The association of maternal diabetes in pregnancy with offspring adiposity into early adulthood: Sibling study in a prospective cohort of 280,866 men from 248,293 families

Abstract

Background

Maternal diabetes in pregnancy results in greater offspring adiposity at birth. It is unclear whether it is associated with greater adiposity into adulthood, and if so whether this is via intrauterine mechanisms or shared familial characteristics.

Methods and Results

A record linkage prospective cohort study of 280,866 singleton-born Swedish men from 248,293 families was used to explore the intrauterine effect of maternal diabetes on offspring body mass index (BMI) in early adulthood. Maternal diabetes during pregnancy was associated with greater mean BMI at age 18 in their sons. The difference in BMI was similar within brothers and between non-siblings. BMI of men whose mothers had diabetes during their pregnancy was on average 0.94kg/m² greater (95%CI: 0.35, 1.52) than in their brothers born before their mother was diagnosed with diabetes, after adjustment for birth year, maternal age, parity and education, birthweight, gestational age and age at assessment of BMI. Early-pregnancy BMI was positively associated with son’s BMI between non-siblings, but there was no association within brothers. Adjustment of the maternal diabetes-offspring BMI association for maternal BMI did not alter the association either within brothers or between non-siblings. Results were also robust to sensitivity analyses restricting the within sibling analyses to siblings born within 3 years of each other.

Conclusion

Maternal diabetes has long-term consequences for greater BMI in offspring and this association is likely to be via intrauterine mechanisms and is independent of maternal BMI in early pregnancy.

Introduction

Gestational diabetes is associated with greater fetal adiposity.(1;2) Among non-diabetic mothers there is a linear association between fasting and post-challenge glucose and greater birth size.(3) Fuel-mediated teratogenesis, also known as developmental overnutrition, has been suggested as the likely mechanism for these associations.(4-6)

Developmental overnutrition, resulting from maternal hyperglycaemia/diabetes, may also programme offspring to life-long increased adiposity.(7) In studies of Pima Indians, mean body mass index (BMI) is greater from birth to 20 years in offspring born to mothers who had diabetes during their pregnancy compared to either the offspring of mothers who developed diabetes later in their lives or those who never developed diabetes.(8-10) In a sibling study (182 individuals from 52 families), conducted in the Pima Indians, obesity was greater among offspring born after the mother had been diagnosed with diabetes than in their siblings born before their mother’s diagnosis, suggesting that, in this population, exposure to maternal diabetes in utero has long-term effects on the offspring via intrauterine mechanisms.(11) The Pima Indians are a population at very high risk of obesity, type-two diabetes and gestational diabetes and findings in this population may not generalise to other populations.

The long-term consequences of exposure to maternal hyperglycaemia/diabetes in utero beyond the Pima Indian population has been less well studied.(7) In a review of the subject published in 2007 two studies in non-Pima populations were identified that examined the association of diabetes in pregnancy with future (beyond birth) offspring adiposity.(12;13) We have identified a further seven studies of this association. (14-20) The majority, (12-15;18-20) thought not all,(12;16;17) report greater offspring BMI or obesity in those whose mothers had diabetes (any of gestational, type 1 or type 2 diabetes) in pregnancy. In the studies finding an association this persisted after adjustment for maternal early pregnancy BMI in most, but in two the association attenuated to the null with this adjustment.(13;20) The majority of these studies are small, with all except two (13;18) including fewer than 100 mothers with diabetes.

The association of diabetes with later offspring adiposity might be explained by shared familial genetic variation and lifestyle characteristics related to greater adiposity, the major risk factor for gestational and type 2 diabetes. None of the studies in non-Pima populations have compared associations within and between siblings to more directly explore the likely contribution of intrauterine mechanisms.(11) This is important because if intrauterine exposure to maternal diabetes in pregnancy is causally related to later offspring obesity via intrauterine pathways, this could result in an acceleration of the increase in population levels of diabetes and obesity that would continue across several generations even with improvements to the obesogenic environment.(21)

The aim of this study was to examine the associations of diabetes in pregnancy with offspring BMI (at mean age 18) in a general European population. We further aimed to use a sibling study design to explore the extent to which intrauterine mechanisms are likely to play a causal role in any associations. This is a form of natural experiment and is a powerful approach for testing causal inference by dealing with unmeasured confounders that are identical or very similar in siblings.(22) In recent years it has been increasingly used to explore causality in a wide-range of epidemiological studies,(23-26) including for exploring whether gestational diabetes is causally related via intrauterine mechanisms to offspring BMI in Pima Indians.(11) If siblings exposed to maternal diabetes have higher BMI compared to their siblings who were not exposed to maternal diabetes this supports a causal intrauterine mechanism. Such an association could not be explained by mechanisms such as familial socioeconomic position and shared lifestyle or maternal genotype, which will be the same for siblings.

Methods

We used data from the mandatory national conscription examination for offspring BMI and hence included men only, since only men complete this examination. The study consisted of all men born in Sweden between 1973 and 1988, who were still alive and completed their conscription medical examination during 1990-2005 (N = 390,108). Date of birth of the index participant, together with mother’s age at birth and their parents’ unique identity numbers (used to generate a family ID for the purpose of identifying full siblings), were extracted from the Swedish Multi-Generation Register. A linkage was made between these data and the Swedish Medical Birth Register,(27;28) the Swedish Military Service Conscription Register and the Population and Housing Censuses of 1990. The Regional Ethics Committee, Stockholm approved these linkages.

We excluded anyone born outside of Sweden, multiple births and anyone with missing data on any variables included in this study. After these exclusions the study population comprised 280,866 men (73% of eligible men) for analyses of diabetes in pregnancy and 146,894 (38%) for analyses with maternal early-pregnancy BMI. Figure 1 shows the derivation of the eligible cohort and final analysis cohort and subgroup.

Figure 1.

Sampling frame, eligible cohort and numbers included in analyses

Data on maternal weight and height (used to calculate BMI) at first antenatal clinic assessment, which took place around 10 weeks gestation, birthweight, parity and diabetes in pregnancy were measured by midwives, obstetricians or other physicians as part of normal clinical practice. Information on these were taken directly from the obstetric records and entered into the Medical Birth Register. Gestational age was assessed from the first day of the last menstrual period for 80% of the cohort, with ultrasound scan results being used in the remainder. Diabetes during pregnancy was entered onto the Medical Birth Register with no distinction made between gestational and existing diabetes and therefore we use the term maternal diabetes in pregnancy for this exposure. Highest maternal education (4 categories: primary and lower secondary only; upper secondary only; post-secondary or university education) was obtained from the 1990 census.

During the years covered by this study it was a legal requirement that all Swedish males attend the Swedish military service conscription examination; there were almost no exclusions to this requirement. Only individuals with severe mental retardation, being hospitalized for severe psychiatric morbidity, or imprisoned for severe criminality were exempt. At the conscription units across Sweden, height and weight were measured by trained personnel using standard procedures with the men in underclothes and without shoes.

Statistical analyses

We compared distributions of characteristics between men who were included in the study and those excluded because of missing data, using χ²-, t-, and F-tests as appropriate. To compare the within sibling and between unrelated family associations we used fixed and between cluster linear regression models, using the xtreg command in Stata.(29) This approach runs two regression models simultaneously – the within sibling fixed effect model and the between clusters (here unrelated families) model. The random effect is then obtained as the weighted average of the regression coefficients from these two models. For all models our outcome is offspring BMI at age 18. For our main analyses the exposure of interest is maternal diabetes in pregnancy and in a sub-group we have also examined maternal early-pregnancy BMI as an exposure. The equations for the models are provided as Online Supplement Data.

The fixed effect regression coefficient provides the within sibling association. This coefficient represents the association of maternal diabetes with offspring BMI having controlled for fixed maternal characteristics (e.g. her socioeconomic background, lifestyle and her genes). A positive association here supports an intrauterine effect as it would suggest that the sibling exposed to maternal diabetes in utero (with all fixed maternal characteristics controlled for) has higher BMI than the sibling born before the mother had diabetes. The between cluster regression coefficient represents the between non-siblings effect. This coefficient represents the association of maternal diabetes with offspring BMI between unrelated individuals. The estimate still uses data from all participants but relates the mean offspring BMI within a cluster (family) to mean exposure within clusters (family); the clusters are independent of each other. A Hausman statistic is used to compare these two models.(29) If the within sibling and between unrelated clusters coefficients are consistent with each other, and in both there is an association of maternal diabetes with offspring BMI, this suggests that the association is importantly driven by intrauterine mechanisms. If the between unrelated clusters is greater than the within sibling it suggests that much of this association is driven by characteristics that are shared within families (maternal genotype, background socioeconomic position), as once these are controlled for in the fixed within sibling association the coefficient is weaker. The random effects regression coefficient (overall association) is then obtained as the weighted average of the within sibling and between non-sibling effects, each coefficient weighted by the inverse of its variance.(29) This latter represents the overall association between the maternal diabetes and offspring BMI at mean age 18 , taking family clustering into account in the estimation of 95% confidence intervals.

In the basic model (model 1) we adjusted only for year of birth (of all siblings). We then additionally adjusted for potential confounding by maternal age at birth, parity and education (model 2). Note that maternal education does not contribute in the within sibling analyses as it is the same for both siblings. These potential confounding factors were chosen on the basis of previous knowledge of their associations with the exposure (maternal diabetes) and outcome (offspring BMI). In model 3 we explored for possible mediation of associations by gestational age and birthweight (model 3). As noted in the introduction maternal diabetes is associated with greater fetal and infant (at birth) adiposity, with evidence that this is due to intrauterine mechanisms related to fetal insulin secretion. It is also known that birthweight is positively correlated with later BMI. Therefore we wanted to examine whether any association of maternal pregnancy diabetes with later offspring BMI was explained by greater adiposity at birth which persisted into adulthood. Finally, after exploring possible interactions, we adjusted for maternal early-pregnancy BMI in the sub-group with these data. Maternal early-pregnancy BMI an established key risk factor for gestational diabetes and is also associated with offspring BMI and therefore could be a confounder in the association we are examining. We explored whether there was any evidence of interaction between maternal early pregnancy BMI (categorised at normal weight (<24.9kg/m²), overweight (25-30kg/m²) or obese (>30kg/m²) and diabetes in pregnancy in their associations with offspring BMI by including interaction terms in the regression models. Finally, we undertook a sensitivity analyses in which we restricted analyses only to those brothers who were born within 3 years of each other, as done in the previous sibling study undertaken in Pima Indians.(11)

Results

The 280,866 males in the cohort used for exploring associations of maternal diabetes with offspring BMI belonged to 248,293 families: 81,139 men had at least one brother within the cohort. The 146,894 men in the subgroup with information on maternal early-pregnancy BMI belonged to 136,050 families: 46,066 men had at least one brother within the cohort. Characteristics of the cohort and differences between those included and those excluded because of missing data are shown in Table 1. The mothers in this study are a relatively lean population with just 2% being obese and 13% overweight. The differences between those included and excluded were small with respect to effect sizes. However, the large sample size made most of these statistically significant. For example, the prevalence of maternal diabetes in pregnancy in those included in the main analyses was 0.5% and in those excluded it was 0.6% and mean early-pregnancy BMI in those included in these analyses was 21.9kg/m² and was 22.0kg/m² in those excluded, but p-values for all of these differences were <=0.002. Similar small differences (again statistically significant) were also present when we compared the subgroup with data available on maternal BMI to all others (results available from authors on request).

Table 1.

Characteristics of men included in analyses with maternal pregnancy diabetes as exposure (N=280,866) and those excluded because of missing data.

Characteristic	Categories or units	Number with data in excluded category	N (%) or mean (SD)		p-value
			Excluded men*	Included men
Maternal characteristic
Diabetes in pregnancy	No	101,412	101,412 (99.4)	279,391 (99.5)	0.002
	Yes		623(0.4)	1475 (0.5)
Maternal early pregnancy BMI categories	Normal	77,259	64,971 (84.1)	125,748 (85.6)	<0.001
	Overweight		10,450 (13.5)	18,297 (12.5)
	Obese		1838 (2.4)	2849 (1.9)
Mean early pregnancy BMI	Kg/m2	77,259	22.0 (3.2)	21.9 (3.1)	<0.001
Weight gain in pregnancy	Kg	77,259	14.2 (4.5)	14.1 (4.3)	<0.001
Height	Cm	79,428	165.7 (5.8)	166.1 (5.7)	<0.001
Age at birth	Years	102,035	27.6 (5.2)	27.8 (5.0)	<0.001
Parity	1	102,014	40,936 (40.1)	117,792 (41.9)	<0.001
	2		36.956 (36.2)	103,604 (36.9)
	3		17,139 (16.8)	44,492 (15.8)
	4		4931 (4.8)	11,100 (4.0)
	5		1379 (1.4)	2724 (1.0)
	>=6		673 (0.7)	1154 (0.4)
Highest education	Primary or lower secondary	100,328	25,133 (25.0)	55,696 (19.8)	< 0.001
	Upper secondary		51,441 (51.3)	140,598 (50.0)
	Post-secondary		23,586 (23.5)	83,938 (29.9)
	University		168 (0.2)	634 (0.2)
Son’s characteristic
Birth weight	Kg	100,572	3563 (558)	3596 (541)	<0.001
Gestational age	Days	100,852	279 (13)	279 (12)	<0.001
Age at conscription	Years	102,035	17.88 (0.59)	17.83 (0.52)	<0.001
Weight at conscription	Kg	3192	73.6 (12.9)	74.0 (12.8)	0.15
Height at conscription	Cm	3192	180.0 (6.5)	180.2 (6.5)	0.007
BMI at conscription	Kg/m2	3192	22.7 (3.7)	22.7 (3.6)	0.77
BMI category at conscription	Normal	3192	2548 (79.8)	224,655 (80.0)	0.59
	Overweight		483 (15.1)	43,095 (15.3)
	Obese		161 (5.0)	13,116 (4.7)

^*Excluded because of some missing data.

Table 2 shows correlations between maternal and offspring anthropometric measurements. Maternal early-pregnancy BMI was weakly positively associated with birthweight and moderately positively associated with offspring BMI at age 18. Maternal BMI in early-pregnancy was positively associated with odds of diabetes in pregnancy; the odds ratio per 1 unit greater BMI was 1.08 (95%CI: 1.07, 1.09); the odds ratio comparing overweight to normal weight women 2.23 (95%CI: 1.95, 2.56) and comparing obese women to normal weight women 5.25 (95%CI: 4.28, 6.43).

Table 2.

Correlations of maternal and son’s anthropometric data among 146,894 mothers and sons born in Sweden.

	Maternal height*	Maternal weight*	Maternal BMI*	Son’s birth weight	Son’s height**	Son’s weight**	Son’s BMI**
Maternal height*	1
Maternal weight*	0.38	1
Maternal BMI*	−0.12	0.86	1
Son’s birth weight	0.17	0.22	0.15	1
Son’s height**	0.17	0.32	0.25	0.18	1
Son’s weight**	0.46	0.23	0.02	0.27	0.39	1
Son’s BMI**	−0.02	0.25	0.27	0.08	0.91	−0.03	1

^*Measured at first antenatal clinic visit when mothers were largely 10 weeks gestation.

^**Measured at conscription examination when sons were mean age 18.

All p-values < 0.001.

Table 3 shows the overall, within brother, and between unrelated individuals, associations of maternal diabetes in pregnancy and early-pregnancy BMI with offspring BMI at mean age 18. Overall in the cohort, with control for clustering within families, offspring BMI was on average 1.00 kg/m² (95%CI: 0.81, 1.18) greater in men whose mothers had diabetes in pregnancy compared to those who did not. Similar results were found for the within sibling and between non-sibling analyses. Thus, BMI was 0.89 kg/m² (95%CI: 0.31, 1.47) greater at mean age 18 years in men whose mothers had diabetes during their pregnancy compared to their older brothers who were in utero before their mothers were diagnosed with diabetes. Adjustment for maternal age, parity, education, gestational age and birthweight had little impact on any of these associations.

Table 3.

Associations of maternal diabetes in pregnancy and early-pregnancy BMI with offspring BMI at mean age 18 years, within sibling groups and between unrelated individuals.

Maternal exposure	Model	Number included in analyses	Mean difference (kg/m2) in offspring BMI (95%CI) by maternal exposure
			Overall	Within siblings	Between non- siblings	p-value for difference within and between siblings*
Diabetes in pregnancy (yes vs. no)	Model 1	280,866	1.00 (0.81, 1.18)	0.89 (0.31, 1.47)	1.01 (0.81, 1.21)	0.68
	Model 2	280,866	1.00 (0.81, 1.18)	0.90 (0.31, 1.48)	1.01 (0.81, 1.21)	0.68
	Model 3	280,866	0.88 (0.69, 1.07)	0.94 (0.35, 1.52)	0.87 (0.68, 1.07)	0.81
	Model 4	146,894	0.46 (0.21, 0.72)	1.23 (0.11, 2.36)	0.41 (0.15, 0.67)	0.14
Early-pregnancy BMI (per 1 kg/m2)	Model 1	146,894	0.31 (0.30, 0.31)	−0.04 (−0.07, −0.01)	0.32 (0.31, 0.33)	<0.001
	Model 2	146,894	0.30 (0.29, 0.31)	−0.04 (−0.07, −0.01)	0.32 (0.31, 0.32)	<0.001
	Model 3	146,894	0.30 (0.29, 0.30)	−0.04 (−0.07, −0.01)	0.31 (0.30, 0.31)	<0.001
	Model 4	146,894	0.30 (0.29, 0.30)	−0.04 (−0.07, −0.01)	0.31 (0.30, 0.31)	<0.001

All results are mean differences in kg/m²; the null value is 0.

Model 1: Adjusted for year of birth.

Model 2: As model 1, plus additional adjustment for maternal age at birth, parity and education.

Model 3: As model 2, plus additional adjustment for birthweight and gestational age.

Model 4: As model 3, plus mutual adjustment of each of the two exposures for each other.

^*Obtained from the Hausman Test, testing the null hypothesis that the within sibling and between non-sibling associations are identical.

In the subgroup with data on maternal early pregnancy BMI, there was no evidence that associations of maternal diabetes with offspring BMI varied by maternal overweight/obesity status in early-pregnancy (p-values for interactions in models 1-3 were all >0.8). The associations in this subgroup for models 1-3 were essentially the same as those presented in Table 3 for the whole cohort (results available on request). With further adjustment for maternal early-pregnancy BMI, the overall and between non-sibling association of maternal diabetes with offspring BMI at mean age 18 was weakened somewhat, but the within sibling association was strengthened (model 4 in table 3). However, in all models there was no strong statistical evidence that associations within siblings differed from those between non-siblings for the association of maternal diabetes with offspring BMI. Maternal early-pregnancy BMI was positively associated with offspring BMI overall in the cohort and between non-siblings, but there was no association within siblings (table 3).

On average brothers were born 1.71 (95%CI: 1.69, 1.74) years apart from each other. When we restricted the analyses to those who were born 3 years or less between each other 278,240 individuals from 248,153 families remained in the main analyses. The results in this group did not differ from those presented in tables 2 and 3.

Discussion

In this large family-based study of men born in Sweden, we found that offspring BMI at mean age 18 years is greater in those whose mothers had diabetes during their pregnancy than those who did not. The similarity of associations within siblings differentially exposed to maternal diabetes in utero and between unrelated individuals suggests that this association is not fully explained by factors that are fixed (identical or very similar) in siblings. For example, the association is unlikely to be explained by background socioeconomic position or by familial behaviours that are shared by siblings up to age 18 years. Furthermore, it cannot be explained by maternal genotype, including mitochondrial DNA, or parent of origin effects as these would be identical in full siblings. Clearly, the maternal intrauterine environment differed for siblings whose mother had diabetes during their pregnancy compared to their sibling conceived before she was diagnosed with diabetes, and our sibling analyses support an intrauterine mechanism for the association of maternal diabetes with offspring greater BMI. This finding is consistent with one previous sibling study of this association that was conducted in the Pima Indian population but with a considerably smaller sample size than here.(11)

Whilst we found a positive association of maternal early pregnancy BMI with offspring BMI in the cohort overall and between unrelated individuals, there was no such association within siblings. These findings suggest that the general (overall) association seen in this study, and in other studies that have found positive associations of early-pregnancy BMI with offspring BMI,(30-33) might be explained by confounding due to characteristics that are the same or very similar in siblings, including maternal genotype, background socioeconomic position and familial behaviours such as diet and physical activity. These findings are consistent with a study showing that paternal BMI around the time of pregnancy was associated with later offspring BMI with the same magnitude of association as that of maternal pre/early-pregnancy BMI and offspring BMI.(34) Our results are also consistent with findings from a study in which maternal genetic variation in FTO was used as an instrumental variable to explore the causal intrauterine effect of her BMI on offspring adiposity.(35) In contrast, they are inconsistent with a small sibling study in which offspring born to mothers with extreme obesity (>40kg/m²) after they had lost weight following bariatric surgery had lower mean BMI than their siblings born before the mother had this surgery.(36) Although maternal behaviour is likely to have changed following surgery, this changed behaviour will have been present for the majority of both siblings childhood, given their close ages. What clearly differed between the siblings was the intrauterine environment and early infancy. It is possible that maternal extreme obesity during pregnancy does result in greater offspring adiposity in later life, but variation in maternal BMI at lower levels does not. It is notable that in our study, mothers were relatively slender with only 2% classified as obese. In contemporary Western populations levels of obesity in early pregnancy have been found to be as high as 16-20%.(37) That said, it is also notable that in this lean population, as well as in the Pima population who have very high rates of obesity,(11) there is evidence for intrauterine mechanisms linking maternal diabetes in pregnancy to later life offspring BMI.

Several mechanisms could explain the association of pregnancy diabetes with offspring BMI. First, it could be explained by maternal genotype and shared familial lifestyles related to adiposity. For example, mothers with adiposity related genotypes will be more likely to have type 2 and gestational diabetes and if this genotype is inherited by their offspring they will have on average greater BMI. Thus, maternal adiposity related genotypes could explain the association. Similarly, mothers with unhealthy diets and low levels of physical activity will have greater BMI and diabetes risk and if these lifestyles are adopted by their offspring they too will have greater BMI. Our within sibling analyses account for this since the mothers’ genotype and lifestyle during their offspring’s early life will be identical for siblings.

Second, an interuterine causal relationship could occur as a result of tracking of greater adiposity from birth to adulthood. Glucose crosses the placenta from mother to developing fetus freely, whereas insulin does not.(5) Consequently the fetus of a mother with diabetes will be exposed to greater levels of glucose than a mother without diabetes, which will result in increased fetal insulin secretion.(5) This in turn acts as a growth hormone resulting in birth of babies with on average greater birth weight and greater fat mass than those of mothers without diabetes.(2) Babies born with greater adiposity may simply remain more adipose throughout life. Our results, and that of previous study,(7) suggest this is not the case since adjustment for birthweight and gestational age did not importantly attenuate associations. In a recent study cord leptin (a marker of neonatal fat mass (38)) was found to be elevated in infants of mothers with type 1 diabetes and was higher in children of those mothers who were later (age 7) obese or overweight.(19) This might suggest a role for tracking of fat mass from birth. However, in that study none of the control group (offspring of mothers without diabetes) were overweight/obese and whether cord leptin did mediate associations of maternal type 1 diabetes with later overweight/obesity could not be explored.

Lastly, it has been suggested that increased fetal secretion of insulin leads to life-long hyperphagia and hence later greater adiposity that is independent of size at birth.(38) Most research in this area to date has been in animal models but recent evidence from human studies provides some support for this mechanism. Thus, there is evidence that greater amniotic fluid and cord blood insulin are related to later offspring adiposity.(14)

The main strengths of our study are its very large sample size and the ability to examine associations within siblings in addition to unrelated individuals. This made it possible to explore the extent to which associations were explained by familial (maternal genetic or shared family lifestyle) confounding as opposed to causal intrauterine effects. We were unable to distinguish between gestational diabetes or existing type 1 or type 2 diabetes since birth register information simply notes whether the mother had diabetes or not during a particular pregnancy. In general, any form of diabetes would have similar developmental overnutrition effects in terms of exposing the developing fetus to higher levels of glucose with a resultant increase in fetal insulin secretion and studies to date that have reported associations of maternal diabetes with later offspring BMI have included mothers with type 1, type 2, gestational diabetes or a mixture of these. (12-15;18-20) However, women with a known diagnosis of type 1 or type 2 diabetes before becoming pregnant may have been better controlled medically than those who developed gestational diabetes. With actual measurements of diabetes control during pregnancy it is possible we could have identified even stronger associations than those reported here for a heterogeneous group of mothers with diabetes. We used BMI as a measure of adiposity in offspring at age 18 years and for maternal early-pregnancy adiposity; this may not accurately reflect total fat mass. Babies born to mothers with diabetes have greater fat mass at birth even when they have similar birthweights to those born to mothers without diabetes.(2) However, there are strong correlations between directly assessed fat mass and BMI in children and adolescents and similar associations of BMI with cardiovascular risk factors to those seen for fat mass and waist circumference, suggesting that in general BMI is a good proxy for fat.(40) Finally, this study is of men offspring only and findings may not necessarily generalise to women.

In conclusion, our study suggests that in a relatively lean European population, as in the Pima Indian population, maternal diabetes in pregnancy is associated with greater offspring BMI in late adolescence/early adulthood and that this is not due to familial confounding but most likely due to intrauterine mechanisms. The strong association of maternal pregnancy diabetes with offspring BMI that we have found within siblings and between non-siblings in the entire population highlights the importance of identifying and appropriately treating pregnancy diabetes, not only for immediate perinatal reasons but also for the long-term health of the offspring. These findings support long-term funding of randomised controlled trials of pregnancy diabetes treatment to determine the effect of such treatments on long-term offspring risk of greater adiposity and associated consequences.