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Associations of Maternal Diabetes and Body Mass Index With Offspring Birth Weight and Prematurity.

Author information

Affiliations

  • 1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
      Authors
    • Kong L 1
    • Nilsson IAK 1
    • Lavebratt C 1
    (3 authors)
  • 2. National Institute for Health and Welfare, Helsinki and Oulu, Finland.
      Authors
    • Gissler M 2
    (1 author)

ORCIDs linked to this article

JAMA Pediatrics, 01 Apr 2019, 173(4):371-378
https://doi.org/10.1001/jamapediatrics.2018.5541 PMID: 30801637 PMCID: PMC6450270

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Abstract 

Importance

Maternal obesity, pregestational type 1 diabetes, and gestational diabetes have been reported to increase the risks for large birth weight and preterm birth in offspring. However, the associations for insulin-treated diabetes and non-insulin-treated type 2 diabetes, as well as the associations for joint diabetes disorders and maternal body mass index, with these outcomes are less well documented.

Objective

To examine associations of maternal diabetes disorders, separately and together with maternal underweight or obesity, with the offspring being large for gestational age and/or preterm at birth.

Design, setting, and participants

This population-based cohort study used nationwide registries to examine all live births (n = 649 043) between January 1, 2004, and December 31, 2014, in Finland. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.

Exposures

Maternal prepregnancy body mass index, pregestational diabetes with insulin treatment, pregestational type 2 diabetes without insulin treatment, and gestational diabetes.

Main outcomes and measures

Offspring large for gestational age (LGA) at birth and preterm delivery. Logistic regression models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status.

Results

Of the 649 043 births, 4000 (0.62%) were delivered by mothers who had insulin-treated diabetes, 3740 (0.57%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were born in Finland. Statistically significant interactions existed between maternal body mass index and diabetes on offspring LGA and prematurity (insulin-treated diabetes: LGA F = 3489.0 and prematurity F = 1316.4 [P < .001]; type 2 diabetes: LGA F = 147.3 and prematurity F = 21.9 [P < .001]; gestational diabetes: LGA F = 1374.6 and prematurity F = 434.3 [P < .001]). Maternal moderate obesity, compared with normal-weight mothers with no diabetes, was associated with a mildly increased risk of having an offspring LGA (1069 [3.5%] vs 5151 [1.5%]; adjusted odds ratio [aOR], 2.45; 95% CI, 2.29-2.62), and mothers with insulin-treated diabetes had markedly elevated risks of having an offspring LGA (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% CI, 40.88-46.93) and a preterm birth (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93). Mothers who were moderately obese with type 2 diabetes were at increased risks of LGA (132 [16.4%] vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03) and prematurity (83 [10.3%] vs 17 481 [5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). Mothers who were moderately obese with gestational diabetes had a milder risk of LGA (1195 [6.7%] vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04). Among spontaneous deliveries, the risks were strongest for moderately preterm births, but insulin-treated diabetes was associated with an increased risk also for very and extremely preterm births.

Conclusions and relevance

Maternal insulin-treated diabetes appeared to be associated with markedly increased risks for LGA and preterm births, whereas obesity in mothers with type 2 diabetes had mild to moderately increased risks; these findings may have implications for counseling and managing pregnancies.

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Logo of jamasdLink to Publisher's site
JAMA Pediatr. 2019 Apr; 173(4): 371–378.
PMCID: PMC6450270
PMID: 30801637

Associations of Maternal Diabetes and Body Mass Index With Offspring Birth Weight and Prematurity

Linghua Kong, MSc,1,2 Ida A. K. Nilsson, PhD,1,2 Mika Gissler, PhD,3,4,5 and Catharina Lavebratt, MSc, PhDcorresponding author1,2
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Associated Data

Supplementary Materials

Key Points

Question

Are maternal diabetes disorders, alone or with maternal underweight or obesity, associated with the offspring being large for gestational age and/or preterm at birth?

Findings

In this cohort study of 649 043 births, maternal diabetes treated with insulin was associated with a high risk for the offspring to be large and/or preterm at birth, regardless of prepregnancy body mass index, whereas type 2 diabetes not treated with insulin was associated with a mild to moderate, albeit statistically significant, risk that was stronger in mothers who were obese or severely obese. Gestational diabetes was associated with mild increases in birth size.

Meaning

Maternal diabetes, mainly when treated with insulin, appears to be associated with a greater risk for large birth weight and preterm offspring.

Abstract

Importance

Maternal obesity, pregestational type 1 diabetes, and gestational diabetes have been reported to increase the risks for large birth weight and preterm birth in offspring. However, the associations for insulin-treated diabetes and non–insulin-treated type 2 diabetes, as well as the associations for joint diabetes disorders and maternal body mass index, with these outcomes are less well documented.

Objective

To examine associations of maternal diabetes disorders, separately and together with maternal underweight or obesity, with the offspring being large for gestational age and/or preterm at birth.

Design, Setting, and Participants

This population-based cohort study used nationwide registries to examine all live births (n = 649 043) between January 1, 2004, and December 31, 2014, in Finland. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.

Exposures

Maternal prepregnancy body mass index, pregestational diabetes with insulin treatment, pregestational type 2 diabetes without insulin treatment, and gestational diabetes.

Main Outcomes and Measures

Offspring large for gestational age (LGA) at birth and preterm delivery. Logistic regression models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status.

Results

Of the 649 043 births, 4000 (0.62%) were delivered by mothers who had insulin-treated diabetes, 3740 (0.57%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were born in Finland. Statistically significant interactions existed between maternal body mass index and diabetes on offspring LGA and prematurity (insulin-treated diabetes: LGA F = 3489.0 and prematurity F = 1316.4 [P < .001]; type 2 diabetes: LGA F = 147.3 and prematurity F = 21.9 [P < .001]; gestational diabetes: LGA F = 1374.6 and prematurity F = 434.3 [P < .001]). Maternal moderate obesity, compared with normal-weight mothers with no diabetes, was associated with a mildly increased risk of having an offspring LGA (1069 [3.5%] vs 5151 [1.5%]; adjusted odds ratio [aOR], 2.45; 95% CI, 2.29-2.62), and mothers with insulin-treated diabetes had markedly elevated risks of having an offspring LGA (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% CI, 40.88-46.93) and a preterm birth (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93). Mothers who were moderately obese with type 2 diabetes were at increased risks of LGA (132 [16.4%] vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03) and prematurity (83 [10.3%] vs 17 481 [5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). Mothers who were moderately obese with gestational diabetes had a milder risk of LGA (1195 [6.7%] vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04). Among spontaneous deliveries, the risks were strongest for moderately preterm births, but insulin-treated diabetes was associated with an increased risk also for very and extremely preterm births.

Conclusions and Relevance

Maternal insulin-treated diabetes appeared to be associated with markedly increased risks for LGA and preterm births, whereas obesity in mothers with type 2 diabetes had mild to moderately increased risks; these findings may have implications for counseling and managing pregnancies.

Introduction

Exposure to diabetes in the intrauterine environment has long been recognized to affect fetus birth weight. In the pre–insulin-treatment era, most infants to mothers with pregestational diabetes had low birth weight, because maternal starvation was used to reduce serum glucose levels and avoid fetal death. After insulin treatment was introduced, maternal type 1 diabetes was shown to be associated with an elevated risk for increased infant adiposity and overweight,1 and low infant birth weight was observed for mothers with severe type 1 diabetes vascular complications.2 The degree of fetal influence depends on the severity of diabetes, grade of diabetes control, and mode of treatment.2 More recently, in large population-based studies, gestational diabetes was associated with the offspring being large for gestational age (LGA).3,4 Substances thought to be involved in imbalanced fetal growth in a diabetes milieu include insulin, glucose, leptin, ghrelin, adiponectin, and, in poorly controlled pregnancies, growth hormone and insulin-like growth factors.2 Maternal hyperglycemia leads to increased levels of circulating maternal and fetal insulin, itself a fetal growth hormone.5 Moreover, animal studies suggest that fetal hyperinsulinemia alters the expression of hypothalamic neurotransmitters, leading to increased weight of offspring.6 Insulin can also rewire the hypothalamic circuits regulating food intake in mice7 and thus could potentially affect body weight in the longer perspective.

Furthermore, maternal overweight and obesity have been causally associated with increased offspring birth weight,8 probably through maternal and fetal dysregulation of glucose, insulin, lipid, and amino acid metabolism.9 Genetic variants associated with glucose metabolism and high body mass index (BMI) were more common in offspring with higher birth weight.8 A prospective observational cohort study found that, among women without gestational diabetes, maternal adiposity and leptin levels were stronger metabolic determinants of having an LGA offspring compared with glucose intolerance and lipid levels.10 Correspondingly, a systematic review and meta-analysis showed that underweight women had a higher risk of an offspring with low birth weight and prematurity (birth before gestational week 37) compared with mothers with normal weight.11

With regard to dysmetabolic milieu and risk for prematurity, a national population study in Taiwan showed that women with type 1 diabetes had an increased risk of having a premature offspring.12 To our knowledge, no study has been published about the association between type 2 diabetes and prematurity, but a cohort study of 46 230 pregnancies found that gestational diabetes and lower degrees of maternal hyperglycemia (than gestational diabetes) during pregnancy mildly increased the risk of spontaneous preterm birth.13 The association between maternal obesity and prematurity has been extensively studied in a large Swedish population-based cohort study of 1.6 million births. The study showed that maternal prepregnancy underweight, overweight, and obesity are associated with increased risks of preterm delivery, especially extremely preterm.14 Increased risk of prematurity for mothers with obesity is reported to be associated with medical complications, including diabetes, anemia, and hypertension.15

Although previous studies have demonstrated associations of maternal prepregnancy type 1 diabetes, gestational diabetes, and obesity with offspring LGA and prematurity, the associations between insulin-treated pregestational diabetes and type 2 diabetes not treated with insulin have not been studied, and the joint associations of diabetes and BMI with these outcomes have not been well reported. This study aimed to examine the associations of maternal insulin-treated diabetes, type 2 diabetes without insulin treatment, and gestational diabetes, alone and jointly with maternal underweight or obesity, with offspring being LGA and premature at birth. We used the nationwide Finnish registries of births between January 1, 2004, and December 31, 2014.

Methods

Study Population and Data Sources

The Drugs and Pregnancy database steering committee and the data protection authority in Finland approved this study. Because informed consent is not required in Finland for this type of study, the women and children included in the study were not contacted. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.

All pregnancies ending in live births in Finland between January 1, 2004, and December 31, 2014, were identified using the Drugs and Pregnancy database16 and included 649 043 births. There were no exclusion criteria. These data came from the Medical Birth Register, the Register on Induced Abortions, and the Register of Congenital Malformations, all of which are kept at the Finnish National Institute for Health and Welfare. The Medical Birth Register includes information since 1987 on all live births and stillbirths in Finland with the age of at least 22 gestational weeks or a birth weight of 500 g or more. The Medical Birth Register data are supplemented by birth and death certificates and are complemented by the Cause-of-Death Register and maternity hospital records.

Information from the different registers was merged through record linkages based on unique personal identification numbers assigned to all Finnish citizens and permanent residents. Register linkages were conducted as set out in the permission agreement between the register administrators (National Social Insurance Institution and National Institute for Health and Welfare).

Main Exposures

Data on maternal prepregnancy BMI, from the first prenatal visit, were obtained from the Drugs and Pregnancy database, which restricted the inclusion of data to 2004 as the earliest. The information on maternal prepregnancy height and weight was self-reported at first prenatal visit on the 10th week of pregnancy. Body mass index was calculated as weight in kilograms divided by height in meters squared and categorized according to the World Health Organization classification: underweight (BMI <18.5), normal weight (BMI 18.5 to <25), overweight (BMI 25 to <30), moderately obese (BMI 30 to <35), and severely obese (BMI ≥35).

Information on insulin-treated diabetes was identified using the Register on Reimbursement Drugs (KELA), which records the special reimbursement for insulin medication for diabetes (to which all Finnish citizens and permanent residents are entitled) and is maintained by the National Social Insurance Institution. Register on Reimbursement Drugs automatically registers all reimbursed drug prescriptions (ATC-code) dispensed by Finnish pharmacies since 1996. Maternal type 2 diabetes and gestational diabetes diagnoses were obtained from the Finnish Care Registers for Health Care, which contains information on all hospital inpatient stays (since 1969) and outpatient treatments by physicians in specialized care (since 1998).17 Information on type 2 diabetes was identified by using International Classification of Diseases, Tenth Revision, codes E11, E14, and O24.1 and/or by purchase of ATC A10B, according to the Register on Reimbursement Drugs, with the exclusion criteria being insulin treatment according to the purchase of insulin before or during pregnancy. Information on gestational diabetes was identified by International Classification of Diseases, Tenth Revision, code O24.4 recorded in the Finnish Care Registers for Health Care. Births in the category diabetes with insulin treatment were excluded from the categories type 2 diabetes and gestational diabetes diagnoses, and similarly, births in the category type 2 diagnosis were excluded from the category gestational diabetes diagnosis.

Outcomes and Covariates

Small for gestational age (SGA) and LGA are birth weight and/or length more than 2 SDs below (for SGA) or above (for LGA) the sex- and gestational age–specific reference mean using Finnish standards,18 according to the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.19 Appropriate for gestational age is the measure between the SGA and LGA measures. Prematurity was defined as birth before gestational week 37. Data on offspring birth year, sex, number of fetuses, parity, and maternal age at delivery, smoking status, marital status, and country of birth were used as covariates.

Statistical Analysis

Births were categorized for maternal diabetes into 4 groups: (1) no diabetes, (2) diabetes with insulin treatment, (3) non–insulin-treated type 2 diabetes, and (4) gestational diabetes. The distributions of possible covariates were compared between groups (eTable in the Supplement). Next, the groups were stratified by maternal prepregnancy BMI, and the number and proportion of births with SGA, appropriate for gestational age, LGA, and premature birth were examined in each group. Thereafter, we assessed the statistical interaction between maternal BMI (6-category variable shown in Table 1) and maternal diabetes (yes or no) on LGA and prematurity for each of the 3 types of diabetes. Thereafter, odds ratio (OR) estimates and corresponding 95% Wald CIs were calculated using logistic regression, adjusting for prebirth covariates with a distribution difference between exposure groups: offspring birth year, parity; and maternal age, country of birth (Finland or other), and smoking status (yes or no), as in previous studies.3,14 The reference group was no diabetes with normal BMI (18.5-24.9). Rates (proportions) given in the Results and tables are absolute, whereas the ORs given are adjusted (aOR).

Table 1.

Offspring Birth Weight and Prematurity According to Maternal Diabetes and Prepregnancy Body Mass Index
VariableNo. (%)
SGAAGALGAaPrematurityb
Diabetes category stratified by BMI
Diabetes with insulin treatment (n = 4000)60 (1.5)2338 (58.5)1585 (39.6)1483 (37.1)
<18.52 (3.1)41 (63.1)22 (33.9)24 (36.9)
18.5-2423 (1.3)1088 (59.1)724 (39.4)702 (38.2)
25-2915 (1.4)579 (54.2)472 (44.2)397 (37.2)
30-3412 (2.5)275 (57.9)186 (39.2)186 (39.2)
≥356 (1.7)230 (65.9)113 (32.4)101 (28.9)
Missing2 (1.0)125 (61.6)68 (33.5)73 (36.0)
Type 2 diabetesb (n = 3740)109 (21.9)3152 (84.3)469 (12.8)376 (10.1)
<18.54 (13.8)24 (82.8)1 (3.5)2 (6.9)
18.5-2431 (3.5)817 (91.0)50 (2.2)92 (10.2)
25-2922 (2.6)745 (86.9)90 (3.9)81 (9.5)
30-3423 (2.9)648 (80.4)132 (16.4)83 (10.3)
≥3524 (2.6)747 (79.4)169 (18.0)96 (10.2)
Missing5 (2.4)171 (81.2)27 (12.9)22 (10.5)
Gestational diabetesc (n = 98 568)2367 (2.4)90 666 (92.0)5316 (5.4)5023 (5.1)
<18.561 (5.3)1059 (92.1)25 (2.2)71 (6.2)
18.5-24821 (2.5)30 401 (92.6)1263 (3.9)1543 (4.8)
25-29668 (2.2)28 554 (92.6)1547 (5.0)1507 (4.9)
30-34401 (2.3)16 240 (90.9)1195 (6.7)948 (5.3)
≥35278 (2.4)10 217 (88.8)999 (8.7)664 (5.8)
Missing138 (2.9)4195 (89.1)287 (6.1)290 (6.2)
No diabetes (n = 542 735)18 472 (3.4)512 249 (94.4)10 213 (1.9)28 661 (5.3)
<18.51389 (6.4)20 280 (93.0)118 (0.5)1381 (6.3)
18.5-2411 854 (3.4)331 320 (95.0)5151 (1.5)17 481 (5.0)
25-292930 (2.9)95 600 (94.1)2835 (2.8)5315 (5.2)
30-34885 (2.9)28 642 (93.4)1069 (3.5)1833 (6.0)
≥35340 (3.1)10 068 (92.0)513 (4.7)731 (6.7)
Missing1074 (3.7)26 339 (91.4)527 (1.8)1920 (6.7)

Abbreviations: AGA, appropriate for gestational age; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); LGA, large for gestational age; SGA, small for gestational age.

aMissing data on birthweight are not indicated but are below 0.5%.
bBirths in the category insulin-treated diabetes were excluded from the categories type 2 diabetes and gestational diabetes.
cBirths in the category type 2 diabetes were excluded from the category gestational diabetes.

A second round of analysis was performed to explore to what extent the association of diabetes with insulin treatment, type 2 diabetes, and gestational diabetes with prematurity was explained by spontaneous deliveries, specifically extremely (22-27 weeks), very (28-31 weeks), and moderately (32-36 weeks) preterm deliveries. For this analysis, all planned cesarean delivery births were excluded, and aORs and 95% CIs, adjusted as described, were calculated using full-term (≥37 gestational weeks) births to mothers with no diabetes as the reference. Because the ORs for prematurity mostly overlapped between the 5 maternal BMI groups within a diabetes category, stratification by maternal BMI was not performed in this second round. Finally, the association between LGA and prematurity was estimated by calculating aORs and 95% CIs, adjusted as described, using the full-term non–LGA births as the reference. All statistical analyses were performed using SAS, version 9.3 (SAS Institute Inc).

Results

Of the 649 043 births, 4000 (0.62%) were delivered by mothers who had diabetes with insulin treatment, 3740 (0.58%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were born in Finland. Of the mothers with diabetes with insulin treatment, 3880 (97.0%) purchased insulin also during pregnancy. The maternal prepregnancy BMI was normal for 384 169 mothers (59.2%), whereas 23 061 mothers (3.6%) were underweight, 134 320 mothers (20.7%) were overweight, 49 812 mothers (7.7%) were moderately obese, and 23 747 mothers (3.7%) were severely obese (eTable in the Supplement).

First, we tested for maternal diabetes and obesity association with LGA and prematurity. Of the mothers with diabetes with insulin treatment, 39.6% (n = 1585) of newborns were LGA, whereas for the mothers with type 2 diabetes, the percentage was 12.8% (n = 469); for the mothers with gestational diabetes, the proportion of LGA offspring was double that of mothers with no diabetes (gestational diabetes: 5.4% [n = 5316] vs no diabetes: 1.9% [n = 10 213] (Table 1). Thus, using births to normal-weight mothers with no diabetes as the reference, the aOR for LGA for maternal diabetes with insulin treatment was larger (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% CI, 40.88-46.93) than for maternal type 2 diabetes (469 [12.8%] vs 5151 [1.5%]; aOR, 9.57; 95% CI, 8.65-10.58), whereas maternal gestational diabetes showed the lowest risk for LGA (5316 [5.4%] vs 5151 [1.5%]; aOR, 3.80; 95% CI, 3.66-3.96) (Table 2; eFigure 1a in the Supplement). Statistically significant interactions were found between maternal prepregnancy BMI and maternal diabetes (yes or no) on offspring LGA (diabetes with insulin treatment: F = 3489.0 [P < .001]; type 2 diabetes: F = 147.3 [P < .001]; gestational diabetes: F = 1374.6 [P < .001]). Stratification by maternal BMI and using births to normal-weight mothers with no diabetes as the reference, the OR for LGA for maternal diabetes with insulin treatment was very high in all maternal BMI strata (pointwise aOR, 30-53) but peaked for the mothers who were overweight. For mothers with type 2 diabetes or gestational diabetes or with no diabetes, as maternal prepregnancy BMI increased, the ORs for offspring LGA increased gradually. For example, mothers who were moderately obese with no diabetes had a 3-fold higher risk of having an LGA offspring (1069 [3.5%] vs 5151 [1.5%]; aOR, 2.45; 95% CI, 2.29-2.62); aOR, 3.38; 95% CI, 3.08-3.71). Moderate obesity plus gestational diabetes doubled the aOR (1195 [6.7% vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04), and moderate obesity plus type 2 diabetes further doubled it (132 [16.4%] vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03). In addition, mothers who were underweight with no diabetes had a markedly lower risk of having an LGA offspring (118 [0.5%] vs 5151 [1.5%]; aOR, 0.40; 95% CI, 0.33-0.48) (Tables 1 and ​and22).

Table 2.

Adjusted Odds Ratio for Offspring Large for Gestational Age According to Maternal Body Mass Index and Diabetes
VariableaOR (95% CI)
No DiabetesDiabetes With Insulin TreatmentType 2 DiabetesbGestational Diabetesc
Maternal BMIa
<18.50.40 (0.33-0.48)43.69 (25.98-73.48)2.43 (0.33-17.91)1.59 (1.07-2.37)
18.5–241.00 (NA)45.80 (41.51-50.53)3.85 (2.89-5.13)2.61 (2.48-2.81)
25–291.91 (1.83-2.00)53.44 (47.18-60.53)7.40 (5.93-9.23)3.42 (3.23-3.63)
30–342.45 (2.29-2.62)45.04 (37.33-54.34)12.44 (10.29-15.03)4.72 (4.42-5.04)
≥353.38 (3.08-3.71)30.02 (23.92-37.69)13.90 (11.73-16.47)6.37 (5.94-6.84)
Missing1.08 (0.98-1.18)30.82 (22.93-41.42)8.56 (5.68-12.91)3.79 (3.35-4.29)
Total1.28 (1.24-1.32)43.80 (40.88-46.93)9.57 (8.65-10.58)3.80 (3.66-3.96)

Abbreviations: aOR, adjusted odds ratio; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).

aThe models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status. Reference for BMI strata: births to normal-weight mothers with no diabetes.
bBirths in the category insulin-treated diabetes were excluded from the categories type 2 diabetes and gestational diabetes.
cBirths in the category type 2 diabetes were excluded from the category gestational diabetes.

For mothers with diabetes with insulin treatment, the proportion of premature offspring was 37.1% (1483), whereas among mothers with type 2 diabetes, the proportion was 10.1% (376); mothers with gestational diabetes had a similar proportion of preterm births (5.1% [5023]) as mothers with no diabetes (5.3% [28 661]) (Table 1). Furthermore, among mothers with no diabetes, maternal underweight and obesity were associated with a mildly increased risk of offspring prematurity compared with normal weight. Thus, using births to normal-weight mothers with no diabetes as the reference, the aOR for prematurity for maternal diabetes with insulin treatment was larger (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93) than for maternal type 2 diabetes (376 [10.1%] vs 17 481 [5.0%]; aOR, 2.12; 95% CI, 1.90-2.36), whereas maternal gestational diabetes was not associated with prematurity (Tables 1 and ​and3;3; eFigure 1b in the Supplement). Statistically significant interactions were found between maternal pregestational BMI and maternal diabetes (yes or no) on offspring prematurity (diabetes with insulin treatment: F = 1316.4 [P < .001]; type 2 diabetes: F = 21.9 [P < .001]; gestational diabetes: F = 434.3 [P < .001]). Stratification by maternal BMI and using births to normal-weight mothers with no diabetes as the reference, the aOR for prematurity for maternal diabetes with insulin treatment (pointwise aOR, 11.12-11.73) and type 2 diabetes (pointwise aOR, 1.39-2.19) was similar in all maternal BMI strata, except for a lower diabetes with insulin treatment OR for the mothers who were severely obese (101 [28.9%] vs 17 481 [5.0%]; aOR, 7.39; 95% CI, 5.85-9.32). For mothers who were moderately obese with type 2 diabetes, the risk for prematurity was 2-fold compared with mothers without diabetes of normal weight (83 [10.3%] vs 17 481 [5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). For mothers with gestational diabetes or with no diabetes, as maternal prepregnancy BMI increased, ORs for offspring prematurity tended to increase slightly (eFigure 1b in the Supplement).

Table 3.

Adjusted Odds Ratio for Offspring Prematurity According to Maternal Body Mass Index and Diabetes
VariableaOR (95% CI)
No DiabetesInsulin-Treated DiabetesType 2 DiabetesbGestational Diabetesc
Maternal BMIa
<18.51.32 (1.24-1.39)11.54 (6.96-19.12)1.39 (0.33-5.85)1.26 (0.99-1.60)
18.5-241.00 (NA)11.73 (10.66-12.90)2.19 (1.76-2.72)0.93 (0.88-0.98)
25-291.04 (1.00-1.08)11.12 (9.81-12.61)1.95 (1.55-2.45)0.96 (0.91-1.01)
30-341.20 (1.14-1.26)11.66 (9.69-14.04)2.14 (1.70-2.69)1.05 (0.98-1.12)
≥351.36 (1.26-1.47)7.39 (5.85-9.32)2.11 (1.71-2.61)1.15 (1.06-1.24)
Missing1.36 (1.29-1.43)10.89 (8.16-14.53)2.31 (1.48-3.60)1.25 (1.11-1.41)
Total0.99 (0.97-1.01)11.17 (10.46-11.93)2.12 (1.90-2.36)1.02 (0.99-1.05)

Abbreviations: aOR, adjusted odds ratio; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).

aThe models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status. Reference for BMI strata: births to normal-weight mothers with no diabetes.
bBirths in the category insulin-treated diabetes were excluded from the categories type 2 diabetes and gestational diabetes.
cBirths in the category type 2 diabetes were excluded from the category gestational diabetes.

Second, of all the deliveries, 604 973 (93.2%) were spontaneous (ie, without planned cesarean delivery). We explored the associations of diabetes with insulin treatment, type 2 diabetes, and gestational diabetes with the rates of extremely (22-27 weeks), very (28-31 weeks), and moderately (32-36 weeks) preterm deliveries within the spontaneous deliveries (Table 4). Because the aORs for prematurity mostly overlapped between the 5 maternal BMI groups within a diabetes category (Table 1 and Table 3), stratification by maternal BMI was not performed here. The increased adjusted risk for spontaneous prematurity was strongest for moderately preterm deliveries (diabetes with insulin treatment: 944 [34.2%] vs no diabetes: 22 435 [4.4%]; diabetes with insulin treatment aOR, 11.25 [95% CI, 10.39-12.19]; type 2 diabetes: 274 [8.4%] vs no diabetes: 22 435 [4.4%]; type 2 diabetes aOR, 1.98 [95% CI, 1.75-2.24]; gestational diabetes: 4136 [4.6%] vs no diabetes: 22 435 [4.4%]; gestational diabetes aOR, 1.04 [95% CI, 1.00-1.07]) and was, for diabetes with insulin treatment, statistically significant also for very preterm and extremely preterm deliveries (Table 5; eFigure 2 in the Supplement).

Table 4.

Description of Offspring Prematurity According to Maternal Diabetes
Prematurity Category Stratified by Cesarean Deliverya No. (%)
No DiabetesInsulin-Treated DiabetesType 2 DiabetesbGestational Diabetesc
Planned cesarean delivery (n = 44 070)
All34 326 (100.0)1239 (100.0)466 (100.0)8039 (100.0)
Extremely81 (0.2)2 (0.2)1 (0.2)10 (0.1)
Very330 (1.0)18 (1.4)3 (0.6)54 (0.7)
Moderately2309 (6.7)444 (35.8)60 (12.9)364 (4.5)
Term31 606 (92.1)775 (62.6)402 (86.3)7611 (94.7)
Spontaneous delivery (n = 604 973)
All508 409 (100.0)2761 (100.0)3274 (100.0)90 529 (100.0)
Extremely1044 (0.2)16 (0.6)10 (0.3)125 (0.1)
Very2462 (0.5)59 (2.1)28 (0.8)334 (0.4)
Moderately22 435 (4.4)944 (34.2)274 (8.4)4 136 (4.6)
Term482 468 (94.9)1742 (63.1)2962 (90.5)85 934 (94.9)
aExtremely preterm: <28 weeks’ gestation; very preterm: 28-31 weeks’ gestation; moderately preterm: 32-36 weeks’ gestation; term: ≥37 weeks’ gestation.
bBirths in the category insulin-treated diabetes were excluded from the categories type 2 diabetes and gestational diabetes.
cBirths in the category type 2 diabetes were excluded from the category gestational diabetes.

Table 5.

Adjusted Odds Ratio for Offspring Spontaneous Delivery According to Maternal Diabetesa
Prematurity Categories Stratified by Cesarean DeliverybaOR (95% CI)
Insulin-Treated DiabetesType 2 DiabetescGestational Diabetesd
All preterms10.88 (10.06-11.77)1.96 (1.74-2.20)0.99 (0.96-1.03)
Extremely preterm2.83 (1.73-4.65)1.49 (0.80-2.78)0.67 (0.55-0.81)
Very preterm4.49 (3.46-5.83)1.77 (1.22-2.58)0.76 (0.68-0.85)
Moderately preterm11.25 (10.39-12.19)1.98 (1.75-2.24)1.04 (1.00-1.07)

Abbreviation: aOR, adjusted odds ratio.

aSpontaneous delivery excluded planned cesarean delivery.
bThe models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status. Reference: no diabetes and being full term. Extremely preterm: <28 weeks’ gestation; very preterm: 28-31 weeks’ gestation; moderately preterm: 32-36 weeks’ gestation; term: ≥37 weeks’ gestation.
cBirths in the category insulin-treated diabetes were excluded from the categories type 2 diabetes and gestational diabetes.
dBirths in the category type 2 diabetes were excluded from the category gestational diabetes.

Third, we tested for LGA association with prematurity. Compared with non–LGA, LGA was associated with a doubled risk for prematurity irrespective of maternal diabetes (all births aOR, 2.61 [95% CI, 2.49-2.74]; spontaneous births aOR, 2.62 [95% CI, 2.49-2.76]).

Discussion

In this large population-based cohort study, with nationwide effect estimates for 11 years (2004 through 2014), we provide evidence of a markedly increased risk for LGA and prematurity at birth after intrauterine exposure to maternal diabetes with insulin treatment. Smaller, but clearly statistically significant, increased LGA risks were found also for mothers with type 2 diabetes and gestational diabetes not treated with insulin, especially in combination with prepregnancy overweight or obesity that were stronger for type 2 diabetes than gestational diabetes. In addition, prematurity was increased for mothers with type 2 diabetes, independent of prepregnancy BMI. The implication for spontaneous deliveries was strongest for the moderately preterm births, but diabetes with insulin treatment increased the risk also for very and extremely preterm deliveries. Prepregnancy BMI, with no diabetes, affected the risk for LGA and prematurity. The associations of maternal diabetes with LGA and prematurity were not independent, as LGA was associated with a mildly increased risk for premature birth. To our knowledge, this is the first study to explore an association for diabetes with insulin treatment, type 2 diabetes, and gestational diabetes, stratified by maternal BMI, with the risk of LGA and prematurity.

Maternal glucose metabolism during pregnancy differs from that in the nonpregnant state; insulin resistance is increased, directing fat as the mother’s energy source to ensure adequate carbohydrate supply for the growing fetus. This increase in insulin resistance is mediated by a number of factors, such as increased levels of progesterone, estrogen, and human placental lactogen.20 As the fetus grows, insulin resistance increases, and with this postprandial glucose levels, basal and stimulated insulin secretion as well as hepatic glucose production rise, compared with the nonpregnant state. The presence of diabetes can aggravate these pregnancy-related metabolic changes. The association of maternal diabetes with insulin treatment with offspring LGA could also be a consequence of hyperinsulinemia as a result of the treatment with the growth hormone insulin. However, the effect size of diabetes with insulin treatment on LGA in this study was much larger than that reported in a nationwide cohort in Taiwan (OR, 4.44; 95% CI, 3.99-4.95),12 despite similar adjustment for potential confounders. The association of type 2 diabetes and gestational diabetes with increased risk of LGA was found primarily for mothers who were obese, probably because both obesity and diabetes are associated with hyperglycemia and insulin resistance,21,22,23,24 leading to increased placental glucose transfer and fetal secretion of insulin1 in combination with an excess of blood lipids, adiponectin, and leptin.9 In addition, other metabolic factors (eg, ghrelin) seem to be involved.2 Adiponectin, leptin, and ghrelin are hormones that directly affect the hypothalamic regulation of energy homeostasis,25 a system that develops in utero, particularly during the last trimester.26 A direct correlation between the levels of these hormones in cord blood and birth weight has been documented.2

No large study exists, to our knowledge, on the association of maternal type 2 diabetes with LGA, but our effect sizes of gestational diabetes on LGA are in agreement with those in previous studies,3,4 although the joint association with prepregnancy BMI has been explored only to a small extent. In addition, a population-based cohort study showed that gestational diabetes was associated with both increased birth weight and body weight at 5 years.27 Even maternal hyperglycemia, milder than for gestational diabetes diagnosis, showed an association with higher birth weight.28

With regard to the association of maternal diabetes with prematurity, we found a markedly high aOR of diabetes with insulin treatment, and a smaller, but clearly statistically significant aOR of type 2 diabetes, but no association with gestational diabetes. The same was seen for spontaneous deliveries. An increased risk was seen mainly for moderate prematurity, but diabetes with insulin treatment increased the risk also for very and extremely preterm deliveries. Mechanisms that may contribute to preterm delivery for mothers with obesity and diabetes include hyperglycemia, lipotoxicity, insulin resistance, and oxidative stress leading to endothelial dysfunction.29,30 The Hyperglycemia Adverse Pregnancy Outcome study demonstrated increasing risks of preterm delivery with increasing maternal glucose levels in women with no diabetes.28 Furthermore, diabetes increases the risk of preeclampsia, which is associated with higher risk for preterm births.31

Only a few large studies exist on maternal diabetes and offspring prematurity. The cohort study in Taiwan showed that mothers with type 1 diabetes had an increased risk of preterm birth (<37 weeks; OR, 4.21 [95% CI, 3.78–4.71]).12 With regard to the association of gestational diabetes with spontaneous preterm birth, an OR of 1.42 (95% CI,1.15–1.77) was reported in a US study, which was not very different to the present study’s finding.13 Furthermore, in this study, mothers who were underweight or obese had a slightly elevated risk of a preterm delivery. Our risk estimates for mothers who were underweight, obese, or severely obese delivering prematurely were similar to those previously reported in a nationwide study of the association of maternal BMI with prematurity in Sweden.14

Strengths and Limitations

To our knowledge, this study is the largest and most comprehensive population-based study to explore the joint association of maternal diabetes and prepregnancy BMI with the risk for offspring LGA and prematurity. It also covers different diagnoses separately, including diabetes with insulin treatment and non–insulin-treated type 2 diabetes and gestational diabetes, and the BMI groups from underweight to severe obesity, thereby providing novel data. The LGA measure was based on Finnish standards of both body weight and length. For prematurity at birth, we stratified for gestational age.

Limitations of this study should be taken into account as well. First, data on offspring congenital anomalies, maternal complications (eg, preeclampsia), and grade of diabetes control during pregnancy were not available. Second, maternal BMI information was available from only 1 time point; thus, risk of change in maternal gestational BMI on offspring could not be studied. The prepregnancy weight was self-reported but indirectly controlled given that the height and weight are routinely measured during the Finnish prenatal care.

Conclusions

Using data from a large nationwide registry cohort, we estimated the risks of maternal prepregnancy BMI and different types of diabetes, considering both separate and joint associations with offspring birth size and prematurity. In utero exposure to maternal diabetes treated with insulin appeared to be associated with large risks for offspring LGA and prematurity regardless of the maternal prepregnancy BMI. Maternal type 2 diabetes not treated with insulin was also associated with increased risks of offspring LGA and prematurity. The increased rate of prematurity was primarily for moderately preterm deliveries. These findings may have implications for counseling and managing pregnancies to prevent adverse birth outcomes.

Notes

Supplement.

eTable. Demographic Characteristics of Offspring and Their Mothers (N = 649,043 births)

eFigure 1. Odds Ratio (OR) for Offspring Large for Gestational Age (1.a) and Prematurity (1.b) in Relation to Maternal BMI and Diabetes

eFigure 2. Odds Ratio (OR) for Offspring Spontaneous Delivery (Without Planned Caesarean Section) in Relation to Maternal Diabetes

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