The diabetic pregnancy and offspring BMI in childhood: a systematic review and meta-analysis
- First Online:
- Cite this article as:
- Philipps, L.H., Santhakumaran, S., Gale, C. et al. Diabetologia (2011) 54: 1957. doi:10.1007/s00125-011-2180-y
Offspring of mothers with diabetes are at increased risk of metabolic disorders in later life. Increased offspring BMI is a plausible mediator. We performed a systematic review and meta-analysis of studies examining offspring BMI z score in childhood in relation to maternal diabetes.
Papers reporting BMI z scores for offspring of diabetic (all types, and pre- and during-pregnancy onset) and non-diabetic mothers were included. Citations were identified in PubMed; bibliographies of relevant articles were hand-searched and authors contacted for additional data where necessary. We compared offspring BMI z score with and without adjustment for maternal pre-pregnancy BMI. We performed fixed effect meta-analysis except where significant heterogeneity called for use of a random effects analysis.
Data were available from nine studies. In the diabetic group unadjusted mean offspring BMI z score was 0.28 higher (all diabetic mothers vs controls (95% CI 0.09, 0.47; p = 0.004; nine studies; offspring of diabetic mothers n = 927, controls n = 26,384) and with adjustment for maternal pre-pregnancy BMI, 0.07 higher (95% CI −0.15, 0.28; p = 0.54; three studies; offspring of diabetic mothers n = 244, controls n = 11,206). There was no evidence of a difference in offspring BMI z score in relation to type of diabetes (gestational vs type 1, p = 0.95).
Maternal diabetes is associated with increased offspring BMI z score, although this is no longer apparent after adjustment for maternal pre-pregnancy BMI in the limited number of studies in which this is reported. Causal mediators of the effect of maternal diabetes on offspring outcomes remain to be established; we recommend that future research includes adjustment for maternal pre-pregnancy BMI.
KeywordsBMIDiabetesGestational diabetesInfantMaternal diabetesMeta-analysisObesityOffspring of diabetic pregnancyPregnancySystematic review
Gestational diabetes mellitus
Offspring of diabetic mothers
The prevalence of maternal diabetes during pregnancy has increased over the last two decades, with every indication that this rise will continue. In 2004, five pregnancies per 1,000 in the UK were complicated by pre-existing diabetes, an increase of more than 50% since 1996, reflecting a sixfold increase in type 2 diabetes and a 20% increase in type 1 diabetes . Over the same period the prevalence of gestational diabetes mellitus (GDM) has doubled and currently affects 40 pregnancies per 1,000 .
Exposure to a diabetic intrauterine environment has long been recognised as a risk to the fetus. A growing body of evidence suggests that intrauterine exposure to diabetes may ‘programme’ long-term effects in offspring, as first described in 1979 by Freinkel and Metzger as fuel-mediated teratogenesis [3, 4]. Follow-up studies of offspring of diabetic pregnancies have demonstrated an increased rate of diabetes or pre-diabetes in the offspring  and features of the ‘metabolic syndrome’  (obesity, glucose intolerance, hypertension and dyslipidaemia). Animal studies also show that intrauterine exposure to hyperglycaemia increases the risk of overweight, abnormal glucose tolerance and insulin resistance in offspring [7, 8]. Studies in Pima Indians show that the intrauterine environment is an important determinant in the development of diabetes, independent of genetic factors . Children born after their mother developed type 2 diabetes had 3.7 times the risk of developing type 2 diabetes and a higher BMI than siblings born before their mother became diabetic . Although data such as these indicate that a diabetic pregnancy predisposes offspring to obesity and abnormal glucose tolerance independent of genetic determinants , the strength of the association and the mediating biological pathways are unknown.
An elevated BMI is a risk factor for the development of type 2 diabetes and often the first marker of the metabolic syndrome . Given the increased risk of developing type 2 diabetes in later life in children born to mothers with diabetes , it is plausible that this might be mediated through an increase in offspring BMI. However, to date individual studies examining BMI in offspring of diabetic mothers (ODM) have been small with limited power and contradictory results [13–15].
The primary aim of this systematic review and meta-analysis was to establish the impact of maternal diabetes on offspring BMI z score. Secondary objectives were to distinguish the effect of type of maternal diabetes, and effects after adjustment for maternal BMI.
A systematic review of published studies reporting outcomes of diabetic and non-diabetic pregnancies was undertaken in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for systematic reviews of observational studies .
The outcome studied was offspring BMI z score, standardised for age and sex. All types of maternal diabetes mellitus, pre-pregnancy type 1, type 2 and gestational onset, were considered as exposures. For inclusion, an unselected non-diabetic control group must have been reported within the same paper. Inclusion criteria for offspring were age between 3 and 16 years of age and offspring of a singleton pregnancy.
A search was conducted in PubMed (www.ncbi.nlm.nih.gov) for studies published before 1 November 2010, using Medline subject heading keywords (Pregnancy in diabetics OR diabetes, gestational) and (Prenatal exposure delayed effects OR Child). The review was limited to human studies published in English. The primary investigator, L. H. Philipps, assisted by E. Prior, conducted the searches and identified studies relevant to the outcome by evaluating the abstract or obtaining a full copy of the paper if no abstract was available. Reference lists of papers retrieved were hand-searched for inclusion in the review. Wherever possible, forward citations of the studies retrieved during the literature search were traced. In studies where anthropometric data on the offspring had been obtained but no BMI z score reported, efforts were made by M. J. Hyde to contact the author to obtain the relevant data. Review articles and commentaries were excluded. Where one or more papers had been published on the same cohort, only the study that reported the outcomes for the cohort at an age closest to the median age of the studies overall was included.
Data extraction and analysis
Information on the characteristics of the study population, outcome, exposure, covariates, results and conclusions were independently extracted from each paper by L. H. Philipps, C. Gale and checked by M. J. Hyde and S. Santhakumaran. Study quality was examined in respect to blinding of assessors to maternal diabetes status when measuring offspring outcomes.
A meta-analysis of studies examining the association between diabetes during pregnancy and offspring BMI z score was conducted by L. H. Philipps, S. Santhakumaran and M. J. Hyde in RevMan 5 (5.0.24)  using the inverse variance method. Subgroup analysis was carried out to compare offspring BMI z score in relation to type of maternal diabetes. The differences between the subgroup effects were tested for significance using an interaction test .
Where studies only reported subgroup analyses for different types of diabetes, pooled means and standard deviations were calculated for use in the meta-analysis of all diabetes types combined, provided that recruitment was not stratified on the basis of type of diabetes, which would prevent the results being generalisable to the population.
A meta-analysis was carried out on studies that reported offspring BMI z score adjusted for maternal pre-pregnancy BMI. Where data adjusted for maternal pre-pregnancy BMI were not available, difference in mean maternal pre-pregnancy BMI between cases and controls was calculated for each individual study. For each study, the difference in mean maternal BMI was plotted against the mean difference in offspring BMI z score.
A fixed effects analysis was initially carried out for all comparisons. Heterogeneity was assessed using the χ2 test on Cochrane’s Q statistic  and by calculating I2 . If significant heterogeneity was present (p < 0.05 from the χ2 test) a random effects meta-analysis was carried out. Potential sources of heterogeneity were investigated by comparing study designs. If study covariates that might explain heterogeneity were identified, meta-regression was used to investigate the significance of the associations. Similarly, where there was doubt as to the eligibility or quality of a study the meta-analysis was performed both with and without the study in order to verify the sensitivity of the conclusions.
Forest plots were used to illustrate study findings and meta-analysis results, and funnel plots to investigate evidence of publication bias. If funnel plots showed asymmetry, Egger’s test was performed .
Studies included in this meta-analysis examining the association between intrauterine exposure to maternal diabetes and offspring BMI z score
Number of subjects
Age at outcome (years)
Mean (SD) BMI z score in controls
Mean (SD) BMI z score in cases
Details of adjusted analyses (adjusted difference given as mean difference ± SE)
Catalano et al., 2009 
PC; USA; GDM; controls selected from general hospital population; blinding not stated
1 h 50 g glucose screening test at 24–28 weeks gestation. Glucose ≥ 7.5 mmol/l was considered positive. Subjects with a positive result underwent a 3 h 100 g OGTT, according to the National Diabetes Group criteria
Diet controlled unless glycaemic targets not achieved then insulin controlled
0.31 ± 1.16
0.90 ± 1.40
Gillman et al., 2003 
RC; USA; GDM; Growing Up Today Study; controls from same cohort; blinding not stated
Maternal report of diabetes during pregnancy diagnosed by a doctor
0.15 ± 1.02
0.33 ± 1.01
Hunter et al., 2004 
PC; New Zealand; T1 and T2; controls selected from general practice population; blinding not stated
T1: Onset <30 years old and one or more of: autoantibodies, ketoacidosis, normal BMI, no first-degree relative with type 2 diabetes, commencement of insulin therapy at diagnosis.
T1 insulin controlled before pregnancy
−0.2 ± 2.3
T1: 0.7 ± 2.5
T2: BMI > 30 kg/m2 and one or more of: no insulin therapy requirement, non-ketosis, acanthosis nigrans
T2 insulin if glycaemic levels not sufficiently managed by diet
T2: 3.2 ± 2.2
Krishnaveni et al., 2010 
PC; India; GDM; controls selected from general hospital population; blinding not stated
GDM as specified by the Carpenter and Coustan criteria
9.5 (mean, range not stated)
−0.06 ± 1.06
0.79 ± 1.0
Lawlor et al., 2010 
PC–ALSPAC; UK; GDM and PGDM; controls from ALSPAC; blinding not stated
GDM and PGDM diagnosed from maternal medical records
−0.006 ± 0.991
GDM: 0.302 ± 1.225
Maternal age, social class, parity, smoking during pregnancy, mode of delivery and pre-pregnancy BMI.
PGDM: 0.129 ± 1.280
Mean difference in z-score between controls and GDM: 0.01 ± 0.32 (n = 40); controls and PGDM: 0.05 ± 0.20 (n = 26)
Lindsay et al., 2010 
PC; UK; T1; controls selected from general hospital population; blinding not stated
Report of type 1 diabetes from medical records
0.28 ± 0.78
0.69 ± 1.2
Maternal BMI at time of study
Control z score: 0.33 ± 0.16
ODM z score: 0.67 ± 0.11
Manderson et al., 2002 
RC; UK; T1; matched controls selected from general hospital population; blinding not stated
Confirmed type 1 diagnosis before the pregnancy according to maternal records
0.6 ± 1.21
0.59 ± 1.35
Whitaker et al., 1998 
PC; USA; GDM; controls selected from general hospital population; blinding not stated
1 h 50 g glucose screening test at 24–32 weeks gestation. Glucose ≥ 7.77 mmol/l was considered positive. Subjects with a positive result underwent a 3 h 100 g OGTT according to the Carpenter and Coustan criteria
Diet controlled, offspring of mothers receiving insulin excluded from the analysis (n = 5)
0.45 ± 0.93
0.39 ± 0.94
Wright et al., 2009 
PC–Project Viva; USA; GDM; controls from Project Viva; blinding not stated
1 h 50 g glucose screening test at 26–28 weeks gestation. Glucose >7.8 mmol/l was considered positive. Subjects with a positive result underwent a 3 h 100 g OGTT. Abnormal was considered to be >5.3 mmol/l at baseline, >10.0 mmol/l at 1 h, >8.6 mmol/l at 2 h and >7.8 mmol/l at 3 h. Women with two or more abnormal OGTT were classified as having GDM
Followed by nutritionist and given insulin if required
0.44 ± 1.02
0.47 ± 1.20
Maternal age, education, race/ethnicity, smoking history, BMI, pregnancy weight gain, parity, paternal BMI and fetal growth.
Mean adjusted difference −0.08 ± 0.15 (p = 0.61)
Offspring BMI z score
Only one study reports a difference between mothers with pre-pregnancy type 2 diabetes and controls , so no meta-analysis can be performed for this subgroup. Assessor blinding is not specified in any included study, therefore a subgroup analysis by study quality cannot be performed.
This large, comprehensive meta-analysis identifies a strong association between exposure to maternal diabetes in utero and increased offspring BMI in childhood. In studies in which adjustment is made for maternal pre-pregnancy BMI, this relationship is no longer significant. Previous studies have been small with limited power and have provided contradictory results [13–15].
Studies which could not be included in this meta-analysis as they report overweight and obesity as outcomes rather than BMI z score, also show attenuation towards the null following adjustment for maternal pre-pregnancy BMI. Hummel et al.  reported odds ratios for overweight of 1.1 (0.7, 1.9) (unadjusted) and 0.8 (0.5, 1.4) (adjusted), Gillman et al.  1.4 (1.0, 1.9) (unadjusted) and 1.2 (0.8, 1.7) (adjusted) and Whitaker et al.  1.36 (p = 0.4) (unadjusted), and p = 0.53 after adjustment. We also show a correlation between the difference in mean BMI of diabetic and non-diabetic mothers and the difference in mean offspring BMI z score. These data might be interpreted as indicating that the relationship between maternal and offspring BMI in childhood is due to a common genetic potential and/or a shared postnatal obesogenic environment, rather than intrauterine programming secondary to maternal glycaemia of lesser degree than in overt diabetes (for which maternal BMI is a proxy). However, data from studies of Pima Indian siblings show that offspring born before the onset of maternal diabetes have lower childhood BMI than siblings born after the onset of maternal diabetes (with no difference relating to the onset of paternal diabetes) . This suggests the long-term influence of a diabetic intrauterine environment, rather than the impact of postnatal or genetic factors. Similarly, altered offspring glucose tolerance can be induced in rats by intravenous glucose administration during the final days of gestation . Deierlain et al. suggest that blood glucose concentration at 27 weeks gestation is a strong predictor of offspring overweight at 3 years of age, even when adjusted for maternal BMI . Consequently, we suggest that caution should be exercised in rejecting the possibility of intrauterine programming. Adjustment for maternal pre-pregnancy BMI may also mask a potential synergistic relationship with maternal diabetes along a common pathway of hyperglycaemia during fetal development [27, 54]. This underlines the need for well-designed studies to examine the effects of maternal BMI and diabetes, and the interrelationship between them on offspring.
Human and animal studies show that maternal diabetes induces fetal hyperglycaemia, islet cell hypertrophy and beta cell hyperactivity, all of which may result in fetal hyperinsulinaemia and excess growth, particularly at insulin-sensitive sites such as adipose tissue [25, 55]. In keeping with this, fetal hyperinsulinaemia shows a positive correlation with childhood overweight , even in the absence of macrosomia [35, 57].
Rodent models of intrauterine exposure to hyperglycaemia result in hypothalamic malformations in regions that normally produce orexigenic neuropeptides, including neuropeptide Y, and are associated with hyperphagia and obesity in later life . These data would support the suggestion that in humans, a causal pathway might involve hyperglycaemia-induced modification of hypothalamic appetite regulation, hyperphagia and leptin resistance in the offspring . Maternal overweight/obesity is associated with maternal hyperglycaemia and insulin resistance [58, 59], even when the clinical criteria of GDM are not fulfilled. Pre-pregnancy overweight combined with GDM conveys a greater risk of offspring obesity than exposure to either GDM or pre-pregnancy overweight alone . These data indicate that maternal obesity appears to exaggerate the metabolic abnormalities present in GDM , also suggesting that hyperglycaemia, irrespective of aetiology, is the determining mediator.
An additional finding from our meta-analysis is that in the studies in which adjusted data [15, 27, 46] were provided, the size of the observed difference in offspring BMI z score between cases and controls was inversely proportional to the number of covariates included in the adjustment (see Table 1). This would indicate that maternal pre-pregnancy BMI is not the sole confounder and that other genetic and postnatal environmental factors may also be contributory .
Subgroup analysis suggests that the effects on offspring BMI are not influenced by type of maternal diabetes. This is in agreement with a previous study showing no difference in offspring outcome between mothers with type 1 diabetes and GDM . However, given the small number of studies and participants, conclusions drawn from the subgroup analysis must be viewed with caution. There were insufficient data to perform a meta-analysis with regard to offspring of mothers with pre-pregnancy type 2 diabetes.
We acknowledge several limitations to the extent to which conclusions can be drawn from meta-analyses of observational studies with variable treatment of confounders and variable definition of GDM. Some studies used the National Diabetes Data Group  or Carpenter and Coustan criteria  and others, the clinical diagnosis reported in the medical records. The case-definition for diabetes has a significant effect on reported population prevalence of GDM, varying, for example, between 3.17% and 4.48% according to the National Diabetes Data Group and Carpenter and Coustan criteria, respectively . Inclusion of women with lesser degrees of glucose intolerance as diabetic would result in an underestimation of overall effect.
Treatment of diabetes during pregnancy (ultimately glycaemic control) may be an important determinant of offspring outcomes . We reported data on the treatment received by the mothers included in this meta-analysis in Table 1, but insufficient information was available on glycaemic control for us to perform further meaningful analysis. However, treatment regimens were similar across the studies.
Accepted clinical management of maternal diabetes is directed at ameliorating short-term consequences by achieving good glucose control during pregnancy and treating immediate newborn complications. The short-term outcomes of diabetic pregnancies have improved substantially over the past decades , but the potential long-term consequences now pose serious threats to adult wellbeing and population health. In adults, the metabolic syndrome is increasing  and is a leading cause of mortality worldwide . Similarly, in children, obesity and other features of the metabolic syndrome are rising rapidly and are strongly associated with premature death in later life .
We acknowledge that the number of included studies is small. Given the age range of the infants included, BMI z score is the only possible way of including them in this meta-analysis. Several studies report outcomes in the form of obesity, relative body mass, BMI or weight. We contacted the authors of these studies, but not all were able to provide their results as BMI z scores for inclusion in the meta-analysis. We would recommend that future studies on offspring of diabetic mothers during childhood should report their findings as BMI z scores, together with other measures of weight and body composition. The use of standardised units will greatly facilitate future meta-analyses in this area. It also seems logical to suggest that the difference in offspring BMI z score may increase with ageing, and a recent study suggests that this is the case . However, given the overlap in age between the various reported cohorts, we felt that subgroup analyses attempting to address this possibility could be misleading.
Our meta-analysis of observational studies reveals an association between maternal diabetes and offspring BMI that is no longer significant after adjusting for maternal pre-pregnancy BMI. Thus, although diabetic control during pregnancy remains important, given the complex relationship between maternal BMI, maternal diabetes and offspring outcome, the importance of maintaining a healthy weight in women of childbearing age must also be emphasised.
The authors would like to thank M. W. Gillman and G. V. Krishnaveni for contributing additional data to this meta-analysis.
Duality of interest
S. Santhakumaran is funded by the National Institute of Health Research. No external funding was received specifically for this work. The authors declare that there is no duality of interest associated with this manuscript.