BMJ  2004;328:915 (17 April), doi:10.1136/bmj.38043.583160.EE (published 5 April 2004)

Paper

Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands

¹ Department of Obstetrics, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, Netherlands, ² Department of Internal Medicine and Endocrinology, University Medical Center Utrecht

Abstract

Objective To investigate maternal, perinatal, and neonatal outcomes of pregnancies in women with type 1 diabetes in the Netherlands.

Design Nationwide prospective cohort study.

Setting All 118 hospitals in the Netherlands.

Participants 323 women with type 1 diabetes who became pregnant between 1 April 1999 and 1 April 2000.

Main outcome measures Maternal, perinatal, and neonatal outcomes of pregnancy.

Results 84% (n = 271) of the pregnancies were planned. Glycaemic control early in pregnancy was good in most women (HbA_1c 7.0% in 75% (n = 212) of the population), and folic acid supplementation was adequate in 70% (n = 226). 314 pregnancies that went beyond 24 weeks' gestation resulted in 324 infants. The rates of pre-eclampsia (40; 12.7%), preterm delivery (101; 32.2%), caesarean section (139; 44.3%), maternal mortality (2; 0.6%), congenital malformations (29; 8.8%), perinatal mortality (9; 2.8%), and macrosomia (146; 45.1%) were considerably higher than in the general population. Neonatal morbidity (one or more complications) was extremely high (260; 80.2%). The incidence of major congenital malformations was significantly lower in planned pregnancies than in unplanned pregnancies (4.2% (n = 11) v 12.2% (n = 6); relative risk 0.34, 95% confidence interval 0.13 to 0.88).

Conclusion Despite a high frequency of planned pregnancies, resulting in overall good glycaemic control (early) in pregnancy and a high rate of adequate use of folic acid, maternal and perinatal complications were still increased in women with type 1 diabetes. Neonatal morbidity, especially hypoglycaemia, was also extremely high. Near optimal maternal glycaemic control (HbA_1c 7.0%) apparently is not good enough.

Introduction

A goal of the St Vincent declaration is that the outcomes of pregnancy among diabetic women should approximate those of non-diabetic women.¹ The strategy for achieving this is to motivate diabetic women to plan their pregnancies, optimise glycaemic control, and start folic acid supplementation before conception.

Data from centres with a special interest in diabetes and pregnancy have found that outcomes of pregnancy in women with type 1 diabetes approached those of the non-diabetic population.^2-4 However, other large population studies in the United Kingdom have shown high levels of non-attendance at preconceptional care facilities, poor glycaemic control, and poor pregnancy outcome, with high rates of congenital malformations. ^5-7

Data from nationwide populations in other countries have mostly been collected retrospectively,^8-12 and outcomes do not meet the goals of the St Vincent declaration. To determine if these goals are being met in the Netherlands, we conducted a nationwide prospective study in pregnant women with type 1 diabetes during 1999-2000.

Methods

All women with type 1 diabetes presenting for antenatal care between 1 April 1999 and 1 April 2000 were included in the study. All 118 Dutch hospitals participated, and a total of 364 women were eligible. We excluded 41 (11%) women, leaving 323 pregnancies reported here.

Eligible women filled in questionnaires at inclusion (at around 10 weeks' gestation), at the end of the first trimester (around 17 weeks), and during the third trimester (around 34 weeks). Internists filled in a questionnaire including general characteristics, medical history, and diabetes related items; gynaecologists gave information about the outcome of pregnancy; and paediatricians filled in a questionnaire about the newborns.

We recorded maternal characteristics (age, body mass index, marital status, ethnic origin, education level, alcohol use, smoking habits, and parity), duration of diabetes, presence of chronic complications, and treatment of diabetes (continuous subcutaneous insulin infusion or multiple insulin treatment, human insulin or analogue (lispro) insulin).

Glycaemic control during pregnancy
We collected HbA_1c concentrations during the first (n = 283), second (n = 276), and third trimesters (n = 262) from the local hospitals, standardising them to adjust for variations between the local assays. We divided glycaemic control into three categories: mean HbA_1c 6.0% (within normal range; "excellent"), mean HbA_1c 6.1-7.0% ("good"), and mean HbA_1c > 7.0% ("not optimal"). We asked the women to send a self obtained capillary blood sample to a central laboratory for determination of HbA_1c early in pregnancy. We included only samples between 8 and 14 weeks' gestation (n = 227). Severe hypoglycaemia occurring during the first and third trimesters was recorded, defined as all episodes for which external help was needed, including hypoglycaemic coma.

Outcome measures
We collected data on obstetric complications and perinatal and neonatal outcomes. See bmj.com for definitions. We compared maternal and perinatal outcomes with national data from the 1998 Dutch perinatal database and with data from Statistics Netherlands.

Results

The 323 pregnancies included four therapeutic abortions, two due to major congenital malformations and two due to chromosomal abnormalities. One maternal death occurred at 17 weeks' gestation, and four other pregnancies ended before 24 weeks of gestation, leaving 314 ongoing pregnancies. Of these, nine were multiple births, resulting in 324 infants born after 24 weeks of gestation.

Maternal characteristics
Maternal age, parity, and race did not differ significantly from those of the general pregnant population. Mean first trimester HbA_1c was 6.5% (SD 0.7%); glycaemic control was excellent (HbA_1c 6.0%) in 90 (32%), good (6.1-7.0%) in 122 (43%), and not optimal (> 7.0%) in 71 (25%) of the pregnancies. Mean HbA_1c during pregnancy was 6.2% (0.9%); excellent in 113 (40%), good in 121 (43%), and not optimal in 49 (17%) pregnancies. Mean HbA_1c early in pregnancy determined in the central laboratory was 6.7% (0.7%). Two hundred and seventy one (84%) of the women had planned their pregnancy, and 226 (70%) had started folic acid supplementation before conception.

Maternal outcome
Pre-eclampsia—More than 12% of the pregnancies were complicated by pre-eclampsia (table 1), 12 times higher than in the reference group.

View this table: [in this window] [in a new window]   Table 1 Maternal outcome of pregnancies complicated by diabetes mellitus type 1 compared with national data

 

Prematurity and caesarean section—The rate of prematurity was more than four times that of the national population. Reasons for induced preterm delivery were pre-eclampsia (26, 40.6%), fetal distress (20, 31.3%), macrosomia (5, 7.8%), and others (13, 20.3%). The rate of caesarean section was 44.3% (23.9% (n = 75) primary and 20.4% (64) secondary), an almost fourfold increase in risk. Reasons for a primary caesarean section were fetal distress (23, 30.7%), pre-eclampsia (19, 25.3%), macrosomia (15, 20.0%), breech presentation (9, 12.0%), and others (9, 12.0%). Reasons for a secondary caesarean section were failed induction or obstructed labour (33, 51.6%), fetal distress (25, 39.1%), and others (6, 9.3%).

Maternal mortality—Two (0.6%) maternal deaths occurred. One woman probably died owing to severe hypoglycaemia followed by a cardiac arrest at 17 weeks' gestation. The other woman died during parturition owing to an amniotic fluid embolism.

Perinatal and neonatal outcome
Congenital malformations—The rate of congenital malformations (table 2), was three times that of the national population. Major congenital malformations (n = 18) comprised cardiovascular anomalies (8), urogenital anomalies (4), and neural tube defects (3, including one case of caudal regression syndrome). Minor congenital malformations (11) included hypospadia, vertebral anomalies, and clubfoot. The incidence of (all) congenital malformations was 6.3% (n = 14) in the pregnancies with excellent or good first trimester HbA_1c ( 7.0%) compared with 12.9% (9) in those with non-optimal first trimester HbA_1c (> 7.0%) (relative risk 0.49, 95% confidence interval 0.22 to 1.1). The incidences of major congenital malformations in these two groups were 2.7% (n = 6) and 10.0% (7) (relative risk 0.27, 0.09 to 0.79).

View this table: [in this window] [in a new window]   Table 2 Perinatal outcome of pregnancies complicated by diabetes mellitus type 1 compared with national data

 

Perinatal mortality—Nine perinatal deaths (2.8%; 27.8/1000 births) occurred—six stillbirths and three neonatal deaths. See bmj.com for details.

Macrosomia—Mean birth weight of the 324 infants was 3454 (SD 829) g at 37.0 (2.7) weeks of gestation; 170 (52.5%) infants were macrosomic, including 92 (28.4%) severely macrosomic, according to the official growth charts. The equivalent percentages were 45.1% (table 2) and 24.1% (n = 78) according to the growth charts based on data collected in 1998 (figure). Seventy seven (23.8%) infants had a birth weight > 4000 g, including 23 (7.1%) weighing > 4500 g. First, second, and third trimester HbA_1c and mean HbA_1c during pregnancy were slightly but significantly higher in the women with a macrosomic infant (mean HbA_1c during pregnancy 6.4% (SD 0.9%) v 6.0% (0.9%); P = 0.001).

View larger version (18K): [in this window] [in a new window]   Distribution of birth weight among 324 infants of women with type 1 diabetes (reference data from Dutch perinatal database, 199813)

 

Neonatal outcome—Neonatal morbidity (one or more complications) was present in 260 (80.2%) of infants. Neonatal hypoglycaemia in particular occurred very frequently; glucose < 2.6mmol/l occurred in 207 (64.1%) infants, and glucose < 2.0mmol/l occurred in 141 (43.7%). Shoulder dystocia and neonatal hypoglycaemia occurred significantly more often in macrosomic than in non-macrosomic infants—27.4% (n = 20) v 4.7% (5) (relative risk 5.8, 2.3 to 14.7) and 75.4% (107) v 54.5% (91) (relative risk 1.4, 1.2 to 1.6). Hyperbilirubinaemia, respiratory disorders, hypertrophic cardiomyopathy, and asphyxia were significantly more common in preterm infants (all P < 0.005).

Maternal, perinatal, and neonatal outcomes (except for congenital malformations) in women with good glycaemic control (75%, first trimester HbA_1c 7.0%) were comparable to those in women with less good control.

Planned pregnancies
First trimester HbA_1c was significantly lower in the planned pregnancies than in the unplanned ones (6.4% (SD 0.9%) v 7.0% (1.4%); P < 0.001). The incidence of major congenital malformations was significantly lower in the planned pregnancies (4.2% (n = 11) v 12.2% (6); relative risk 0.34, 0.13 to 0.88); other outcomes did not differ.

Severe hypoglycaemia during pregnancy
Forty four (41%) of 264 women were affected by severe hypoglycaemia during the first trimester, and 116/286 (17%) of the women were affected during the third trimester. Mean HbA_1c levels were slightly but significantly lower in these women than in women who did not experience hypoglycaemia (6.4% (SD 0.8%) v 6.7% (0.7%); P = 0.03). The incidence of macrosomia was significantly lower in women affected by severe hypoglycaemia (37.5% (n = 48) v 56.4% (92); relative risk 0.66, 0.51 to 0.85). All other outcomes were similar.

Use of lispro during pregnancy
Thirty five (11%) of the women used insulin lispro during pregnancy. The HbA_1c levels, occurrence of severe hypoglycaemia, and rate of congenital malformations in these women did not differ from those in women using human insulin.

What is already known on this topic Pregnancy in women with type 1 diabetes mellitus is associated with increased risk of maternal, perinatal, and neonatal complications Data from nationwide populations are scarce, and most have been collected retrospectively What this study adds Despite overall adequate glycaemic control (HbA1c 7.0%), maternal and perinatal complications remained high in women with type 1 diabetes The very high incidence of neonatal hypoglycaemia (64.1%) occurred in both macrosomic and non-macrosomic infants; neonatologists should pay special attention to this Population data are of great importance in assessing the real effects of current treatment strategies

Discussion

Although most women planned their pregnancy and had good glycaemic control and adequate folic acid supplementation, outcome was not comparable to that of the general population. The risks of congenital malformations, macrosomia, and pre-eclampsia were increased three to 12-fold, and neonatal morbidity, especially hypoglycaemia, was also extremely high.

The American Diabetes Association has stated that in pregnancy tight glycaemic control is accomplished when HbA_1c is within 1% above the upper limit of the normal range (4.0-6.0%). HbA_1c concentrations 7.0% are assumed to be associated with rates of congenital malformations and macrosomia no greater than those in pregnancies in non-diabetic women.¹⁴ However, our study shows that such levels of control are not good enough to prevent these complications. This indicates that current criteria for strict glycaemic control are not "safe" enough or that HbA_1c does not sufficiently reflect short term glucose variability, as shown with the continuous glucose monitoring system.^15-17

Congenital malformations were related (but not significantly) to HbA_1c, but the incidence was higher than that of the general population, even with normal and almost normal HbA_1c values. The incidence of macrosomia was also much higher than that published by other authors, despite overall adequate HbA_1c levels.^{10 12 18 19} HbA_1c was the most powerful predictor for macrosomia, but its predictive capacity was only weak (explained variance < 5%).²⁰

Almost all women in our study were white (98%) and married (98%), and 81% were medium to highly educated. This probably explains the high rate of planned pregnancies (84%) compared with other studies, in which percentages of 26% and 59% have been reported.^{21 22} The incidence of major congenital malformations was very high in the unplanned pregnancies.

In general, neonatal morbidity (one or more complications) was extremely high (> 80%). Neonatal hypoglycaemia in particular occurred very frequently and more often than reported by other authors, although comparison is difficult owing to differences in definition. Appropriate for gestational age infants had a lower risk of neonatal hypoglycaemia than other infants, but the incidence of hypoglycaemia was still unexpectedly high in this group. This deserves attention from paediatricians.

Conclusion
Despite a high frequency of planned pregnancies, resulting in overall good glycaemic control (early) in pregnancy and a high rate of adequate use of folic acid, maternal and perinatal complications were still greatly increased in women with type 1 diabetes. Neonatal morbidity, especially hypoglycaemia, was also extremely high. Near optimal maternal glycaemic control (HbA_1c 7.0%) is apparently not good enough.

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This is the abridged version of an article that was posted on bmj.com on 5 April 2004: http://bmj.com/cgi/doi/10.1136/bmj.38043.583160.EE

We thank all the gynaecologists, paediatricians, internists, and diabetes nurse educators in the Netherlands for including their patients in this nationwide study; the women who participated for their willingness to fill in the questionnaires; PRISMANT Health Care Information who gave us permission to use their perinatal register of 1998; and TNO Prevention and Health for their statistical analysis of this register.

Contributors: See bmj.com

Funding: Novo Nordisk Farma BV, Alphen aan De Rijn, the Netherlands.

Competing interests: None declared.

Ethical approval: The study was approved by the medical ethics committee of the University Medical Center Utrecht.

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(Accepted 18 February 2004)

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