Differing Causes of Pregnancy Loss in Type 1 and Type 2 Diabetes

Home , Birth trauma (physical), Stillbirth

Pathophysiology/Complications ORIGINAL ARTICLE

1,2 2 TIM CUNDY, MD PAUL MCPHERSON, FRACOG (6,10–13). A number of centers have 1 2 GREG GAMBLE, MSC PATRICK HENLEY, FRACP reported higher rates of stillbirth or con- 2 2 LEONIE NEALE, RM JANET ROWAN, FRACP 2 genital anomalies in type 2 diabetic preg- ROSE ELDER, FRACOG nancy, suggesting that the outcomes of pregnancy in type 2 diabetes can be worse than that for type 1 diabetes (6,14,15). OBJECTIVE — Women with type 2 and type 1 diabetes have differing risk factors for preg- There are many reasons why pregnancy loss. We compared the rates and causes of pregnancy loss in women with type 1 and type 2 diabetes. nancy and neonatal losses might differ between type 1 and type 2 diabetes. Women RESEARCH DESIGN AND METHODS — We utilized prospectively collected data on with type 2 diabetes tend to be older, all pregnancies in a 20-year period (1986–2005) from a single center with a high prevalence of poorer, more obese, of higher parity, and type 2 diabetes. Pregnancy losses included terminations for medical reasons and deaths up to 1 Ͻ to be from minority communities, all risk month postpartum but not spontaneous pregnancy losses 20 weeks’ gestation. factors for poor pregnancy outcome, RESULTS — There were 870 pregnancies in women with known diabetes (330 with type 1 whereas women with type 1 diabetes are and 540 with type 2 diabetes) and 325 in women with diabetes diagnosed in pregnancy but more likely to have vascular complica- persisting postpartum (97% type 2 diabetes). The rate of pregnancy loss was similar in type 1 and tions of diabetes. In this article, we report type 2 diabetes (2.6 vs. 3.7%, P ϭ 0.39), but the causes of pregnancy loss differed. In type 1 20-year data from a single center on the diabetes Ͼ75% were attributable to major congenital anomalies or prematurity; in type 2 dia- Ͼ ϭ rates and causes of pregnancy loss in betes 75% were attributable to stillbirth or chorioamnionitis (P 0.017). Women with type 2 women with type 1 and type 2 diabetes. and type 1 diabetes had similar A1C at presentation and near term, but the former were older (P Ͻ 0.001) and more obese (P Ͻ 0.0001). RESEARCH DESIGN AND CONCLUSIONS — There are significant differences in the main causes of pregnancy loss in METHODS — Data were collected women with type 1 and type 2 diabetes. The higher rates of stillbirth in women with type 2 prospectively in diabetic women attend- diabetes, suggest that other features, such as obesity, contribute significantly to pregnancy losses. ing the Diabetes Pregnancy Service at the National Women’s Hospital, whose preg- Diabetes Care 30:2603–2607, 2007 nancies ended between 1 January 1986 and 31 December 2005. The service pro- efore the discovery of insulin, a to those in nondiabetic women (4–7). vides pregnancy care to diabetic women woman with type 1 diabetes had al- Pregnancy losses due to congenital anom- throughout the central, northern, and B most no chance of successful deliv- alies (resulting from poor glycemic con- western areas of Auckland. The region has ery of a healthy baby. With the advent of trol in early pregnancy) have proven a large population of Polynesian origin, insulin treatment, pregnancy losses con- harder to reduce, so terminations of preg- comprising the native Maôri and people tinued to be high, predominantly through nancy or neonatal death resulting from from various Pacific Island nations and an stillbirth, but neonatal deaths due to con- severe congenital anomalies now account increasing population of south and east genital malformation, birth trauma, hy- for a large proportion of pregnancy losses Asian origin. Type 2 diabetes is common poglycemia, and respiratory distress in women with type 1 diabetes (6,8,9). in these groups (16). This report incorpo- syndrome all took their toll (1). Substan- The developing epidemic of obesity rates data included in two previously tial improvement in the rates of perinatal over the last two decades has seen a sub- published studies (6,17). Data collected mortality followed the development of stantial reduction in the age of onset of included age, ethnic origin, parity, smok- centralized care and regimens focused on type 2 diabetes and its emergence in ing status, height, and prepregnancy achieving strict glycemic control and en- women of childbearing age. In many areas weight (from which BMI was calculated). suring early delivery (2,3). Several centers of the world, the number of pregnancies have reported stillbirth rates in women in women with type 2 diabetes now ex- Classification of diabetes with type 1 diabetes that are comparable ceeds that of women with type 1 diabetes Patients were classified as having type 1 diabetes if insulin had been used since ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● diagnosis, or if there were serologic mark- From the 1Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, ers of islet autoimmunity. Patients were Auckland, New Zealand; and the 2Diabetes Pregnancy Service, National Women’s Health, Auckland City classified as having type 2 diabetes if they Hospital, Auckland, New Zealand. were not ketosis prone and did not re- Address correspondence and reprint requests to Dr. Tim Cundy, Department of Medicine, Faculty of quire insulin for extended periods. Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: [email protected]. Women with what we term “newly recog- Received for publication 20 March 2007 and accepted in revised form 15 June 2007. nized ” diabetes were diagnosed in preg- Published ahead of print at http://care.diabetesjournals.org on 22 June 2007. DOI: 10.2337/dc07-0555. nancy as having gestational diabetes, but A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion on glucose tolerance testing 6 weeks post- factors for many substances. partum still had diabetes, according to © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby World Health Organization criteria. The marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. majority of these women probably had

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Table 1—Demographic features

Type 1 Type 2 Type 2 Type 1 diabetes diabetes diabetes diabetes Genetic All (known) (known) (new) (new) causes Number of pregnancies 1,200 330 540 314 11 5 Number of twin pregnancies 16 8710 0 Age (years) 31.9 Ϯ 5.5 29.2 Ϯ 5.2 33.0 Ϯ 5.1 32.9 Ϯ 5.2 28.5 Ϯ 6.3 35.4 Ϯ 5.6 Prepregnancy BMI (kg/m2) 31.1 Ϯ 7.9 25.2 Ϯ 4.5 33.9 Ϯ 7.4 33.3 Ϯ 7.9 23.2 Ϯ 3.8 23.1 Ϯ 5.1 Nulliparous (%) 29 50 18 24 46 40 Smoking in pregnancy (%) 15.3 13.6 20.2 8.6 4.3 0 Gestational age at presentation to service 16.0 Ϯ 9.7 9.7 Ϯ 5.3 14.5 Ϯ 7.9 25.3 Ϯ 9.4 21.4 Ϯ 7.8 12.0 Ϯ 10.2 (weeks) A1C at presentation (%)* 7.6 Ϯ 1.6 7.6 Ϯ 1.6 7.6 Ϯ 1.7 7.1 Ϯ 1.3 8.1 Ϯ 3.3 6.7 Ϯ 0.7 A1C at term (%)† 6.1 Ϯ 0.9 6.1 Ϯ 0.9 6.1 Ϯ 0.9 6.4 Ϯ 1.0 6.7 Ϯ 1.3 5.6 Ϯ 0.2 Number on insulin before pregnancy 395 (33) 329 (99.7) 57 (10.6) 0 (0) 0 (0) 1 (20) Number not on insulin in pregnancy 61 (5.0) 0 (0) 17 (3.1) 43 (13.7) 1 (9.1) 0 (0) Proportion with induction of labor 83.9 89.7 83.5 79.2 72.7 60.0 or elective Cesarean section (%) Gestational age at induction of labor or 37.5 Ϯ 2.7 37.2 Ϯ 2.3 37.4 Ϯ 3.1 37.9 Ϯ 2.4 37.6 Ϯ 1.8 35.0 Ϯ 5.2 elective Cesarean section (weeks) Cesarean section rate (%) 51.0 56.2 53.2 42.9 27.2 20.0 Ethnic group (%) European 35 91 16 6 64 100 Ma៮ori/Pacific 52 7 67 74 18 0 All others 13 2 17 20 18 0 Data are means Ϯ SD or n (%) recorded in *583 pregnancies or †547 pregnancies. undetected diabetes antedating their Pregnancy losses RESULTS — In the 20-year period, pregnancy. Data are included also from a The time of pregnancy loss was recorded there were 1,200 pregnancies in 903 small group of women with inherited as either elective termination for medical women, including 16 twin pregnancies. forms of diabetes, proven by genetic test- reasons, intermediate fetal death (20–28 In 325 women (27%), diabetes was un- ing. As these tests have become available weeks’ gestation), late fetal death (28 recognized before pregnancy; of these, only in recent years, it is probable that some weeks’ gestation to term), or early neona- 314 (97%) had type 2 diabetes. Because women with genetic forms of diabetes have tal death (1 day to 1 month postpartum). they were usually identified by screening been classified as having type 2 diabetes. Spontaneous miscarriages before 20 for gestational diabetes, women with Management of diabetes and weeks’ gestation and terminations for newly recognized diabetes presented to pregnancy nonmedical reasons were not included, our diabetes pregnancy service later in All subjects undertook self-blood glucose because complete ascertainment was not gestation than women with known diabe- Ͻ monitoring. Insulin doses were adjusted possible. The primary cause of pregnancy tes (P 0.0005). Women with known type to try to maintain fasting blood glucose in loss was assigned to one of five categories: 2 diabetes presented an average 5 weeks the range 4.0–5.5 mmol/l and 2-h post- major congenital anomalies, prematurity, later in gestation than women with known Ͻ prandial levels Ͻ6.8 mmol/l. Glycemic chorioamnionitis, unexplained stillbirth type 1 diabetes (P 0.0001) (Table 1). control was assessed by A1C (nondiabetic (fetal death in utero), asphyxia during de- The A1C at presentation was similar values in the first trimester 4.6–5.6%). livery, or other causes. Chorioamnionitis in women with known type 1 and type 2 This assay was not accessible locally until was diagnosed by the findings of inflam- diabetes. Women with newly recognized 1997, so these data are available for only matory cells in the placenta and positive type 2 diabetes had a lower A1C at pre- 583 pregnancies. Standard antenatal care bacterial cultures of amniotic fluid. sentation than women with known type 2 included an ultrasound scan performed at Statistics diabetes (P ϭ 0.0047). Women with 18–22 weeks’ gestation to screen for fetal Proportions were compared using the ␹2 newly recognized diabetes did not differ malformations. If detected before 24 test and Fisher’s exact test. Mean values in age, BMI, or ethnic group distribution weeks’ gestation, women with fetuses were compared by Student’s t test and from women in the respective group of with major malformation were offered ANOVA, with Tukey’s post hoc test. Re- known diabetes. Women with type 2 di- termination of pregnancy. In otherwise sults are given as mean Ϯ SD. Nonnor- abetes had significantly greater BMI than uncomplicated pregnancies, labor was mally distributed variables were compared women with type 1 diabetes (P Ͻ 0.0001) induced (or elective Cesarean section un- by nonparametric tests. All analyses were and were more commonly of non- dertaken) between 37 and 40 weeks’ performed using SAS version 9.1 (SAS European descent (P Ͻ 0.0001) (Table 1). gestation in women who had not deliv- Institute). CIs were calculated using the All women with type 1 diabetes and ered earlier. Neonatologists attended all Confidence Interval Analysis Program 97% of women with type 2 diabetes were deliveries. version 2.1.1 (BMJ Publications). treated with insulin during pregnancy,

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Table 2—Timing of pregnancy loss

Elective Number of termination Intermediate Late Early Total fetuses* Ͻ24 weeks fetal death fetal death neonatal death losses Type 1 diabetes (known) 338 5 (1.5) 1 (0.3) 0 (0) 3 (0.9) 9 (2.7) Type 2 diabetes (known) 547 3 (0.5) 7 (1.3) 6 (1.1) 3 (0.5) 19 (3.4) Type 1 diabetes (newly recognized) 11 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Type 2 diabetes (newly recognized) 315 0 (0) 4 (1.3) 5 (1.6) 4 (1.3) 13 (4.1) Other diabetes 5 0 (0) 0 (0) 0 (0) 1 (20) 1 (20) Total 1,216 8 (0.6) 12 (1.0) 11 (0.9) 11 (0.9) 42 (3.4) Data are n (%). *Includes twin pregnancies. but only 10.6% of women with known type 2 diabetes. There were 18 stillbirths, anomalies or prematurity, whereas in type 2 diabetes used insulin before preg- 17 of which were in women with known type 2 diabetes Ͼ75% of losses were due nancy. Mean A1C values near term were or newly recognized type 2 diabetes. The to stillbirth, chorioamnionitis, or birth as- similar in women with known type 1 and stillbirths clustered in two groups: eight phyxia (Fig. 2). Stillbirth was significantly known type 2 diabetes. Women with newly occurring between 22 and 29 weeks’ and more prevalent in type 2 than in type 1 recognized diabetes had higher mean A1C 10 between 35 and 42 weeks’ gestation diabetes (P ϭ 0.028). values near term than women with known (Fig. 1). The mean pregnancy BMI of To examine secular trends, we com- diabetes (P ϭ 0.011) (Table 1), reflecting women with stillbirths was 2 kg/m2 pared pregnancy losses across the two 10- their shorter duration of treatment. greater than the mean of all women with year periods of the study (1986–1995 There were a total of 42 pregnancy type 2 diabetes (P ϭ 0.084). The woman and 1996–2005). There were no substan- losses, 41 of which were in women with who had a stillbirth at 42 weeks’ gestation tial changes to diabetes management or known type 1, known type 2, or newly had declined elective induction of labor. fetal monitoring protocols over this time. recognized type 2 diabetes. The timing of Comparing women with known or newly In women with type 1 diabetes (both the pregnancy loss according to type of recognized type 1 diabetes with known or known and newly recognized), the rate of diabetes is shown in Table 2. Comparing newly recognized type 2 diabetes, the pregnancy loss was similar in the two pe- women with known or newly recognized cause of pregnancy loss differed signifi- riods (2.0% [95% CI 0.4–5.8] vs. 3.1% type 1 diabetes with known or newly rec- cantly between the groups (P ϭ 0.017). [1.2–6.7]). In women with type 2 diabe- ognized type 2 diabetes, there was a sig- More than 75% of pregnancy losses in tes (both known and newly recognized), nificant difference in the distribution of type 1 diabetes were due to congenital it fell from 4.9% (3.0–7.5) to 2.8% (1.5– pregnancy losses (P ϭ 0.006), with intermediate and late fetal losses being uncom- mon in type 1 diabetes. The causes of pregnancy loss are shown in Fig. 1. Twelve pregnancies were lost as a direct result of severe congenital anomalies; five were in women with type 1 and six in women with type 2 diabetes. In seven of these cases, the pregnancy was terminated after identification of severe malformations. In three cases (all in women with type 1 diabetes), the fetuses were affected by aneuploidy (trisomy 21 or trisomy 18). One baby born to a woman with mitochondrial diabetes died at the age of 10 days from a severe congenital cardiac anomaly. Four pregnancy losses were due to severe prematurity (the result of preterm labor at 23–30 weeks’ gestation); in two cases, one of a twin pair was lost, and in two prematurity was the consequence of severe preeclampsia. Two babies born to women with newly recognized type 2 diabetes were born with se- Figure 1—Timing and cause of pregnancy loss in type 1 and type 2 diabetes (including newly vere hypoxia and died at 3 and 5 days of recognized diabetes). Symbols beneath the lower dotted line represent terminations of pregnancy age, respectively. Five pregnancies were Ͻ24 weeks’ gestation; symbols above the upper dotted line represent early neonatal deaths. Causes lost as a result of chorioamnionitis, all in of pregnancy loss are indicated by the following symbols: o, congenital anomalies; u, prematurity; f, women with known or newly recognized chorioamnionitis; E, unexplained stillbirth; F, birth asphyxia; , termination for severe hyperemesis.

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age (22), but the difference in mean age between the women with type 1 and women with type 2 diabetes was only 3 years. Maternal obesity is strongly linked to pregnancy loss (23–25). For example, in the study of Kristensen et al. (25), the risk of stillbirth and neonatal death was doubled in women with a mean BMI Ͼ30 kg/m2. The prepregnancy BMI exceeded this value in Ͼ70% of our subjects with type 2 diabetes. Maternal obesity, pov- erty, and hyperglycemia are all risk factors for chorioamnionitis (23,26,27). It is likely that obesity and low socioeconomic status (which cluster together) are major additional risk factors for pregnancy loss in our type 2 diabetes population. Women with known type 2 diabetes typically present later to the Diabetes Pregnancy Service than women with known type 1 diabetes. This likely reflects the social disadvantage of many women with type 2 diabetes, lack of awareness (many had successful pregnancies before Figure 2—Rates and causes of pregnancy loss in type 1 and type 2 diabetes (including newly developing diabetes), and a lack of aware- recognized diabetes). The scale indicates percentage of the total number of fetuses. ness of referring physicians. However, the glycemic control of women with type 2 4.8), mainly because of a lower rate of late lies in women with diabetes is related to diabetes was similar to that of women with type 1 diabetes, both at presentation stillbirth (2.3% falling to 0.6%, P ϭ glycemic control in early pregnancy and near term, so it is not clear what im- 0.081). In the first decade, women with (18,19). Although effective prepregnancy pact earlier referral in pregnancy might known type 2 diabetes presented to our counseling reduces rates of congenital have. The temporal association between service at a significantly later gestation anomalies (20), it has proven hard to the earlier referral of women with type 2 than in the second decade (1986–1995: achieve nondiabetic rates (6,8,9). Three diabetes and a lower rate of late stillbirth 16.5 Ϯ 8.0 weeks vs. 1996–2005: 13.0 Ϯ of 12 pregnancy losses attributable to 7.5; P Ͻ 0.0001). The proportion of in the second decade of this study is en- congenital anomalies in our study were couraging, although one cannot infer cau- women with type 2 diabetes whose diabe- the result of fetal aneuploidy. The risk of tes was not recognized before pregnancy sation. aneuploidy is not related to glycemic con- We have argued that women with decreased significantly in the second de- trol, and if these losses are excluded from cade (1986–1995: 43% vs. 1996–2005: gestational diabetes who are shown to the calculation, then the rate of pregnancy have diabetes on early postpartum testing 32%; P ϭ 0.0007). In the second decade, loss due to congenital anomalies was the the age at presentation of women with should be considered as having newly same in type 1 and type 2 diabetes (0.6 vs. recognized diabetes that likely antedated known diabetes was just over a year 0.7%). Over 20 years, mean maternal age greater than in the first decade (P Ͻ 0.04; the pregnancy. Such pregnancies have the increased in both type 1 and type 2 dia- same risk of pregnancy loss and major both type 1 and type 2 diabetes), and the betes, reflecting changes in patterns of proportion of women who smoked in congenital anomalies as established dia- childbearing in the general population. In betes (6,17). Others (28) have also com- pregnancy decreased from 20% (1986– addition to an increased risk of aneu- ϭ mented that the current definition of 1995) to 15% (1996–2005) (P 0.014). ploidy, later pregnancy is associated with In women with known type 2 diabetes, gestational diabetes is unhelpful as it increased rates of twinning and stillbirth groups together women with very differ- the Cesarean section rate increased from (21–23). 48% (in 1986–1995) to 58% (in 1996– ing degrees of glucose intolerance and, ϭ In type 2 diabetes, the major causes of presumably, different degrees of risk. 2005) (P 0.033), but Cesarean section pregnancy loss were stillbirth, birth as- rates were otherwise unchanged. Most women with newly recognized dia- phyxia, and chorioamnionitis. Unex- betes have type 2 diabetes and share the CONCLUSIONS — In this 20-year plained stillbirth and chorioamnionitis same demographic and anthropometric prospective study, we found that the rate were strikingly more prevalent in women features as women with known type 2 di- of pregnancy loss was similar in type 1 with type 2 diabetes than in women with abetes. In our population, for every three and type 2 diabetes, but the causes of type 1 diabetes. There were two clusters women with known type 2 diabetes we pregnancy loss differed significantly. In in unexplained stillbirths, and it is possi- saw two with newly recognized type 2 di- type 1 diabetes, the main causes were ma- ble that some in the early cluster (20–29 abetes. However, this ratio has changed, jor congenital anomalies and neonatal weeks’ gestation) were the result of unrec- and in the second decade the proportion complications of prematurity. The in- ognized chorioamnionitis (Fig. 1). Still- in whom type 2 diabetes was previously creased rate of major congenital anoma- birth is associated with greater maternal unrecognized was significantly smaller.

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