Martina Persson

Obstetric and Perinatal Outcomes in Type 1 Diabetic Pregnancies: A large, population-based study

OBJECTIVE To perform comparative analyses of obstetric and perinatal outcomes between type 1 diabetic pregnancies and the general obstetric population in Sweden between 1991 and 2003. RESEARCH DESIGN AND METHODS This was a population-based study. Data were obtained from the Medical Birth Registry, covering >98% of all pregnancies in Sweden. A total of 5,089 type 1 diabetic pregnancies and 1,260,207 control pregnancies were included. Odds ratios (ORs) were adjusted for group differences in maternal age, parity, BMI, chronic hypertensive disease, smoking habits, and ethnicity. RESULTS In type 1 diabetes, preeclampsia was significantly more frequent (OR 4.47 [3.77–5.31]) as was delivery by cesarean section (5.31 [4.97–5.69]) compared with results for the general population. Stillbirth (3.34 [2.46–4.55]), perinatal mortality (3.29 [2.50–4.33]), and major malformations (2.50 [2.13–2.94]) were more common in type 1 diabetic than in control pregnancies. The risk of very preterm birth (<32 gestational weeks) was also higher among type 1 diabetic women (3.08 [2.45–3.87]). The incidence of fetal macrosomia (birth weight ≥2 SD above the mean) was increased in the diabetic group (11.45 [10.61–12.36]). CONCLUSIONS Type 1 diabetes in pregnancy is still associated with considerably increased rates of adverse obstetric and perinatal outcomes. The eightfold increased risk for fetal macrosomia in type 1 diabetic pregnancies is unexpected and warrants further investigation.

Pre-pregnancy body mass index and the risk of adverse outcome in type 1 diabetic pregnancies: a population-based cohort study.

Objective To assess the risk of perinatal complications in overweight and obese women with and without type 1 diabetes (T1DM). Design Prospective population-based cohort study. Setting This study was based on data from the Swedish Medical Birth Registry from 1998 to 2007. Participants 3457 T1DM and 764 498 non-diabetic pregnancies were included. T1DM was identified based on ICD code O24.0. Mothers were categorised according to pre-pregnancy body mass index (BMI: weight in kilograms per height in square metres) as normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9) or obese (BMI ≥30). Only women with singleton pregnancies and with data on BMI were included. Primary/secondary outcomes The primary outcome was large for gestational age (LGA: birth weight >90th percentile) infants. Secondary outcomes were major malformations, pre-eclampsia (PE), preterm delivery, perinatal mortality, delivery by Caesarean section and neonatal overweight. Logistic regression analysis was performed with normal weight non-diabetic women as the reference category and also within the diabetic cohort with normal weight type 1 diabetic women as the reference. The ORs were adjusted for ethnicity, maternal age, height, parity, smoking and chronic hypertension. Results 35% of women with T1DM were overweight and 18% were obese, as compared with 26% and 11%, respectively, in non-diabetic pregnancies. The incidences of adverse outcome increased with greater BMI category. As compared with non-diabetic normal weight women, the adjusted OR for obese T1DM for LGA was 13.26 (95% CI 11.27 to 15.59), major malformations 4.11 (95% CI 2.99 to 5.65) and PE 14.19 (95% CI 11.50 to 17.50). T1DM was a significant effect modifier of the association between BMI and LGA, major malformations and PE (p<0.001). Conclusion High pre-pregnancy BMI is an important risk factor for adverse outcome in type 1 diabetic pregnancies. The combined effect of both T1DM and overweight or obesity constitutes the greatest risk. It seems prudent to strive towards normal pre-pregnancy BMI in women with T1DM.

Birth Size Distribution in 3,705 Infants Born to Mothers With Type 1 Diabetes: A population-based study

OBJECTIVE To characterize birth size distribution in infants born to mothers with type 1 diabetes. In particular, the relationship between birth weight (BW) and length (BL) was studied because it may provide information on different causal pathways of fetal macrosomia commonly seen in diabetic pregnancies. RESEARCH DESIGN AND METHODS This was a population-based cohort study of 3,705 infants of type 1 diabetic mothers (1,876 boys), with a gestational age of 28–43 weeks, born in Sweden between 1998 and 2007. BW and BL were retrieved from the Medical Birth Registry and expressed as SD scores (SDS). Ponderal index (PI) was calculated as BW in g/length in cm3. A BW >90th and a PI ≤90th percentile was defined as proportionate large-for-gestational age (LGA), whereas if both BW and PI >90th percentile, the infant was categorized as disproportionately large. Values are mean (SD). RESULTS The BW distribution for offspring of type 1 diabetic mothers was bell-shaped, significantly broader, and markedly shifted to the right (BWSDS: 1.27 [1.48]) of the reference. Of the infants born to diabetic mothers, 47% were LGA, and among them, 46% were disproportionately large compared with 35% in nondiabetic LGA infants (P < 0.001). Female offspring of type 1 diabetic mothers had significantly higher BWSDS than males (1.34 vs. 1.20, P < 0.01), and preterm infants had higher BWSDS than term infants (1.41 vs. 1.23, P < 0.01) CONCLUSIONS Fetal macrosomia in type 1 diabetic pregnancies is due to a right-shift and broadening of the entire BW distribution. The large number of disproportionate LGA infants born to type 1 diabetic mothers suggests an underlying metabolic problem. Fetal macrosomia was more pronounced in preterm and female offspring of type 1 diabetic mothers.

Risk of major congenital malformations in relation to maternal overweight and obesity severity: cohort study of 1.2 million singletons

Objective To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (≥40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy. Design Population based cohort study. Setting Nationwide Swedish registries. Participants 1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages. Exposure Maternal BMI at the first prenatal visit. Main outcome measures Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year. Results A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers. Conclusions Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range.

Maternal overweight and obesity are associated with increased risk of type 1 diabetes in offspring of parents without diabetes regardless of ethnicity.

Aims/hypothesisThe incidence of type 1 diabetes in children is increasing in Sweden, as is the prevalence of maternal overweight/obesity. Therefore, the aim of this study was to investigate if maternal overweight/obesity increases the risk of type 1 diabetes in offspring of parents with and without diabetes, and of different ethnicities.MethodsThe study cohort comprised 1,263,358 children, born in Sweden between 1992 and 2004. Children were followed from birth until diagnosis of type 1 diabetes, emigration, death or end of follow-up in 2009, whichever occurred first. First trimester maternal BMI was calculated (kg/m2). Poisson regression was used to calculate incidence rate ratios (IRRs) with 95% CI for type 1 diabetes in the offspring.ResultsThe risk of type 1 diabetes was increased in offspring of parents with any type of diabetes regardless of parental ethnicity. High first trimester maternal BMI was associated with increased risk of type 1 diabetes only in offspring of parents without diabetes (IRR 1.33 [95% CI 1.20, 1.48]).Conclusions/InterpretationIncreasing incidence of type 1 diabetes in children with non-diabetic parents may partly be explained by increasing prevalence of maternal overweight/obesity.

The trends and the risk of type 1 diabetes over the past 40 years: an analysis by birth cohorts and by parental migration background in Sweden

Objective To investigate the trends and the risk of developing type 1 diabetes in the offspring of Swedes and immigrants by specific parental migration background, age, sex and birth cohort. Design Registry-based cohort study. Setting Using Swedish nationwide data we analysed the risk of developing type 1 diabetes in 3 457 486 female and 3 641 304 male offspring between 0 and 30 years of age, born to native Swedes or immigrants and born and living in Sweden between 1969 and 2009. We estimated incidence rate ratios (IRRs) with 95% CIs using Poisson regression models. We further calculated age-standardised rates (ASRs) of type 1 diabetes, using the world population as standard. Results We observed a trend of increasing ASRs among offspring below 15 years of age born to native Swedes and a less evident increase among offspring of immigrants. We further observed a shift towards a younger age at diagnosis in younger birth cohorts in both groups of offspring.Compared with offspring of Swedes, children (0–14 years) and young adults (15–30 years) with one parent born abroad had an overall 30% and 15–20% lower IRR, respectively, after multivariable adjustment. The reduction in IRR was even greater among offspring of immigrants if both parents were born abroad. Analysis by specific parental region of birth revealed a 45–60% higher IRR among male and female offspring aged 0–30 years of Eastern Africa. Conclusions Parental country of birth and early exposures to environmental factors play an important role in the aetiology of type 1 diabetes.

Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes.

The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1–18 years with islet autoantibody–positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB1*03:01:01 was affected by DRB3*01:01:02 and DRB3*02:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA-2A, and IAA. The negative association between type 1 diabetes and DRB1*13:01:01 was affected by DRB3*01:01:02 to increase the risk and by DRB3*02:02:01 to maintain a negative association. DRB4*01:03:01 was strongly associated with type 1 diabetes (P = 10−36), yet its association was extensively affected by DRB1 alleles from protective (DRB1*04:03:01) to high (DRB1*04:01:01) risk, but its association with DRB1*04:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials.

Perinatal outcome in relation to fetal sex in offspring to mothers with pre‐gestational and gestational diabetes—a population‐based study

The objective of the present study was to investigate if perinatal outcome differs with fetal sex in pregnancies with maternal Type 1 diabetes, Type 2 diabetes or gestational diabetes.

Disproportionate Body Composition and Neonatal Outcome in Offspring of Mothers With and Without Gestational Diabetes Mellitus

OBJECTIVE High birth weight is a risk factor for neonatal complications. It is not known if the risk differs with body proportionality. The primary aim of this study was to determine the risk of adverse pregnancy outcome in relation to body proportionality in large-for-gestational-age (LGA) infants stratified by maternal gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS Population-based study of all LGA (birth weight [BW] >90th percentile) infants born to women with GDM (n = 1,547) in 1998–2007. The reference group comprised LGA infants (n = 83,493) born to mothers without diabetes. Data were obtained from the Swedish Birth Registry. Infants were categorized as proportionate (P-LGA) if ponderal index (PI) (BW in grams/length in cm3) was ≤90th percentile and as disproportionate (D-LGA) if PI >90th percentile. The primary outcome was a composite morbidity: Apgar score 0–3 at 5 min, birth trauma, respiratory disorders, hypoglycemia, or hyperbilirubinemia. Logistic regression analysis was used to obtain odds ratios (ORs) for adverse outcomes. RESULTS The risk of composite neonatal morbidity was increased in GDM pregnancies versus control subjects but comparable between P- and D-LGA in both groups. D-LGA infants born to mothers without diabetes had significantly increased risk of birth trauma (OR 1.19 [95% CI 1.09–1.30]) and hypoglycemia (1.23 [1.11–1.37]). D-LGA infants in both groups had significantly increased odds of Cesarean section. CONCLUSIONS The risk of composite neonatal morbidity is significantly increased in GDM offspring. In pregnancies both with and without GDM, the risk of composite neonatal morbidity is comparable between P- and D-LGA.

Disproportionate body composition and perinatal outcome in large-for-gestational-age infants to mothers with type 1 diabetes

Please cite this paper as: Persson M, Pasupathy D, Hanson U, Norman M. Disproportionate body composition and perinatal outcome in large‐for‐gestational‐age infants to mothers with type 1 diabetes. BJOG 2012;119:565–572.