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Impaired glucose tolerance associated with adverse pregnancy outcome: A population-based study in southern Sweden
Impaired glucose tolerance associated with adverse pregnancy outcome: A population-based study in southern Sweden Anders Åberg, MD,a Hakan Rydhstroem, MD, PhD,a, c and Anders Frid, MD, PhDb Lund and Helsingborg, Sweden OBJECTIVE: We conducted a population-based study of maternal and neonatal characteristics and delivery complications in relation to the outcome of a 75-g, 2-hour oral glucose tolerance test at 25 to 30 weeks’ gestation. STUDY DESIGN: An oral glucose tolerance test was offered to pregnant women in a geographically defined population. Pregnancy outcome was analyzed according to the test result. RESULTS: Among women delivered at Lund Hospital, we identified 4526 women with an oral glucose tolerance value of <7.8 mmol/L (<140 mg/dL), 131 women with a value of 7.8 to 8.9 mmol/L (140-162 mg/dL), and 116 women with gestational diabetes (≥9.0 mmol/L [≥162 mg/dL]). A further 28 cases of gestational diabetes were identified, giving a prevalence of 1.2%. An increased rate of cesarean delivery and infant macrosomia was observed in the group with a glucose tolerance value of 7.8 to 8.9 mmol/L (140-162 mg/dL) and in the gestational diabetes group. Advanced maternal age and high body mass index were risk factors for increased oral glucose tolerance values in 12,657 screened women in the area. CONCLUSION: The study stresses the significance of moderately increased oral glucose tolerance values. (Am J Obstet Gynecol 2001;184:77-83.)
Key words: Adverse pregnancy outcome, cesarean delivery, impaired glucose tolerance, macrosomia
Gestational diabetes mellitus (GDM) is frequently associated with adverse pregnancy outcomes. However, the magnitude of the problem has been debated since the 1960s. An increased perinatal mortality rate was reported in association with GDM.1-3 Three separate studies4-6 reported increased birth weights and frequency of macrosomia, cesarean delivery, and shoulder dystocia and other birth trauma in untreated or minimally treated women with GDM. On the other hand, a normal perinatal outcome with modern antenatal care and obstetric management of GDM has been described.7, 8 Some studies2, 9-12 have suggested a continuum of perinatal risks for women with glucose tolerance within the normal range. The factors studied were frequency of assisted delivery, perinatal mortality rate, frequency of macrosomia, and prolonged hospital stay of the newborn infant. From Melbourne,13 after a review of >116,000 glucose tolerance tests, it was concluded that the identification and treatment of GDM significantly From the Department of Obstetrics and Gynaecologya and the Department of Internal Medicine/Diabetes,b Lund University Hospital, and the Department of Obstetrics and Gynaecology, Helsingborg Central Hospital.c Received for publication September 29, 1999; revised March 8, 2000; accepted April 18, 2000. Reprint requests: Anders Åberg, MD, Department of Obstetrics and Gynecology, Lund University Hospital, SE-221 85 Lund, Sweden. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/108085 doi:10.1067/mob.2001.108085
reduced perinatal mortality rates. Evidence for the importance of diagnosing gestational diabetes has been reviewed,14, 15 and Weeks et al16 concluded that selective screening would have failed to identify 43% of women with GDM. Critical authors, however, believe that general screening for GDM is not worthwhile.17-19 The Fourth International Workshop-Conference on Gestational Diabetes Mellitus20 (1998) recommended screening of average and high-risk populations but not of low-risk populations. In Sweden almost all delivered women have obtained free antenatal care. This is an excellent prerequisite for population studies of events during pregnancy. In our region of southern Sweden we offer a 75-g oral glucose tolerance test (GTT) to all pregnant women at 27 to 28 weeks’ gestation. The purpose of our study was to examine pregnancy outcome in relation to this oral GTT in a relatively large population from this area. Our special interest was to study the risks in the “sub-GDM” group— women who had a 2-hour oral GTT value between the cutoff point for defining GDM in Sweden (9.0 mmol/L [162 mg/dL]) and the World Health Organization limit for decreased glucose tolerance in pregnancy (7.8 mmol/L [140 mg/dL]). Material and methods Pregnant women were offered an oral GTT, which was recommended to be done at week 27 or 28 of pregnancy. The tests were performed in the morning after overnight 77
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Table I. Odds ratio to participate in oral GTT screening according to various maternal characteristics—Maternal age, parity, and smoking Characteristic Maternal age ≤19 y 20-24 y 25-29 y 30-34 y 35-39 y 40-44 y ≥45 y Parity 1 2 3 4 ≥5 Smoking
Odds ratio
95% Confidence interval
0.73 1.14 1.07 0.91 0.93 0.97 1.26
0.58-0.91 1.04-1.24 1.01-1.14 0.86-0.97 0.84-1.02 0.77-1.22 0.49-3.25
0.94 1.06 1.06 0.94 0.88 1.05
0.89-1.00 0.99-1.12 0.97-1.16 0.81-1.10 0.73-1.07 0.96-1.14
At the analysis of each factor, stratification for the other 2 factors and for the delivery hospital was made (N = 14,078).
fasting. Anhydrous 75 g glucose dissolved in 300 mL of water was given. After 2 hours a sample for determination of a 5-µL capillary whole-blood glucose value was collected in a microcuvet and immediately analyzed for glucose level in a Hemocue (Hemocue AB, Ängelholm, Sweden) apparatus. We used the definition of GDM recommended in Sweden—a 2-hour value of at least 9 mmol/L (≥162 mg/dL) after a 75-g oral GTT.21 Wholeblood venous glucose values are 1.1 mmol/L lower than whole-blood capillary values and are similar to plasma venous values. During the period from January 1, 1995, to December 31, 1997, GTTs performed in 4 geographic areas (Malmö, Lund-Orup, Trelleborg, and Ystad) were registered. These areas were served by 4 delivery units. Results of the first test performed during weeks 25 to 30 of pregnancy were used to identify 2 groups of women according to the mean 2-hour glucose level, <7.8 mmol/L (<140 mg/dL) and 7.8 to 8.9 mmol/L (140-162 mg/dL). The cutoff value of 7.8 has been recommended by the World Health Organization for diagnosing impaired glucose tolerance. We designated the former group as the control group and the latter as the sub-GDM group. To these 2 groups were added women with manifested GDM (defined as a glucose value of ≥9 mmol/L [≥162 mg/dL]) if delivery was in the Lund University Hospital. These women were identified either during the screening procedure mentioned earlier or as a result of testing performed outside the defined weeks because of clinical signs, heredity, or previous GDM. Each woman entered the study with only 1 pregnancy (the first tested). We made a detailed study in an antenatal clinic in Lund during 1 year (1997) to study the reasons for not having the oral GTT. In the clinical care of the pregnant woman, the control
and the sub-GDM groups were treated in the same way, without any consideration of the glucose level. All women with identified GDM were treated at the center for antenatal care in Lund University Hospital. All were given a device for home blood glucose monitoring. Blood glucose was tested 6 times daily if the woman was insulin treated and 6 times every other day if not. All women with GDM had telephone contact with a diabetologist every week or every second week. Approximately 40% of the women were treated with insulin. Some further information on the patients was recorded from the antenatal care centers, as follows: body weight, height, and parity reported at the first antenatal visit (usually during weeks 8-12). Body mass index (BMI) (Weight [in kilograms]/ Height2 [in meters]) was calculated when both variables were known. For infants born in the Lund University Hospital, data on delivery outcome were linked to the gathered information by means of the computerized register of all deliveries at the hospital. The following information was used: maternal weight at delivery, method of delivery, gestational duration, infant’s birth weight, umbilical artery pH, Apgar score, and placental weight. A further matching was made with the Swedish Medical Birth Registry, from which information on nationality and smoking in early pregnancy was obtained for all 4 delivery units in the study. The analysis is restricted to singleton pregnancies and was made on the following material of singleton deliveries in Lund University Hospital for which data from the computerized register of deliveries could be matched. Among the women studied, 4657 did not fulfill criteria for GDM (oral GTT value of at least 9 mmol/L [≥162 mg/dL]). The data on women with GDM were collected as described, and a total of 144 such women were identified. Some studies described herein included 10,375 singleton deliveries (irrespective of delivery unit) for which data could be matched from the Medical Birth Registry. All matching was made by using the unique personal identification number given to each person living in Sweden and extensively used in society, including all health care. Statistical analysis was performed with the MantelHaenszel method after various stratifications, as described in the next section. Each group was compared with all other groups. The 95% confidence intervals were determined by a test-based method. Results Coverage of screening procedure. During the observation period a total of 20,865 deliveries occurred in the 4 hospitals involved in the study. A total of 14,078 women had oral GTT values recorded (67% coverage), 12,657 of whom underwent testing during weeks 25 to 30 (93%).
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Table II. Odds ratio for having increased glucose level according to maternal age (stratified for parity) or parity (stratified for age) Blood glucose value of 7.8-8.9 mmol/L (140-162 mg/dL)
Maternal age 15-19 y 20-24 y 25-29 y 30-34 y 35-39 y 40-44 y 45-49 y Parity 0 1 2 3 ≥4
Gestational diabetes
Odds ratio
95% Confidence interval
Odds ratio
95% Confidence interval
0.61 0.39 0.95 1.09 1.50 1.99 —
0.09-4.39 0.19-0.80 0.66-1.37 0.76-1.56 0.96-2.36 0.88-4.50 —
— 0.34 1.16 0.79 1.56 3.13 10.87
— 0.15-0.77 0.79-1.70 0.54-1.17 0.95-2.56 1.57-6.25 1.79-66.1
0.89 1.29 0.65 1.08 1.35
0.62-1.28 0.90-1.84 0.37-1.17 0.46-2.55 0.50-3.62
0.85 1.15 1.03
0.60-1.25 0.79-1.69 0.67-1.68
Reference values are for women with a glucose value of <7.8 mmol/L (<140 mg/dL). Each maternal age or parity group is compared with all other age or parity groups.
In 773 cases the test was performed before week 25 and in 277 cases after week 30; in 371 cases the week of the test was not stated. The material was limited to women with an oral GTT performed in weeks 25 to 30. In some of the missing cases, an oral GTT may have been performed but had not been recorded properly. The impact on participation of 3 maternal characteristics (age, parity, and smoking habits as a proxy for socioeconomic condition) is shown in Table I. Participation was decreased among teenagers; the highest participation was by women between 20 and 29 years old. No significant effect of parity or maternal smoking was seen. The odds ratio for participation among non–Swedish-born women (15% of all), in comparison with Swedish-born women (after stratification for year of birth, age, and parity), was 1.33 (95% confidence interval, 1.27-1.40). Various reasons for nonparticipation were identified. Women with delivery before week 25 could not participate, for instance, and patients with test results that were positive for GDM before 25 weeks’ gestation or with insulin-dependent diabetes were not eligible. In a detailed study of the reasons for nonparticipation based on one antenatal clinic in Lund, 332 pregnant women were registered, 20 of whom miscarried. Of the remaining 312 women available for oral GTT, 16% (n = 49) did not participate. Instead 11 women had a glucose test 2 hours after breakfast, 21 were out of town during the relevant period of pregnancy, 14 refused participation, and 3 gave other reasons. Prevalence of GDM. Among 12,382 women who underwent delivery during the period from May 1, 1995, to April 30, 1998, and who were from areas where a woman with GDM would be referred to the Lund University Hospital for delivery, GDM was identified in 144 women (116
of whom had data matched with the other data sources). This represents a GDM prevalence of 1.2%. Maternal characteristics and glucose values. The analysis was made on data obtained by matching with the Medical Birth Registry data on all singleton deliveries in the studied area (from all 4 delivery units). Table II shows the effect of age and parity (at glucose testing) on the risk of having an increased glucose value. There is a clear-cut trend according to glucose class for maternal age (P < .001 for both glucose classes) but none for parity (P = .39 and P = .25, respectively). Fig 1 illustrates the relationships between blood glucose group and initial weight (reported at first antenatal visit), weight at delivery, maternal height, and prepregnancy BMI. The maternal BMI was lower in the group with the lowest glucose level than in the groups with higher levels, which seems to be partly a result of greater body weight but also of shorter height. With the use of the data obtained by matching with the Medical Birth Registry, the impact of maternal smoking and BMI (registered in early pregnancy) on glucose level at testing could be studied. This also made it possible to compare Swedish-born women with women born abroad. The odds ratio for being in the sub-GDM group in a woman born abroad compared with women born in Sweden (after stratification for maternal age, parity, smoking, and BMI) was 1.33 (95% confidence interval, 0.96-1.86); for having GDM the odds ratio was 0.59 (95% confidence interval, 0.31-1.12). The study was restricted to deliveries occurring in the 4 hospitals located in the study area. Maternal smoking was more prevalent in the sub-GDM group (22% of women with known smoking habits; n = 299) than in the control group (17%; n = 9725). After stratification for
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A
B
C
D
Fig 1. Maternal body dimensions (mean ± SEM) according to glucose levels at oral glucose tolerance testing. A, Initial weight; B, weight at delivery; C, height; D, BMI (prepregnancy values). Data are from all singleton births in region with information on maternal weight and height (N = 10,375).
delivery hospital, maternal age, parity, country of origin, and BMI group, the odds ratio for being a smoker in the sub-GDM group compared with the control group was 1.66 (95% confidence interval, 1.21-2.28). Smoking <10 cigarettes a day gave an odds ratio of 1.52 (95% confidence interval, 1.01-2.30), and smoking ≥10 cigarettes gave an odds ratio of 1.84 (95% confidence interval, 1.19-2.84). Among women with GDM (all delivered in Lund), 9 of 94 women with known smoking habits smoked during pregnancy (9.6%). The odds ratio for smoking compared with the control group (stratified as above) was 0.64 (95% confidence interval, 0.32-1.27). This odds ratio is significantly lower than that for the sub-GDM group. A similar analysis was made for 4 BMI groups (<19.8, 19.8-25.9, 26-28.9, ≥29), with the second group used as a reference. Stratification was made for delivery hospital, maternal age, parity, country of origin, and smoking. The odds ratio for having sub-GDM in the 26-28.9 BMI group was 1.13 (95% confidence interval, 0.75-1.71), and in the ≥29 BMI group the odds ratio was increased to 1.91 (95% confidence interval, 1.34-2.72). The odds ratio for having GDM was increased both at a BMI between 26 and 28.9 (odds ratio, 2.39; 95% confidence interval, 1.39-4.10) and
at a BMI of ≥29 (odds ratio, 3.88; 95% confidence interval, 2.37-6.36). Mode of delivery. Table III describes mode of delivery according to glucose levels. In the sub-GDM group, the total cesarean delivery rate was 13.8%, versus 7.7% in the control group. An odds ratio comparing elective cesarean delivery in the sub-GDM group and in the control group with all other delivery methods, stratified for year of birth, maternal age, and parity, was 1.77 (95% confidence interval, 1.00-3.12). For emergency cesarean delivery the corresponding odds ratio was 1.69 (95% confidence interval, 1.01-2.86). At GDM the corresponding odds ratio for elective cesarean delivery was 4.15 (95% confidence interval, 2.347.38), and for emergency cesarean delivery the odds ratio was 6.94 (95% confidence interval, 3.29-14.65). Gestational duration. The mean (±SD) gestational duration among deliveries in the Lund University Hospital in the control group was 278.3 ± 0.19 days, in the subGDM group it was 276.5 ± 1.10 days, and in the GDM group it was 272.9 ± 1.38 days. The percentage of deliveries at <37 weeks’ gestation was 5.7% in the control group, 8.4% in the sub-GDM group, and 13.8% in the GDM group. The trend is statistically significant (P < .001).
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A
B
Fig 2. Quotients (mean ± SEM) for infant/maternal initial weight (weight at first antenatal visit) (A) and infant/placental weight (B). Data are on women delivered at Lund University Hospital (N = 4773).
Table III. Mode of delivery (at Lund University Hospital) of singleton pregnancies according to blood glucose level Blood glucose level <7.8 mmol/L (<140 mg/dL)
7.8-8.9 mmol/L (140-162 mg/dL)
Gestational diabetes
Mode of delivery
No.
%
No.
%
No.
%
Noninstrumental Forceps or vacuum extraction Elective cesarean Emergency cesarean Unknown
3985 251 108 249 23 4526
86.3 5.4 2.3 5.4 0.5
104 7 6 12 2 131
79.4 5.3 4.6 9.2 1.5
85 7 8 13 3 116
73.3 6.0 6.9 11.2 2.6
TOTAL
Birth weight. Among Lund deliveries, the mean (±SD) birth weight was 3564.3 ± 8.4 g in the control group, 3661.2 ± 54.8 g in the sub-GDM group, and 3542.2 ± 66.3 g in the GDM group. The percentages of infants weighing <2500 g were 3.5%, 2.3%, and 7.8% in the 3 groups (P = .06 for heterogeneity). The percentages of infants with a birth weight of ≥4500 g were 4.5%, 9.9%, and 10.3%, respectively (P = .03 for heterogeneity; P < .001 for trend). Birth weight according to gestational duration. Among infants in the control group, the mean (±SD) birth weight was determined for each gestational week (smoothed between 3 successive weeks) and according to maternal age, parity, and BMI group. Among infants born to sub-GDM women, 28 (24%) had a weight above +1 SD and 9 (8%) below –1 SD. The corresponding numbers for infants born to GDM mothers were 25 (29%) and 14 (16%), respectively. Birth weight, maternal weight, and placental weight. Fig 2 shows that the ratio between infant and maternal initial weights (at first antenatal visit) increased slightly in the sub-GDM group but decreased in the GDM group. Fig 2
also shows that the ratio of infant weight over placental weight decreased with increasing glucose values. Umbilical artery pH and Apgar score. The mean (±SD) umbilical artery pH was 7.259 ±.001 in the control group, 7.249 ± 0.008 in the sub-GDM group, and 7.249 ± 0.009 in the GDM group. In the first group, 46 infants (1%) had a 5-minute Apgar score of <7, none of the 131 infants in the second group had a 5-minute Apgar score of <7, and 2 of 116 infants in the third group had an Apgar score of <7. Perinatal mortality rate. We matched records of infants with the Medical Birth Registry to identify perinatal deaths. Among 4827 singleton deliveries, 4721 could be matched with the Medical Birth Registry. Among 4515 singleton infants born to control women, 11 were stillborn and 2 died during the first week of life (perinatal death rate, 0.3%). The low perinatal death rate is explained by exclusion of infants born before the time for an oral GTT test and the exclusion of multiple births. Among 126 infants born to women with a glucose value of 7.8 to 9 mmol/L, 1 infant was stillborn (0.8%) but no live infant died. Among 116 cases of
82 Åberg, Rydhstroem, and Frid
GDM, 2 infants were stillborn, and 1 of them had multiple malformations. Comment To our knowledge, we are reporting the largest prospective and population-based study of GDM. The high rate of antenatal care in Sweden and the unique personal identification number of every person living in Sweden are excellent prerequisites for studies of this kind. At least 65% of all women delivered of infants were tested with an oral GTT. The nonparticipation was partly the result of various irrelevant factors, but we found increased nonparticipation, notably in pregnant teenagers, whereas socioeconomic conditions (as estimated by smoking habits) seemed to play a minor role. Most of the findings agree with earlier studies, but some are new. Thus our study confirms other reports that a suboptimal pregnancy outcome is associated with maternal glucose tolerance even in the sub-GDM region.2, 6, 7 The increased BMI value in this group of women was caused not only by increased weight but also by shorter height, which has been reported in other studies. Women in this group are delivered of babies with increased birth weights, even with consideration of maternal weight. This increase was found despite the surprising new fact that these women smoked more than women with a glucose level of <7.8 mmol/L (with consideration given to maternal age, parity, BMI, and country of birth). After stratification for smoking, the difference in birth weight increased. One explanation could be that smoking increases insulin resistance.22 On the other hand, women with gestational diabetes smoked significantly less than the control group. An explanation of differences regarding smoking in these groups could be that the insulin resistance caused by smoking was sufficient to place an otherwise normal woman in the sub-GDM group but not to cause GDM. In the GDM group it is possible that the inherited metabolic disturbances outweighed the effects of smoking. However, it is difficult to explain the decreased frequency of smoking in women with GDM. Perhaps there was an increased health awareness if there was a family history of type II diabetes and the associated metabolic syndrome. The ratio between birth weight and placental weight decreased with increasing maternal glucose intolerance. Thus placental weight increased more than birth weight, as previously demonstrated.23 Our finding that women with GDM, despite having an increased BMI, were delivered of normal-size babies was probably an effect of the intense treatment given. This agrees with the Toronto Tri-Hospital Gestational Diabetes Project.24 In the sub-GDM group, only 8% were at <1 SD and 24% were at >1 SD in birth weight. The increased rate of cesarean delivery among women
January 2001 Am J Obstet Gynecol
with GDM agrees with what is known from the literature. We also found an increased rate among women in the sub-GDM group, not explainable from the maternal age–parity distribution. The greater likelihood of delivery before 37 weeks’ gestation in the GDM group was probably caused, to some extent, by induction of delivery because of the GDM diagnosis. However, because the sub-GDM group was treated in the same way as the control group, the higher prematurity rate in the former group is unlikely to have been a result of delivery induction. The rate of induced deliveries at Lund University Hospital is low, ~6%. Data on umbilical cord pH, Apgar score, and perinatal survival did not indicate any significant effect on infant perinatal morbidity. The size of the study, however, would make it possible to detect only more than a doubling in the perinatal mortality rate (α = .05; β = .80). We conclude that women with 2-hour oral GTT values of 7.8 to 8.9 mmol/L have an increased risk of having a nonoptimal delivery outcome. We are thankful to Anders Ericson, National Board of Health, Stockholm, for giving us access to the Medical Birth Registry. REFERENCES
1. O’Sullivan JB, Charles D, Mahan CM, Dandrow RV. Gestational diabetes and perinatal mortality rate. Am J Obstet Gynecol 1973;116:901-4. 2. Pettitt DJ, Knowler WC, Baird HR, Bennett PH. Gestational diabetes: infant and maternal complications of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care 1980;3:458-64. 3. Hod M, Merlob P, Friedman S, Schoenfeld A, Ovadia J. Gestational diabetes mellitus: a survey of perinatal complications in the 1980s. Diabetes 1991;40:74-8. 4. Coustan DR, Imarah J. Prophylactic insulin treatment of gestational diabetes reduces the incidence of macrosomia, operative delivery and birth trauma. Am J Obstet Gynecol 1984;150: 836-42. 5. Langer O, Berkus M, Conway D. Gestational diabetes is a clinical entity: the price of not treating [abstract]. Am J Obstet Gynecol 1997;176(1 Pt 2):S182. 6. Adams KM, Li H, Nelson RL, Ogburn PL, Danilenko-Dixon DR. Sequelae of unrecognized gestational diabetes. Am J Obstet Gynecol 1998;178:1321-32. 7. Drexel H, Bichler A, Sailer S, Breier C, Lisch HJ, Braunsteiner H, et al. Prevention of perinatal morbidity by tight metabolic control in gestational diabetes mellitus. Diabetes Care 1988;11: 761-8. 8. Langer O, Rodriquez DA, Xenakis EMJ, McFarland MB, Berkus MD, Arredondo F. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994;170: 1036-47. 9. Tallarigo L, Giampietro O, Penno G, Miccoli R, Gregori G, Navalesi R. Relation of glucose tolerance to complications of pregnancy in nondiabetic women. N Engl J Med 1986;315: 989-92. 10. Moses RG, Calvert D. Pregnancy outcomes in women without gestational diabetes mellitus related to the maternal glucose level. Diabetes Care 1995;18:1527-33. 11. Nord E, Hanson U, Persson B. Blood glucose limits in the diagnosis of impaired glucose tolerance during pregnancy: relation to morbidity. Acta Obstet Gynecol Scand 1995;74:589-93. 12. Sacks DA, Greenspoon JS, Abu-Fadil S, Henry HM, Wolde-Tsadik
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G, Yao JFF. Toward universal criteria for gestational diabetes: the 75-gram glucose tolerance test in pregnancy. Am J Obstet Gynecol 1995;172:607-14. Beischer NA, Wein P, Sheedy MT, Steffen B. Identification and treatment of women with hyperglycemia diagnosed during pregnancy can significantly reduce perinatal mortality rates. Aust N Z J Obstet Gynaecol 1996;36:239-47. Dornhorst A, Beard RW. Gestational diabetes: a challenge for the future. Diabet Med 1993;10:897-905. Coustan DR. Methods of screening for and diagnosing of gestational diabetes. Clin Perinatol 1993;20:593-602. Weeks JW, Major CA, de Veciana M, Morgan MA. Gestational diabetes: does the presence of risk factors influence perinatal outcome? Am J Obstet Gynecol 1994;171:1003-7. Jarrett RJ. The concept of gestational diabetes was popularised before considerations of evidence-based medicine came on the scene. BMJ 1997;315:736-7. Helton MR, Arndt J, Kebede M, King M, Hill C. Do low-risk pre-
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natal patients really need a screening glucose challenge test? J Fam Pract 1997;44:556-61. Greene MF. Screening for gestational diabetes mellitus. N Engl J Med 1997;337:1625-6. Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes. Diabetes Care 1998;21:B161-7. Lind T, Phillips PR. Influence of pregnancy on the 75-g OGTT: a prospective multicenter study. Diabetes 1991;40(Suppl 2):8-13. Attvall S, Fowelin J, Lager I, von Schenck H, Smith U. Smoking induces insulin resistance: a potential link with the insulin resistance syndrome. J Intern Med 1993;233:327-32. Lao TT, Lee CP, Wong WM. Placental weight to birthweight ratio is increased in mild gestational glucose intolerance. Placenta 1997;18:227-30. Sermer M, Naylor CD, Farine D, Kenshole AB, Ritchie JWK, Gare DJ, et al. The Toronto Tri-Hospital Gestational Diabetes Project: a preliminary review. Diabetes Care 1998;21:B33-42.
Key words: Adverse pregnancy outcome, cesarean delivery, impaired glucose tolerance, macrosomia
Gestational diabetes mellitus (GDM) is frequently associated with adverse pregnancy outcomes. However, the magnitude of the problem has been debated since the 1960s. An increased perinatal mortality rate was reported in association with GDM.1-3 Three separate studies4-6 reported increased birth weights and frequency of macrosomia, cesarean delivery, and shoulder dystocia and other birth trauma in untreated or minimally treated women with GDM. On the other hand, a normal perinatal outcome with modern antenatal care and obstetric management of GDM has been described.7, 8 Some studies2, 9-12 have suggested a continuum of perinatal risks for women with glucose tolerance within the normal range. The factors studied were frequency of assisted delivery, perinatal mortality rate, frequency of macrosomia, and prolonged hospital stay of the newborn infant. From Melbourne,13 after a review of >116,000 glucose tolerance tests, it was concluded that the identification and treatment of GDM significantly From the Department of Obstetrics and Gynaecologya and the Department of Internal Medicine/Diabetes,b Lund University Hospital, and the Department of Obstetrics and Gynaecology, Helsingborg Central Hospital.c Received for publication September 29, 1999; revised March 8, 2000; accepted April 18, 2000. Reprint requests: Anders Åberg, MD, Department of Obstetrics and Gynecology, Lund University Hospital, SE-221 85 Lund, Sweden. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/108085 doi:10.1067/mob.2001.108085
reduced perinatal mortality rates. Evidence for the importance of diagnosing gestational diabetes has been reviewed,14, 15 and Weeks et al16 concluded that selective screening would have failed to identify 43% of women with GDM. Critical authors, however, believe that general screening for GDM is not worthwhile.17-19 The Fourth International Workshop-Conference on Gestational Diabetes Mellitus20 (1998) recommended screening of average and high-risk populations but not of low-risk populations. In Sweden almost all delivered women have obtained free antenatal care. This is an excellent prerequisite for population studies of events during pregnancy. In our region of southern Sweden we offer a 75-g oral glucose tolerance test (GTT) to all pregnant women at 27 to 28 weeks’ gestation. The purpose of our study was to examine pregnancy outcome in relation to this oral GTT in a relatively large population from this area. Our special interest was to study the risks in the “sub-GDM” group— women who had a 2-hour oral GTT value between the cutoff point for defining GDM in Sweden (9.0 mmol/L [162 mg/dL]) and the World Health Organization limit for decreased glucose tolerance in pregnancy (7.8 mmol/L [140 mg/dL]). Material and methods Pregnant women were offered an oral GTT, which was recommended to be done at week 27 or 28 of pregnancy. The tests were performed in the morning after overnight 77
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Table I. Odds ratio to participate in oral GTT screening according to various maternal characteristics—Maternal age, parity, and smoking Characteristic Maternal age ≤19 y 20-24 y 25-29 y 30-34 y 35-39 y 40-44 y ≥45 y Parity 1 2 3 4 ≥5 Smoking
Odds ratio
95% Confidence interval
0.73 1.14 1.07 0.91 0.93 0.97 1.26
0.58-0.91 1.04-1.24 1.01-1.14 0.86-0.97 0.84-1.02 0.77-1.22 0.49-3.25
0.94 1.06 1.06 0.94 0.88 1.05
0.89-1.00 0.99-1.12 0.97-1.16 0.81-1.10 0.73-1.07 0.96-1.14
At the analysis of each factor, stratification for the other 2 factors and for the delivery hospital was made (N = 14,078).
fasting. Anhydrous 75 g glucose dissolved in 300 mL of water was given. After 2 hours a sample for determination of a 5-µL capillary whole-blood glucose value was collected in a microcuvet and immediately analyzed for glucose level in a Hemocue (Hemocue AB, Ängelholm, Sweden) apparatus. We used the definition of GDM recommended in Sweden—a 2-hour value of at least 9 mmol/L (≥162 mg/dL) after a 75-g oral GTT.21 Wholeblood venous glucose values are 1.1 mmol/L lower than whole-blood capillary values and are similar to plasma venous values. During the period from January 1, 1995, to December 31, 1997, GTTs performed in 4 geographic areas (Malmö, Lund-Orup, Trelleborg, and Ystad) were registered. These areas were served by 4 delivery units. Results of the first test performed during weeks 25 to 30 of pregnancy were used to identify 2 groups of women according to the mean 2-hour glucose level, <7.8 mmol/L (<140 mg/dL) and 7.8 to 8.9 mmol/L (140-162 mg/dL). The cutoff value of 7.8 has been recommended by the World Health Organization for diagnosing impaired glucose tolerance. We designated the former group as the control group and the latter as the sub-GDM group. To these 2 groups were added women with manifested GDM (defined as a glucose value of ≥9 mmol/L [≥162 mg/dL]) if delivery was in the Lund University Hospital. These women were identified either during the screening procedure mentioned earlier or as a result of testing performed outside the defined weeks because of clinical signs, heredity, or previous GDM. Each woman entered the study with only 1 pregnancy (the first tested). We made a detailed study in an antenatal clinic in Lund during 1 year (1997) to study the reasons for not having the oral GTT. In the clinical care of the pregnant woman, the control
and the sub-GDM groups were treated in the same way, without any consideration of the glucose level. All women with identified GDM were treated at the center for antenatal care in Lund University Hospital. All were given a device for home blood glucose monitoring. Blood glucose was tested 6 times daily if the woman was insulin treated and 6 times every other day if not. All women with GDM had telephone contact with a diabetologist every week or every second week. Approximately 40% of the women were treated with insulin. Some further information on the patients was recorded from the antenatal care centers, as follows: body weight, height, and parity reported at the first antenatal visit (usually during weeks 8-12). Body mass index (BMI) (Weight [in kilograms]/ Height2 [in meters]) was calculated when both variables were known. For infants born in the Lund University Hospital, data on delivery outcome were linked to the gathered information by means of the computerized register of all deliveries at the hospital. The following information was used: maternal weight at delivery, method of delivery, gestational duration, infant’s birth weight, umbilical artery pH, Apgar score, and placental weight. A further matching was made with the Swedish Medical Birth Registry, from which information on nationality and smoking in early pregnancy was obtained for all 4 delivery units in the study. The analysis is restricted to singleton pregnancies and was made on the following material of singleton deliveries in Lund University Hospital for which data from the computerized register of deliveries could be matched. Among the women studied, 4657 did not fulfill criteria for GDM (oral GTT value of at least 9 mmol/L [≥162 mg/dL]). The data on women with GDM were collected as described, and a total of 144 such women were identified. Some studies described herein included 10,375 singleton deliveries (irrespective of delivery unit) for which data could be matched from the Medical Birth Registry. All matching was made by using the unique personal identification number given to each person living in Sweden and extensively used in society, including all health care. Statistical analysis was performed with the MantelHaenszel method after various stratifications, as described in the next section. Each group was compared with all other groups. The 95% confidence intervals were determined by a test-based method. Results Coverage of screening procedure. During the observation period a total of 20,865 deliveries occurred in the 4 hospitals involved in the study. A total of 14,078 women had oral GTT values recorded (67% coverage), 12,657 of whom underwent testing during weeks 25 to 30 (93%).
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Table II. Odds ratio for having increased glucose level according to maternal age (stratified for parity) or parity (stratified for age) Blood glucose value of 7.8-8.9 mmol/L (140-162 mg/dL)
Maternal age 15-19 y 20-24 y 25-29 y 30-34 y 35-39 y 40-44 y 45-49 y Parity 0 1 2 3 ≥4
Gestational diabetes
Odds ratio
95% Confidence interval
Odds ratio
95% Confidence interval
0.61 0.39 0.95 1.09 1.50 1.99 —
0.09-4.39 0.19-0.80 0.66-1.37 0.76-1.56 0.96-2.36 0.88-4.50 —
— 0.34 1.16 0.79 1.56 3.13 10.87
— 0.15-0.77 0.79-1.70 0.54-1.17 0.95-2.56 1.57-6.25 1.79-66.1
0.89 1.29 0.65 1.08 1.35
0.62-1.28 0.90-1.84 0.37-1.17 0.46-2.55 0.50-3.62
0.85 1.15 1.03
0.60-1.25 0.79-1.69 0.67-1.68
Reference values are for women with a glucose value of <7.8 mmol/L (<140 mg/dL). Each maternal age or parity group is compared with all other age or parity groups.
In 773 cases the test was performed before week 25 and in 277 cases after week 30; in 371 cases the week of the test was not stated. The material was limited to women with an oral GTT performed in weeks 25 to 30. In some of the missing cases, an oral GTT may have been performed but had not been recorded properly. The impact on participation of 3 maternal characteristics (age, parity, and smoking habits as a proxy for socioeconomic condition) is shown in Table I. Participation was decreased among teenagers; the highest participation was by women between 20 and 29 years old. No significant effect of parity or maternal smoking was seen. The odds ratio for participation among non–Swedish-born women (15% of all), in comparison with Swedish-born women (after stratification for year of birth, age, and parity), was 1.33 (95% confidence interval, 1.27-1.40). Various reasons for nonparticipation were identified. Women with delivery before week 25 could not participate, for instance, and patients with test results that were positive for GDM before 25 weeks’ gestation or with insulin-dependent diabetes were not eligible. In a detailed study of the reasons for nonparticipation based on one antenatal clinic in Lund, 332 pregnant women were registered, 20 of whom miscarried. Of the remaining 312 women available for oral GTT, 16% (n = 49) did not participate. Instead 11 women had a glucose test 2 hours after breakfast, 21 were out of town during the relevant period of pregnancy, 14 refused participation, and 3 gave other reasons. Prevalence of GDM. Among 12,382 women who underwent delivery during the period from May 1, 1995, to April 30, 1998, and who were from areas where a woman with GDM would be referred to the Lund University Hospital for delivery, GDM was identified in 144 women (116
of whom had data matched with the other data sources). This represents a GDM prevalence of 1.2%. Maternal characteristics and glucose values. The analysis was made on data obtained by matching with the Medical Birth Registry data on all singleton deliveries in the studied area (from all 4 delivery units). Table II shows the effect of age and parity (at glucose testing) on the risk of having an increased glucose value. There is a clear-cut trend according to glucose class for maternal age (P < .001 for both glucose classes) but none for parity (P = .39 and P = .25, respectively). Fig 1 illustrates the relationships between blood glucose group and initial weight (reported at first antenatal visit), weight at delivery, maternal height, and prepregnancy BMI. The maternal BMI was lower in the group with the lowest glucose level than in the groups with higher levels, which seems to be partly a result of greater body weight but also of shorter height. With the use of the data obtained by matching with the Medical Birth Registry, the impact of maternal smoking and BMI (registered in early pregnancy) on glucose level at testing could be studied. This also made it possible to compare Swedish-born women with women born abroad. The odds ratio for being in the sub-GDM group in a woman born abroad compared with women born in Sweden (after stratification for maternal age, parity, smoking, and BMI) was 1.33 (95% confidence interval, 0.96-1.86); for having GDM the odds ratio was 0.59 (95% confidence interval, 0.31-1.12). The study was restricted to deliveries occurring in the 4 hospitals located in the study area. Maternal smoking was more prevalent in the sub-GDM group (22% of women with known smoking habits; n = 299) than in the control group (17%; n = 9725). After stratification for
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A
B
C
D
Fig 1. Maternal body dimensions (mean ± SEM) according to glucose levels at oral glucose tolerance testing. A, Initial weight; B, weight at delivery; C, height; D, BMI (prepregnancy values). Data are from all singleton births in region with information on maternal weight and height (N = 10,375).
delivery hospital, maternal age, parity, country of origin, and BMI group, the odds ratio for being a smoker in the sub-GDM group compared with the control group was 1.66 (95% confidence interval, 1.21-2.28). Smoking <10 cigarettes a day gave an odds ratio of 1.52 (95% confidence interval, 1.01-2.30), and smoking ≥10 cigarettes gave an odds ratio of 1.84 (95% confidence interval, 1.19-2.84). Among women with GDM (all delivered in Lund), 9 of 94 women with known smoking habits smoked during pregnancy (9.6%). The odds ratio for smoking compared with the control group (stratified as above) was 0.64 (95% confidence interval, 0.32-1.27). This odds ratio is significantly lower than that for the sub-GDM group. A similar analysis was made for 4 BMI groups (<19.8, 19.8-25.9, 26-28.9, ≥29), with the second group used as a reference. Stratification was made for delivery hospital, maternal age, parity, country of origin, and smoking. The odds ratio for having sub-GDM in the 26-28.9 BMI group was 1.13 (95% confidence interval, 0.75-1.71), and in the ≥29 BMI group the odds ratio was increased to 1.91 (95% confidence interval, 1.34-2.72). The odds ratio for having GDM was increased both at a BMI between 26 and 28.9 (odds ratio, 2.39; 95% confidence interval, 1.39-4.10) and
at a BMI of ≥29 (odds ratio, 3.88; 95% confidence interval, 2.37-6.36). Mode of delivery. Table III describes mode of delivery according to glucose levels. In the sub-GDM group, the total cesarean delivery rate was 13.8%, versus 7.7% in the control group. An odds ratio comparing elective cesarean delivery in the sub-GDM group and in the control group with all other delivery methods, stratified for year of birth, maternal age, and parity, was 1.77 (95% confidence interval, 1.00-3.12). For emergency cesarean delivery the corresponding odds ratio was 1.69 (95% confidence interval, 1.01-2.86). At GDM the corresponding odds ratio for elective cesarean delivery was 4.15 (95% confidence interval, 2.347.38), and for emergency cesarean delivery the odds ratio was 6.94 (95% confidence interval, 3.29-14.65). Gestational duration. The mean (±SD) gestational duration among deliveries in the Lund University Hospital in the control group was 278.3 ± 0.19 days, in the subGDM group it was 276.5 ± 1.10 days, and in the GDM group it was 272.9 ± 1.38 days. The percentage of deliveries at <37 weeks’ gestation was 5.7% in the control group, 8.4% in the sub-GDM group, and 13.8% in the GDM group. The trend is statistically significant (P < .001).
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A
B
Fig 2. Quotients (mean ± SEM) for infant/maternal initial weight (weight at first antenatal visit) (A) and infant/placental weight (B). Data are on women delivered at Lund University Hospital (N = 4773).
Table III. Mode of delivery (at Lund University Hospital) of singleton pregnancies according to blood glucose level Blood glucose level <7.8 mmol/L (<140 mg/dL)
7.8-8.9 mmol/L (140-162 mg/dL)
Gestational diabetes
Mode of delivery
No.
%
No.
%
No.
%
Noninstrumental Forceps or vacuum extraction Elective cesarean Emergency cesarean Unknown
3985 251 108 249 23 4526
86.3 5.4 2.3 5.4 0.5
104 7 6 12 2 131
79.4 5.3 4.6 9.2 1.5
85 7 8 13 3 116
73.3 6.0 6.9 11.2 2.6
TOTAL
Birth weight. Among Lund deliveries, the mean (±SD) birth weight was 3564.3 ± 8.4 g in the control group, 3661.2 ± 54.8 g in the sub-GDM group, and 3542.2 ± 66.3 g in the GDM group. The percentages of infants weighing <2500 g were 3.5%, 2.3%, and 7.8% in the 3 groups (P = .06 for heterogeneity). The percentages of infants with a birth weight of ≥4500 g were 4.5%, 9.9%, and 10.3%, respectively (P = .03 for heterogeneity; P < .001 for trend). Birth weight according to gestational duration. Among infants in the control group, the mean (±SD) birth weight was determined for each gestational week (smoothed between 3 successive weeks) and according to maternal age, parity, and BMI group. Among infants born to sub-GDM women, 28 (24%) had a weight above +1 SD and 9 (8%) below –1 SD. The corresponding numbers for infants born to GDM mothers were 25 (29%) and 14 (16%), respectively. Birth weight, maternal weight, and placental weight. Fig 2 shows that the ratio between infant and maternal initial weights (at first antenatal visit) increased slightly in the sub-GDM group but decreased in the GDM group. Fig 2
also shows that the ratio of infant weight over placental weight decreased with increasing glucose values. Umbilical artery pH and Apgar score. The mean (±SD) umbilical artery pH was 7.259 ±.001 in the control group, 7.249 ± 0.008 in the sub-GDM group, and 7.249 ± 0.009 in the GDM group. In the first group, 46 infants (1%) had a 5-minute Apgar score of <7, none of the 131 infants in the second group had a 5-minute Apgar score of <7, and 2 of 116 infants in the third group had an Apgar score of <7. Perinatal mortality rate. We matched records of infants with the Medical Birth Registry to identify perinatal deaths. Among 4827 singleton deliveries, 4721 could be matched with the Medical Birth Registry. Among 4515 singleton infants born to control women, 11 were stillborn and 2 died during the first week of life (perinatal death rate, 0.3%). The low perinatal death rate is explained by exclusion of infants born before the time for an oral GTT test and the exclusion of multiple births. Among 126 infants born to women with a glucose value of 7.8 to 9 mmol/L, 1 infant was stillborn (0.8%) but no live infant died. Among 116 cases of
82 Åberg, Rydhstroem, and Frid
GDM, 2 infants were stillborn, and 1 of them had multiple malformations. Comment To our knowledge, we are reporting the largest prospective and population-based study of GDM. The high rate of antenatal care in Sweden and the unique personal identification number of every person living in Sweden are excellent prerequisites for studies of this kind. At least 65% of all women delivered of infants were tested with an oral GTT. The nonparticipation was partly the result of various irrelevant factors, but we found increased nonparticipation, notably in pregnant teenagers, whereas socioeconomic conditions (as estimated by smoking habits) seemed to play a minor role. Most of the findings agree with earlier studies, but some are new. Thus our study confirms other reports that a suboptimal pregnancy outcome is associated with maternal glucose tolerance even in the sub-GDM region.2, 6, 7 The increased BMI value in this group of women was caused not only by increased weight but also by shorter height, which has been reported in other studies. Women in this group are delivered of babies with increased birth weights, even with consideration of maternal weight. This increase was found despite the surprising new fact that these women smoked more than women with a glucose level of <7.8 mmol/L (with consideration given to maternal age, parity, BMI, and country of birth). After stratification for smoking, the difference in birth weight increased. One explanation could be that smoking increases insulin resistance.22 On the other hand, women with gestational diabetes smoked significantly less than the control group. An explanation of differences regarding smoking in these groups could be that the insulin resistance caused by smoking was sufficient to place an otherwise normal woman in the sub-GDM group but not to cause GDM. In the GDM group it is possible that the inherited metabolic disturbances outweighed the effects of smoking. However, it is difficult to explain the decreased frequency of smoking in women with GDM. Perhaps there was an increased health awareness if there was a family history of type II diabetes and the associated metabolic syndrome. The ratio between birth weight and placental weight decreased with increasing maternal glucose intolerance. Thus placental weight increased more than birth weight, as previously demonstrated.23 Our finding that women with GDM, despite having an increased BMI, were delivered of normal-size babies was probably an effect of the intense treatment given. This agrees with the Toronto Tri-Hospital Gestational Diabetes Project.24 In the sub-GDM group, only 8% were at <1 SD and 24% were at >1 SD in birth weight. The increased rate of cesarean delivery among women
January 2001 Am J Obstet Gynecol
with GDM agrees with what is known from the literature. We also found an increased rate among women in the sub-GDM group, not explainable from the maternal age–parity distribution. The greater likelihood of delivery before 37 weeks’ gestation in the GDM group was probably caused, to some extent, by induction of delivery because of the GDM diagnosis. However, because the sub-GDM group was treated in the same way as the control group, the higher prematurity rate in the former group is unlikely to have been a result of delivery induction. The rate of induced deliveries at Lund University Hospital is low, ~6%. Data on umbilical cord pH, Apgar score, and perinatal survival did not indicate any significant effect on infant perinatal morbidity. The size of the study, however, would make it possible to detect only more than a doubling in the perinatal mortality rate (α = .05; β = .80). We conclude that women with 2-hour oral GTT values of 7.8 to 8.9 mmol/L have an increased risk of having a nonoptimal delivery outcome. We are thankful to Anders Ericson, National Board of Health, Stockholm, for giving us access to the Medical Birth Registry. REFERENCES
1. O’Sullivan JB, Charles D, Mahan CM, Dandrow RV. Gestational diabetes and perinatal mortality rate. Am J Obstet Gynecol 1973;116:901-4. 2. Pettitt DJ, Knowler WC, Baird HR, Bennett PH. Gestational diabetes: infant and maternal complications of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care 1980;3:458-64. 3. Hod M, Merlob P, Friedman S, Schoenfeld A, Ovadia J. Gestational diabetes mellitus: a survey of perinatal complications in the 1980s. Diabetes 1991;40:74-8. 4. Coustan DR, Imarah J. Prophylactic insulin treatment of gestational diabetes reduces the incidence of macrosomia, operative delivery and birth trauma. Am J Obstet Gynecol 1984;150: 836-42. 5. Langer O, Berkus M, Conway D. Gestational diabetes is a clinical entity: the price of not treating [abstract]. Am J Obstet Gynecol 1997;176(1 Pt 2):S182. 6. Adams KM, Li H, Nelson RL, Ogburn PL, Danilenko-Dixon DR. Sequelae of unrecognized gestational diabetes. Am J Obstet Gynecol 1998;178:1321-32. 7. Drexel H, Bichler A, Sailer S, Breier C, Lisch HJ, Braunsteiner H, et al. Prevention of perinatal morbidity by tight metabolic control in gestational diabetes mellitus. Diabetes Care 1988;11: 761-8. 8. Langer O, Rodriquez DA, Xenakis EMJ, McFarland MB, Berkus MD, Arredondo F. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994;170: 1036-47. 9. Tallarigo L, Giampietro O, Penno G, Miccoli R, Gregori G, Navalesi R. Relation of glucose tolerance to complications of pregnancy in nondiabetic women. N Engl J Med 1986;315: 989-92. 10. Moses RG, Calvert D. Pregnancy outcomes in women without gestational diabetes mellitus related to the maternal glucose level. Diabetes Care 1995;18:1527-33. 11. Nord E, Hanson U, Persson B. Blood glucose limits in the diagnosis of impaired glucose tolerance during pregnancy: relation to morbidity. Acta Obstet Gynecol Scand 1995;74:589-93. 12. Sacks DA, Greenspoon JS, Abu-Fadil S, Henry HM, Wolde-Tsadik
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