NSW, 3Women’s and Children’s Health, St George Hospital, Kogarah, NSW, and 4Clinical and Population Perinatal Health Research, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
Accepted 19 January 2016
Abstract Aims In women with a twin pregnancy, to determine the incidence of, risk factors for and outcomes of women with gestational diabetes mellitus, and assess how these have changed with a change in gestational diabetes screening. Methods Retrospective cohort study of women with a twin pregnancy attending an Australian tertiary hospital, 2002– 2013. Information on gestational diabetes status, gestational diabetes risk factors and pregnancy outcomes was ascertained. Pregnancy outcomes included hypertensive disorders, twin birthweight centile and a composite adverse pregnancy outcome. Analysis was stratified pre/post screening protocol change (epoch 1: 2002–2009, epoch 2: 2010– 2013) and by gestational diabetes status.
Gestational diabetes was diagnosed in 86/982 (8.8%) women, increasing from 4.4% to 14.7% between epochs (P = 0.0001). The proportion of women with hypertensive disorders increased (11.7% vs. 13.4%, P = 0.009), but the proportion of infant’s birthweight > 90th centile decreased (11.0% vs. 7.6%, P = 0.02) between epochs. Overall, 33.6% of women had ≥ 1 risk factors for gestational diabetes. Three-quarters (73.7%) of women overall had an adverse pregnancy outcome, with a slightly higher proportion in women with gestational diabetes compared with those with no gestational diabetes (79.7% vs. 73.1%, P = 0.06). The rate of the adverse pregnancy outcome did not change by epoch, after adjusting for maternal and pregnancy risk factors (adjusted odds ratio = 0.96, 95% confidence interval 0.73–1.26). Results
Conclusions Almost 1 in 10 women with a twin pregnancy were diagnosed with gestational diabetes, with the incidence of gestational diabetes increasing threefold with a new screening protocol. The pregnancy outcomes of women with a twin pregnancy did not change with increased detection and treatment for gestational diabetes.
Diabet. Med. 00, 000–000 (2016)
Introduction Gestational diabetes mellitus is defined as carbohydrate intolerance resulting in hyperglycaemia of varying severity, with onset or first recognition during pregnancy [1]. The landmark observational Hyperglycaemia and Adverse Pregnancy Outcomes study found strong, linear associations between increasing maternal hyperglycaemia and adverse pregnancy outcomes, including Caesarean section, preeclampsia, perineal trauma, a large for gestational age infant and neonatal hypoglycaemia [2]. Recognition of these associations has led to a plethora of new screening guidelines for gestational diabetes, including the International Correspondence to: Antonia W. Shand. E-mail: [email protected]
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Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel, the Australasian Diabetes in Pregnancy Society (ADIPS) [4] and the World Health Organisation (WHO) [5]. The IADPSG and ADIPS guidelines recommend that women at increased risk of gestational diabetes should undergo blood testing for diabetes mellitus at the first antenatal visit [3,4]. ADIPS recommends fasting or random plasma glucose testing for ‘moderate risk’ women and a 75–g oral glucose tolerance test (75–g OGTT) for ‘high risk’ women, as defined in Appendix 1 [4]. In addition, both guidelines, recommend that all women not known to have diabetes mellitus have a 75–g OGTT at 24–28 weeks’ gestation [3,4]. Twin pregnancy is associated with adverse pregnancy outcomes, including an increased risk of gestational diabetes, pre-eclampsia and preterm birth [6]. Women with gestational
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Gestational diabetes mellitus in twin pregnancies G. K. Dinham et al.
What’s new? Rates of gestational diabetes in twin pregnancy increased threefold from 4.4% to 14.7% with a change towards universal early pregnancy glucose-tolerance testing. Adverse pregnancy outcomes in twin pregnancies did not change with increased screening and treatment of gestational diabetes, although there was a decrease in large for gestational age infants. Nearly half of women with a twin pregnancy had risk factors for gestational diabetes, apart from twin pregnancy.
diabetes and women with twin pregnancies frequently have shared risk factors, including older maternal age, obesity, polycystic ovarian syndrome, and the use of assisted reproductive technology [7–9]. It is uncertain how much gestational diabetes exacerbates the underlying maternal or fetal risks associated with a twin pregnancy. However, it is known that twin fetuses are at lower risk of macrosomia [11] than singletons, partly because of the very high rates of preterm birth [12], but also due to in utero placental size restrictions leading to higher rates of small for gestational age infants. In systematic reviews and meta-analyses, treatment of gestational diabetes compared with no treatment has been found to result in less pre-eclampsia and macrosomia [13] and lower rates of large for gestational age infants, shoulder dystocia and gestational hypertension [14]. However, of the two largest randomized controlled trials of treatment of gestational diabetes, one excluded twin pregnancies [15] and one included only small numbers of twin pregnancies [16]. Disappointingly, the Hyperglycaemia and Adverse Pregnancy Outcomes study also excluded women with twin pregnancies [2] and, hence, the IADPSG [3] and the ADIPS [4] guidelines, based on the Hyperglycaemia and Adverse Pregnancy Outcomes study, do not specifically mention twin pregnancy as a risk factor for gestational diabetes. Thus, clinicians have been left to use screening guidelines developed by observation or treatment of gestational diabetes in mostly singleton pregnancies, the appropriateness of which has not been investigated in twin pregnancies. The Royal Hospital for Women twins clinic, commenced in April 2009, recommended that all women with a twin pregnancy have screening for gestational diabetes twice during pregnancy, with a 75–g OGTT at 14–16 weeks and again at 26– 28 weeks’ gestation. Gestational diabetes was diagnosed if the blood glucose level was ≥ 5.5 mmol/l (99 mg/dl) at 0 h or ≥ 8.0 mmol/l (144 mg/dl) at 2 h. Prior to that time, women with a twin pregnancy received gestational diabetes screening, similar to women with a singleton pregnancy, in whom screening involved a two-step process: a 50–g glucose challenge test at 26–28 weeks (random, non-fasting),
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followed by a 75–g OGTT if the glucose challenge test was abnormal [blood glucose level ≥ 7.8 mmol/l (140 mg/dl) at 1 h]. The 75–g OGTT criteria for gestational diabetes diagnosis were the same in both epochs. The aim of this study was to assess in women with twin pregnancies, the pregnancy outcomes of women with gestational diabetes and the impact of changing gestational diabetes screening guidelines on gestational diabetes diagnoses, including whether this changed pregnancy outcomes. In addition we aimed to examine the proportion of women with a twin pregnancy with risk factors for gestational diabetes as defined by ADIPS.
Materials and methods The study was a 12-year retrospective cohort of all women with a twin pregnancy who delivered at the Royal Hospital for Women, Sydney, NSW, Australia between 1 January 2002 and 31 December 2013. The Royal Hospital for Women is a tertiary maternity hospital with over 4000 births per year and a neonatal intensive care unit. It is the also the main centre for laser for twin-to-twin transfusion syndrome in NSW [17]. Women were excluded if they had pre-existing diabetes mellitus. Where a woman had more than one twin pregnancy, only the first twin pregnancy was included. Demographic and pregnancy data were obtained from the electronic hospital records, Obstet and ObstetriX (Obstetrix Consortium, NSW Health). These databases contain information about all births of ≥ 20 weeks’ gestation (or 400 g birthweight where the gestational age is unknown), including maternal demographics, pregnancy, birth and infant outcomes, which are entered by a midwife at the point of care. More detailed information about women with gestational diabetes was also extracted from the Royal Hospital for Women Diabetes Clinic database and medical records. Maternal outcomes analysed included diagnosis of gestational diabetes, gestation at diagnosis and type of treatment for gestational diabetes. Pregnancy outcomes included mode of birth, induction of labour, maternal hypertensive disorders (pre-eclampsia, gestational hypertension and superimposed pre-eclampsia) classified according to the Society of Obstetric Medicine of Australia and New Zealand [18], prematurity < 37 weeks’ gestation, birthweight < 10th centile or birthweight > 90th centile (using twin birthweight centile charts [19]), congenital anomaly and perinatal death, a composite of stillbirth (birth with no signs of life ≥ 20 weeks’ gestation or birthweight > 400 g) and neonatal death (any infant death within 28 days of birth). A composite adverse pregnancy outcome comprising preterm birth, birthweight < 10th centile, birthweight > 90th centile, birth trauma, perinatal death, pre-eclampsia or gestational hypertension was also defined. Maternal characteristics that were assessed included age, BMI, parity and smoking. BMI (kg/m2) was calculated using a pre-pregnancy weight where known, or other pregnancy
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weight where pre-pregnancy weight was not known. Placental chorionicity was classified as dichorionic, monochorionic (monoamniotic or diamniotic) or unknown, based on placental histology, ultrasound findings or discordant sex where ultrasound or placental histology was not known. Nine broad ethnic groups were defined according to the Australian Standard Classification of Cultural and Ethnic Groups [20]. Six of the nine ethnic groups, Asian, Indian subcontinent, Middle Eastern, Aboriginal or Torres Strait Islander, Pacific Islander or Maori and non-white African, were classified as high-risk ethnicity according to the ADIPS criteria [4]. Where ethnicity was not known, country of birth was used as a surrogate. A family history of diabetes mellitus was defined as having a first-degree relative with diabetes mellitus or a sister with gestational diabetes. ADIPS risk status was defined based on ADIPS risk factors, and women were classified as having one or more medium risk, one or more high-risk factors or no risk factors (see Appendix 1). The cohort was divided into two epochs based on infant birth dates: epoch 1 (2002–2009) and epoch 2 (2010–2013). This was to account for the change in screening protocol for gestational diabetes after the commencement of the twins’ clinic in April 2009. Because of a lag time between commencement of the twins clinic, change in screening protocol and infant birth dates, the beginning of 2010 was chosen as reflective of a time when early pregnancy screening
would have been applied to all women with twin pregnancy at birth. Descriptive statistics were calculated to examine maternal characteristics and pregnancy outcomes by gestational diabetes status and epoch. The chi-squared test was used to assess the association between gestational diabetes, maternal characteristics including ADIPS risk factors, epoch of birth and pregnancy outcomes. Multivariate logistic regression analysis was then used to adjust for potential confounding by relevant maternal and pregnancy characteristics including maternal age, placental chorionicity, model of care and ADIPS risk factors and where P < 0.2 on univariate analysis. Given that chorionicity is one of the major risk factors for perinatal mortality we evaluated this specific factor in relation to perinatal mortality [21], to assess its contribution to overall adverse composite pregnancy outcome. Data were analysed using SAS 9.3 (SAS Inc., Cary, NC, USA) and a P-value < 0.05 was considered to be statistically significant. Ethics approval was obtained from the South Eastern Sydney Local Health District Human Research Ethics Committee, HREC Ref: 13/333 – LNR /13/POWH/718.
Results A flow chart of participants in the study is shown in Fig. 1. After exclusion of the women with pre-pregnancy diabetes
Women with a twin pregnancy who delivered at the Royal Hospital for Women, January 2002 – December 2013 n=995
Women with pre-GDM (n=9) and pregnancies where a woman had a second twin pregnancy (n=4) excluded n=982 women
No GDM n=896
Epoch 1 (January 2002December 2010) n=542
Epoch 2 (January 2010December 2013) n=354
GDM n=86
Epoch 1 (January 2002December 2010) n=25
Epoch 2 (January 2010December 2013) n=61
FIGURE 1 Flowchart of participants in the study.
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Gestational diabetes mellitus in twin pregnancies G. K. Dinham et al.
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with rates of gestational diabetes continuing to rise to 26.0% in 2013 (data not shown). Almost one quarter (23.1%) were diagnosed with gestational diabetes prior to 20 weeks’ gestation and 76.9% diagnosed beyond 20 weeks. Gestational diabetes diagnoses also increased at both < 20 weeks’ and ≥ 20 weeks’ gestation in epoch 2 compared with epoch 1 (P < 0.001). Maternal and infant outcomes by epoch are presented in Table 2. The proportion of women with hypertensive disorders increased significantly between epochs (11.7% epoch 1 vs. 13.4% epoch 2, P = 0.009), whereas the proportion of infants large for gestational age decreased (11.0% epoch 1 vs. 7.6% epoch 2, P = 0.02). No infant had a birthweight > 4000 g. Compared with epoch 1, there was a higher rate of perinatal death in epoch 2 (2.6% vs. 5.4%, P = 0.002), however, there was no difference in the rate of composite adverse pregnancy outcome between epochs (74.4% vs.
mellitus and the second pregnancies of women who had two twin pregnancies during the study period, 982 women with a twin pregnancy (1964 fetuses) were included in the analysis. Overall, gestational diabetes was diagnosed in 86 (8.8%) women, with 567 women who delivered in epoch 1 and 415 who delivered in epoch 2. Demographic characteristics and gestational diabetes status by epoch are shown in Table 1. Compared to epoch 1, women in epoch 2 were more likely to be ≥ 35 years of age (35.8% in epoch 1 vs. 43.4% in epoch 2, P = 0.001), to have a known monochorionic twin pregnancy (16.9% vs. 34.5%, P = 0.001), and less likely to have a pregnancy of unknown chorionicity (28.9% vs. 4.8%, P < 0.001). One third (34.6%) of women had one or more ADIPS risk factors for gestational diabetes, and this increased over time (26.8% vs. 45.3%, P = 0.001). The proportion of women diagnosed with gestational diabetes also increased, from 4.4% in epoch 1 to 14.7% in epoch 2 (P = 0.001),
Table 1 Demographic characteristics and gestational diabetes mellitus status of 982 women with a twin pregnancy by screening epoch
Maternal age (years) < 20 20–34 35–39 ≥ 40 Booking BMI (kg/m2) (n = 549) < 25 25–29.9 ≥ 30–34.9 ≥ 35 Parity (n = 417) 0 1 ≥2 Smoker Chorionicity Monochorionic Dichorionic Unknown ADIPS risk status† None ≥ 1 Medium risk ≥ 1 High risk Gestational diabetes Gestational diabetes diagnosis (n=78) < 20 weeks ≥ 20 weeks Gestational diabetes treatment Diet Insulin Insulin/oral hypoglycaemic
All women
Epoch 1 2002–2009
Epoch 2 2010–2013
N = 982
N = 567
N = 415
n
%
n
%
n
%
P*
43 556 278 105
4.4 56.6 28.3 10.7
29 335 156 47
5.1 59.1 27.5 8.3
14 221 122 58
3.4 53.3 29.4 14
0.001
358 120 42 28
65.2 21.9 7.6 5.1
127 44 20 12
62.6 21.7 9.9 5.9
231 76 22 16
67 22 6.4 4.6
0.13
140 198 79 47
33.6 47.5 18.9 4.8
60 90 41 27
31.4 47.1 21.5 4.8
80 108 38 20
35.4 47.8 16.8 4.8
0.2
239 559 184
24.3 56.9 18.7
96 307 164
16.9 54.1 28.9
143 252 20
34.5 60.7 4.8
0.0001
642 210 130 86
65.4 21.4 13.2 8.8
415 100 52 25
73.2 17.6 9.2 4.4
227 110 78 61
54.7 26.5 18.8 14.7
0.0001
18 60
1.8 6.1
6 17
1.1 3
12 43
2.9 10.4
0.0001
5.6 2.5 0.6
16 9 0
2.8 1.6 0
39 16 6
9.4 3.9 1.4
0.0001
55 25 6
0.9
0.0001
ADIPS, Australasian Diabetes In Pregnancy Society. *P-values indicate difference between epoch 1 and 2. † ADIPS risk criteria. Medium risk – Ethnicity: Asian, Indian subcontinent, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African or BMI 25–35 kg/m2. High risk – Previous gestational diabetes, previously elevated blood glucose level, maternal age ≥ 40 years, family history of diabetes (first-degree relative with diabetes or a sister with gestational diabetes), BMI > 35 kg/m2, polycystic ovarian syndrome, corticosteroids, antipsychotics.
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Table 2 Maternal and neonatal outcomes of 982 women with a twin pregnancy and their 1964 infants by screening epochs
Overall n Women Mode of delivery Any Caesarean section Caesarean section both twins Vaginal both twins Vaginal/Caesarean Induction of labour Hypertensive disorder† Infants Gestational age at birth < 37 weeks Birthweight centile‡ < 10th 10–90th > 90th Congenital anomaly Perinatal death§ Stillbirth Neonatal death Adverse pregnancy outcome||
%
N = 982
Epoch 1: 2002– 2009
Epoch 2: 2010– 2013
n
n
%
N = 567
%
P*
N = 415 0.17
660 648 322 12 267 121 N = 1964
67.2 66 32.8 1.2 27.2 12.3
391 384 176 7 90 66 N = 1134
68.9 67.7 31 1.2 15.9 11.7
269 264 146 5 177 55 N = 830
64.8 63.6 35.2 1.2 30.6 13.4
1280
65.2
743
65.5
537
64.7
178 1576 185 34 74 42 32 1448
9.1 80.2 9.4 1.7 3.8 2.1 1.6 73.7
97 901 123 22 29 14 15 844
8.7 80.4 11 1.9 2.6 1.2 1.3 74.4
81 675 62 12 45 28 17 604
9.9 82.5 7.6 1.5 5.4 3.4 2.1 72.8
0.0001 0.009 0.62
0.49 REF 0.02 0.4 0.002
0.4
*P-values indicate difference between epoch 1 and 2. Gestational hypertension or pre-eclampsia. ‡ Using twin birthweight centile charts. § Stillbirth or neonatal death in hospital. || Defined as preterm birth < 37 weeks, perinatal death, birthweight < 10th centile, birthweight > 90th centile or 4500 g, birth trauma, preeclampsia, gestational hypertension or pre-eclampsia. †
72.8%, P = 0.4). Even after adjusting for maternal and pregnancy risk factors, there remained no association between the composite adverse pregnancy outcome and epoch [adjusted odds ratio (AOR) 0.96, 95% confidence interval (CI) 0.73–1.26]. Overall, women with a monochorionic twin pregnancy were almost four times more likely to have a composite adverse pregnancy outcome (including perinatal mortality) than women with a dichorionic twin pregnancy [odds ratio (OR) 3.8, 95% CI 2.8–5.3]. Maternal ADIPS risk status and maternal and infant outcomes, by maternal gestational diabetes status, are presented in Table 3. Two thirds of women (69.8%) with gestational diabetes had any ADIPS risk factors for gestational diabetes, compared with fewer than a third of women without gestational diabetes (31.2%) (P = 0.001). Women with gestational diabetes had a higher rate of hypertensive disorders (19.8% vs. 11.6%, P = 0.003), and a trend towards more adverse pregnancy outcomes (79.7% vs. 73.1%; P = 0.06) compared with women without gestational diabetes. After adjusting for maternal and pregnancy risk factors, women with gestational diabetes were almost 1.6 times more likely to have an adverse pregnancy outcome (AOR 1.58, 95% CI 1.02–2.47) than women without gestational diabetes. There were no differences in any pregnancy outcomes in women with gestational diabetes, if they were treated with diet alone compared to whether they
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were treated with insulin and/or oral hypoglycaemic therapy (P > 0.05).
Discussion This is one of the largest contemporary cohort studies of twin pregnancies with a well-defined screening policy for gestational diabetes applied in the study setting. The overall proportion of women with twin pregnancies diagnosed with gestational diabetes was 8.8%, which increased more than threefold with a change in screening from 4.4% to 14.7%. Women with gestational diabetes were more likely to have hypertensive disorders, late preterm birth and composite adverse pregnancy outcomes than those without gestational diabetes. Despite overall findings that about one third of women had risk factors for gestational diabetes and both these and pregnancy hypertension increased even with a change in gestational diabetes screening, there was a reduction in large for gestational age infants between epochs, but no change in composite adverse pregnancy outcomes. The incidence of gestational diabetes in this study was higher than that reported in the NSW population [9], a Canadian population-based study of twin pregnancies (7.3%) [11] and a single centre USA study of twin pregnancies (6.5%) [22], but lower than for Chinese twin pregnancies screened using the new IADPSG glucose thresholds (20.4%) [23]. However, the
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Table 3 Mother ADIPS risk status and mother and infant outcomes of women with a twin pregnancy by gestational diabetes mellitus status No gestational diabetes n Mother ADIPS risk status† No medium or high risk ≥ 1 Medium risk ≥ 1 High risk Mode of delivery Any Caesarean section Caesarean section both twins Vaginal both twins Vaginal/Caesarean Induction of Labour Hypertensive disorder‡ Infant Gestational age at birth < 37 weeks Birthweight centile§ < 10th 10th–90th > 90th Neonatal complication birth Hypoglycaemia Respiratory distress Congenital anomaly Perinatal Death|| Stillbirth Neonatal death Adverse pregnancy outcome¶
Gestational diabetes %
N = 896
n
%
P*
N = 86 0.001
616 185 95
68.8 20.6 10.6
26 25 35
30.2 29.1 40.7
597 586 299 11 194 104 N = 1792
66.6 65.4 33.4 1.2 21.6 11.6
63 62 23 1 23 17 N = 172
73.3 72.1 26.6 1.2 26.7 19.8
1157
64.6
123
71.5
164 1433 171
9.3 81.1 9.7
14 143 7
8.2 83.6 8.2
0.59 REF 0.5
20 277 33 71 41 30 1311
1.1 15.5 1.8 4.0 2.3 1.7 73.1
19 34 1 3 1 2 137
11.1 19.8 0.6 1.7 0.6 1.2 79.7
0.0001 0.13 0.2 0.3
0.2
0.1 0.0003 0.08
0.06
ADIPS, Australasian Diabetes In Pregnancy Society. *P-value indicates difference between women with and without gestational diabetes. ADIPS criteria. Medium risk – ethnicity: Asian, Indian subcontinent, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African or BMI 25–35 kg/m2. High risk – previous gestational diabetes, previously elevated blood glucose level, maternal age ≥ 40 years, family history of diabetes mellitus (first-degree relative with diabetes or a sister with gestational diabetes), BMI > 35 kg/m2, polycystic ovarian syndrome, corticosteroids, antipsychotics. ‡ Gestational hypertension or pre-eclampsia. § Using twin birthweight centile charts. || Stillbirth or neonatal death in hospital. ¶ Defined as preterm birth < 37 weeks, perinatal death, birthweight < 10th centile, birthweight > 90th centile or 4500 g, birth trauma, preeclampsia or gestational hypertension. †
increase in gestational diabetes diagnoses with a change in gestational diabetes screening seen in this study is consistent with other studies [11,24] and the recent increase seen in the overall NSW maternity population (4.8% in 2008 to 7.4% in 2012) [9], which may be explained by change in ADIPS screening guidelines. Evidence of the impact of changing gestational diabetes screening criteria was recently reported in a study that reported a twofold increase in the incidence of gestational diabetes in singleton pregnancies [25]. It is also possible that the change in incidence with a change in gestational diabetes screening may be explained by a real change in risk factors for gestational diabetes, such as maternal age and BMI, and/or improved identification and documentation of risk factors. Overall, we found that one third of all women with a twin pregnancy had at least one ADIPS risk factor, which almost doubled from 26.8% to 45.3% in the most recent epoch. This translates into about half of women with a twin pregnancy who would meet ADIPS criteria for early gestational diabetes
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screening. For the women who are ultimately diagnosed with gestational diabetes, but do not meet ADIPS criteria for early screening, screening at 26–28 weeks’ gestation may result in later detection and commencement of treatment than if all women with a twin pregnancy had screening for gestational diabetes in early pregnancy. The impact of earlier screening and subsequent treatment is difficult to predict, given that the randomized controlled trials of treatment for gestational diabetes [15,16,26] have been predominantly undertaken in singleton pregnancies, and the optimal timing of diagnosis in singleton pregnancies, let alone twin pregnancies, remains unclear [27]. The cost-effectiveness of universal early screening with the 75–g OGTT has not been evaluated; however, the procedure discomfort and inconvenience are well recognized. In addition, increased screening, higher rates of diagnosis and treatment generated an increase in clinic visits, laboratory tests and costs, as well as inconvenience to women who had to see both diabetes and twin clinics. Thus, our findings suggest that an assessment of risk factors for gestational diabetes should be
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undertaken for women with twin pregnancies as is recommended for singleton pregnancies, in order to determine whether early pregnancy screening for gestational diabetes should be undertaken. Women with twin pregnancies and gestational diabetes were found to have higher rates of hypertensive disorders, which is consistent with other studies [8,11,28,29]. However, despite increased rates of gestational diabetes diagnoses with a change in gestational diabetes screening, there was no decrease in hypertensive disorders. This contrasts with a recent study, which found decreased rates of pre-eclampsia in women with twin pregnancies following a change of gestational diabetes screening policy that resulted in increased diagnosis and treatment of gestational diabetes [23]. In terms of infant characteristics, the number of large for gestational age infants (using twin charts) decreased with a change in gestational diabetes screening, and there was no association found between gestational diabetes and large for gestational age. In some studies of twin pregnancies, women with gestational diabetes have been found to have higher rates of large for gestational age infants [8,11] and Caesarean section [11]. By contrast, an Israeli cohort study of twin pregnancies found no difference in Caesarean section rates in women with gestational diabetes compared with no gestational diabetes and a reduction in perinatal mortality in infants born to women with gestational diabetes [29], which is consistent with our study. Given that twins are smaller than singletons at all gestational ages, and therefore at lower risk of shoulder dystocia, birth trauma and significant maternal perineal trauma, and that no infant was > 4000 g, the clinical significance of this reduction in the rate of large for gestational age infants with a change in screening protocol is uncertain. Although the rate of perinatal death doubled between epochs, we found that maternal gestational diabetes status was not associated with an increased rate of perinatal death, which is in keeping with findings from other studies of twin pregnancies [6,8,29]. However, the increased mortality may be due to an increasing prevalence of known monochorionic twin pregnancies attending the hospital; the proportion of which doubled to one third of twin pregnancies from epoch 1 to epoch 2 (despite the larger proportion of unknown chorionicity in epoch 1), particularly with the establishment of the NSW Fetal Therapy Centre undertaking laser for twin-to-twin transfusion during this time [17]. We also found that women with a monochorionic pregnancy were up to four times more likely to have the composite adverse pregnancy outcome (including perinatal mortality) than women with a dichorionic twin pregnancy. This is consistent with other studies, which have shown that monochorionic pregnancies, especially those complicated by twin–twin transfusion syndrome or intrauterine growth restriction, carry an increased risk of perinatal death compared with dichorionic twin pregnancies [21]. The strength of this study was the ethnic diversity of the study population, which increases its external validity.
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However, it was limited by the single centre, retrospective study design and use of routinely collected data over a long period. In general, the ascertainment of demographic characteristics and perinatal outcomes was good and increased over time. But the large proportion of unknown placental chorionicity was a weakness, as this is a potential confounder of fetal and neonatal outcomes in twin pregnancies. The diagnostic blood glucose thresholds recommended in the new IADPSG and ADIPS guidelines were not used in this study, and the effect that these criteria would have on gestational diabetes diagnoses and the outcomes of twin pregnancies is not known, although other studies in twin and singleton pregnancies have found higher rates of gestational diabetes diagnoses after a change to new glucose thresholds [23,25,30]. In addition, the blood glucose levels or HbA1c levels of women with gestational diabetes were not known, nor whether women with gestational diabetes were diagnosed with diabetes mellitus post-partum. In conclusion, this study has shown that the rate of gestational diabetes diagnoses in women with a twin pregnancy increased threefold with a change in screening, and that women with gestational diabetes and their infants have poorer perinatal outcomes than those without gestational diabetes. With improved detection of gestational diabetes there has been a reduction in large for gestational age infants, however, it is debateable as to whether this is a meaningful clinical outcome in twin pregnancies. Overall, our findings suggest that for women with a twin pregnancy, ADIPS risk factors for gestational diabetes should be used to determine timing and type of screening for gestational diabetes. Further studies of gestational diabetes should include women with twin pregnancies, taking into account placental chorionicity and blood glucose levels at diagnosis and during pregnancy.
Funding sources
None.
Competing interests
None declared.
Acknowledgements
Natasha Nassar is supported by an NHMRC Career Development Fellowship (APP1067066). The authors wish to thank the diabetic educators who maintained the diabetes database and the midwives for data collection.
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Appendix 1 Australasian Diabetes in Pregnancy Society (ADIPS) risk factors for gestational diabetes in pregnancy
ADIPS recommends that women not known to have preexisting glucose abnormalities but with risk factors for gestational diabetes in pregnancy should be tested early in pregnancy.
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Moderate risk factors for gestational diabetes Ethnicity: Asian, Indian subcontinent, Aboriginal, Torres
Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African. BMI 25–35 kg/m2.
DIABETICMedicine Maternal age ≥ 40 years. Family history diabetes mellitus (first-degree relative with
diabetes mellitus or a sister with gestational diabetes). BMI > 35 kg/m2. Previous macrosomia (baby with birthweight > 4500 g
or > 90th centile). High risk factors for gestational diabetes Previous gestational diabetes. Previously elevated blood glucose level.
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Polycystic ovarian syndrome. Medications: corticosteroids, antipsychotics.
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