Fetal development requires the continuous availability of nutrients for transfer across the placenta. Glucose is the primary nutrient required for fetal growth, followed by amino acids and lipids. Factors contributing to increased levels of maternal glucose during normal pregnancy include increased insulin resistance and increased levels of cortisol in the maternal circulation. These include being of non-European origin, 20 lower pre-gravid levels of physical activity, 21 and higher pre-pregnancy BMI. Cortisol, which rises exponentially during pregnancy as a result of a dysregulated hypothalamic—pituitary—adrenal axis, 27 has actions that include increasing insulin resistance and vasoconstriction.
The cumulative effect of these could lead to proportionately greater uptake of glucose by the placenta. During pregnancy there is a net protein synthesis leading to tissue deposition in the mother and the fetus, and synthesis of other metabolically active compounds eg, DNA [deoxyribonucleic acid], RNA, and neurotransmitters , thus the demand for amino acids is increased.
The effects of obesity on amino acid metabolism are not fully understood. In the non-pregnant state, obesity is associated with lower protein synthesis when compared with lean women, with no difference in protein oxidation. During normal pregnancy, lipid metabolism is altered to promote the accumulation of maternal fat stores in early-mid pregnancy and enhance fat mobilization in late pregnancy.
In late pregnancy, lipolysis and fat mobilization are promoted. The increases in plasma fatty acid and glycerol concentrations are consistent with mobilization of lipid stores for use by the fetus to aid growth and development. A recent study has investigated the pattern of changes in lipid profiles during pregnancy in obese and normal healthy-weight women.
However, the obese mothers had higher triglyceride levels than normal healthy-weight women at the start of pregnancy. Levels of triglycerides and triglyceride-rich lipoproteins reached the same maximal level in both groups, suggesting less metabolic flexibility in the obese. In addition, the obese had an atherogenic low density lipoprotein subfraction phenotype, which may be important for their own future vascular health as well as health of the offspring.
Modifications described in placentas of obese women include placental vascular function, changes of cell turnover, and increase of maternal inflammatory lesions Figure 2. Placenta weight has been noted to increase with increasing maternal BMI. This suggests that lower rates of apoptosis in placentas of LGA infants may positively influence placental and fetal growth. Figure 2 Placental modifications in obese pregnancy. Notes: In obese pregnancy, reduced placental cell turnover as demonstrated by lower detected levels of apoptosis marker cytokeratin M30 may contribute to overall larger size of placenta.
Alterations of vessel muscularity and vasodilatation properties may affect placental oxygen and nutrient transport and place the fetus at risk. A higher rate of maternal inflammatory response lesions consistent with chorioamnionitis has also been reported. The mechanism underlying the obesity-related increased risk of miscarriage is not known. Insulin resistance has been described as an independent risk factor for spontaneous miscarriage, 54 and insulin-sensitizing agents such as metformin have been shown to reduce miscarriage rates. Stillbirth rates are higher among obese women who have conceived naturally or through assisted reproductive techniques.
A meta-analysis of nine studies 56 suggested that obese women are at almost twice as high risk of stillbirth when compared with normal-weight women, and that the risk of stillbirth increases with increasing maternal BMI. The causal pathway for this association has not yet been defined. Most cohort studies have found the association of maternal obesity with stillbirth to be independent of potential confounding factors, including ethnicity, maternal age, parity, smoking, and history of preexisting diabetes or hypertensive disorders. Proposed explanations include maternal sleep apnea-associated fetal hypoxia and placental atherosclerosis secondary to maternal metabolic derangements.
The association of maternal obesity and stillbirth may also, in part, be related to different patterns of availability, uptake, and quality of antenatal health surveillance for obese and overweight women versus non-overweight women. Fetal growth and wellbeing assessments such as fundal height measurement and detection of fetal movements may also be less reliable in obese women.
It is yet to be determined whether enhanced antenatal surveillance and monitoring would reduce these adverse outcomes in obese pregnant women. One thing that remains certain is that maternal obesity is a potentially modifiable risk factor for this devastating pregnancy outcome.
Maternal obesity is associated with an increased risk of congenital malformations. The results of a systematic review and meta-analysis 58 estimating the increased risk of pregnancies complicated by a number of defects are summarized in Table 1. The cause of the increased risk of abnormalities is unclear. Potential mechanisms may include deficiencies in folic acid, chronic hypoxia, as well as metabolic changes including maternal hyperglycemia, increased insulin resistance, and incremented circulating levels of triglycerides and uric acid as described above.
Another possible contributor to this apparent increase in congenital abnormalities may relate to the relative difficulties with antenatal detection. Ultrasound scanning of obese pregnant women may lead to suboptimal visualization of fetal anatomy, 59 lower detection rates of structural abnormalities, and therefore an increased prevalence at birth. Table 1 Increased risk of congenital malformations in obese pregnancy Note: Increased risk of congenital malformations in offspring of obese mothers.
Table adapted with permission from Stothard et al. American Medical Association. All rights reserved. Abbreviations: CI, confidence interval; OR, odds ratio. Maternal obesity is associated with increased fetal growth, which can lead to infants being LGA. LGA infants are predisposed to a variety of obstetric and neonatal outcomes, largely due to potential difficulties during labor and delivery, including shoulder dystocia and brachial plexus injury.
An interesting paradox exists between maternal obesity and intrauterine growth restriction, with some reports that the offspring of obese women are also at an increased risk of being growth restricted in utero unrelated to preeclampsia. This suggests that unrecognized fetal growth restriction may complicate the pregnancies of a subpopulation of obese women.
Shoulder dystocia is an uncommon complication that occurs in 0. However, when adjusting for confounding variables, maternal obesity has not been found to be significant as an independent risk factor for shoulder dystocia, 77 suggesting birth size rather than maternal obesity per se is the key risk for this delivery complication. It therefore recommended early resort to the internal rotatory maneuvers or extraction of the posterior arm during shoulder dystocia. Despite this, hypoglycemia is the only reason for admission to the NNU that has been found to be increased in babies from obese mothers.
Within the neonatal ward cohort, they seem to be the healthiest. A systematic review of nineteen studies reported that maternal obesity is associated with a decreased intention of breastfeeding, a shortened duration of breastfeeding, a less adequate milk supply, and a delayed onset of lactation defined as onset after 72 hours post-partum. Obese women have also been found to report more difficulties with breastfeeding such as cracked nipples, fatigue, or difficulty initiating feeding at 1 month and 3 months postpartum, when compared with normal-weight women.
The Barker hypothesis states that environmental influences acting in fetal life are reflected in impaired growth and development which permanently affect structure and metabolism, leading to increased risk of metabolic disease later in life. Lifestyle factors such as current levels of obesity, behavior, activity, and diet are often considered as confounding factors. Indeed, there is much evidence for clustering of lifestyle factors, such as diet and exercise within families.
This Series in The Lancet Diabetes & Endocrinology examines the growing burden of maternal obesity worldwide in terms of its impact on. The increasing rate of maternal obesity provides a major challenge to obstetric practice. Maternal obesity can result in negative outcomes for both women and.
Studies involving siblings have also been used in an attempt to separate out intrauterine events from shared environmental and genetic factors. A prospective cohort study of , individuals from , families compared within-sibling and between-nonsibling associations of maternal weight gain on offspring BMI. However, another sibling study found that shared familial traits may have a greater influence than maternal obesity on offspring BMI, 87 highlighting the difficulties of distinguishing intrauterine influences from postnatal influences in humans.
Maternal obesity and its association with an increased risk of childhood and adult obesity among offspring has been well documented. This would support a programming influence of maternal obesity on offspring obesity. Further evidence that maternal obesity programs offspring obesity comes from another sibling study using a cohort of mothers who underwent surgical interventions for obesity. Offspring born before surgical intervention had significantly higher bodyweights at 12 years and at 21—25 years than offspring born after the surgery, in principle supporting the hypothesis that obesity has long-term influences on offspring bodyweight and BMI independent of genetic, environmental and lifestyle factors.
Maternal obesity and its association with offspring insulin resistance which is a precursor for type 2 diabetes has been reported at up to 20 years of age. Newborn babies of obese mothers have been found to have increased insulin resistance, as estimated by the homeostatic model assessment of insulin resistance. The Jerusalem Perinatal Family Follow-up Study showed that maternal obesity was independently correlated with higher systolic and diastolic blood pressure in offspring at age 17 years 97 and at age 32 years.
This study did not assess the influence of directly measured genetic factors to the observed associations. There is accumulating evidence supporting a link between maternal obesity and offspring obesity and cardiometabolic risk factors. In , a study of 3, Finnish men reported increased death from coronary heart disease in those who were thin at birth and whose mothers had an increased BMI during pregnancy.
However, this finding was restricted to mothers who were of short stature. The risk was independent of current socioeconomic status. Further studies are needed to understand the underlying mechanisms and to determine whether the adverse effects of maternal obesity can be modified in childhood and adulthood by lifestyle changes. Maternal obesity has been linked with offspring developing other diseases such as asthma and neurodevelopmental disorders. There may also be a relationship between maternal obesity and the risk of some cancers.
Maternal BMI and gestational weight gain were not associated with atopic eczema and hay fever, suggesting that pathways may be nonallergenic, and a lack of effect in sibling-pair analysis in this study favors genetic and shared environment risk factors to explain this association rather than intrauterine programming. Maternal obesity has been associated with an increased risk of developing autism spectrum disorders 1. Observational evidence suggests that increased maternal BMI is an independent risk factor for schizophrenia in offspring, when controlling for other potentially confounding maternal characteristics.
The effects of the positive feedback loop of adiposity from obese mothers to the child may increase the risk of some cancers for the offspring, with which birth weight is positively associated. Maternal obesity is a potentially modifiable risk factor for adverse outcomes that can occur during pregnancy and the neonatal period.
There is emerging evidence to suggest that maternal obesity also has longer-lasting effects for the offspring, including increased risk of developing cardiovascular risk factors and disease. The physiological changes during pregnancy including increased inflammatory cytokines with associated insulin resistance, resulting in increased nutrient supply to the fetus may contribute to this risk with compensatory fetal hyperinsulinemia, increased fetal adiposity, and lifelong increased cardiometabolic risk.
Evidence in support of a programming effect on the offspring of obese women would suggest there is a resultant positive loop effect on the prevalence of obesity, increasing the magnitude of the health care challenges posed by obesity. In an age where obesity has been described as a new worldwide epidemic, further work to understand more about the effects of maternal obesity for offspring is crucial. LIS is funded by Tommys. We acknowledge both Tommys and the British Heart Foundation. Linne Y. Obes Rev. Setting maternity care standards for women with obesity in pregnancy.
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Obes Facts. Chen X, Scholl TO. J Clin Endocrinol Metab. Pre-gravid physical activity and reduced risk of glucose intolerance in pregnancy: the role of insulin sensitivity. Clin Endocrinol Oxf. Hormonal and metabolic factors associated with variations in insulin sensitivity in human pregnancy. Zeyda M, Stulnig TM. Obesity, inflammation, and insulin resistance — a mini-review. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. Effect of insulin on fat metabolism during and after normal pregnancy.
Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. Duthie L, Reynolds RM. Changes in the maternal hypothalamic—pituitary—adrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes. On the function of placental corticotropin-releasing hormone: a role in maternal-fetal conflicts over blood glucose concentrations. Biol Rev Camb Philos Soc. Curr Diab Rep. Relationship of maternal protein turnover and lean body mass during pregnancy and birth length.
Clin Sci Lond. Fetoplacental transport and utilization of amino acids in IUGR — a review.
More recently, a Swedish study replicated these findings and demonstrated that obese and overweight mothers had children with an increased risk of ADHD Chen et al. This review has two main goals. Additionally, two rodent studies have indicated that maternal HFD increases depressive-like behavior, as offspring spent less time swimming and climbing in the Porsolt swim test indicating less escape attempts Can et al. However, when these studies were conducted standardized tests were not yet established; thus neither study used standardized assessments to examine the children's eating patterns. Leung, T. However, these studies only examined male offspring. Heerwagen, and J.
Placental amino acids transport in intrauterine growth restriction. J Pregnancy. Higher weight at birth is related to decreased maternal amino acid oxidation during pregnancy. Am J Clin Nutr. Whole-body protein anabolic response is resistant to the action of insulin in obese women. Maternal metabolism and obesity: modifiable determinants of pregnancy outcome. Hum Reprod Update. Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. Am J Physiol Cell Physiol. Obesity, pregnancy, inflammation, and vascular function. Higa R, Jawerbaum A.
Intrauterine effects of impaired lipid homeostasis in pregnancy diseases. Curr Med Chem. Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinemia in the third trimester. Swanson LD, Bewtra C. Increase in normal placental weights related to increase in maternal body mass index. J Matern Fetal Neonatal Med. Placental histopathological findings in obese and nonobese women with complicated and uncomplicated pregnancies.
The epigenome is especially vulnerable to alterations during gestation because the DNA methylation patterning required for normal tissue development is established and the DNA synthesis rate is high [ 12 ]. To our knowledge this is the first study that has investigated the correlation between maternal BMI and age at onset of type 1 diabetes in the offspring. One explanation for this could be the influence of maternal obesity. It is known that the pace of disease progress, from trigger to clinical disease, can vary [ 32 ].
It could be that children of obese mothers progress faster or that children of underweight women are not exposed to a necessary trigger or accelerant. In view of the growing obesity epidemic, these results highlight the importance of preventive work to reduce overweight and obesity in reproductive age women as a means to decrease the incidence of type 1 diabetes. Our study failed to confirm an association between gestational weight gain and type 1 diabetes in the offspring. This is in accordance with most studies [ 13 ] but not with that of Rasmussen et al [ 5 ].
The latter, however, investigated children with high susceptibility for type 1 diabetes, which might be a reason for the diverging results. Also, in this study we were only able to look at the total gestational weight gain, not the rate of gestational weight gain or whether a high weight gain early or late in pregnancy could be a risk factor for type 1 diabetes in the offspring. However, this correlation disappeared in the adjusted model, in accordance with findings in other studies [ 14 , 16 ]. Our finding that smoking may protect against type 1 diabetes is not a novel association. Several studies have reported this before, and it is possible that maternal smoking could somehow influence the immune system or DNA methylation in the offspring [ 13 , 16 , 33 ].
However, maternal smoking may also just be another confounding factor and our result should be interpreted with caution. The fact that certain risk factors seem to influence each other might help to explain the conflicting evidence from previous studies. The major strengths of using data from national registries are the large quantity of prospectively collected data and the fact that population-based information is free from recall bias.
It is also possible to investigate confounding factors and adjust the analysis. However, there may of course be other potential confounders, such as paternal diabetes, but unfortunately we do not have access to this information. Register data can involve misclassification problems caused by incorrect registration of diagnostic codes, and this might have affected the validity of the data used in our study. If so, the incorrect registration is random and not systematic.
BMI was calculated from self-reported height, whereas weight was sometimes measured and sometimes self-reported. Self-reported data can bias the results, but as individuals tend to over-report their height and under-report their weight any potential bias would probably underestimate the risks associated with maternal obesity. In conclusion, maternal obesity, in the absence of maternal diabetes, is a risk factor for the development of type 1 diabetes in the offspring and it also influences the age of diabetes onset in the affected child.
As mentioned above, this emphasises the importance of preventive work to maintain normal weight among women of reproductive age as a means to potentially decrease the incidence of type 1 diabetes. We thank M. Without these data this study would not have been possible. The study sponsors were not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; or the decision to submit the report for publication.
The authors declare that there are no conflicts of interest associated with this manuscript. NL and US designed and performed the statistical analyses. NL and US wrote the first draft of the manuscript. All authors edited and reviewed the manuscript and approved the final version. US is the guarantor of this manuscript. Skip to main content Skip to sections. Advertisement Hide.
Download PDF. Maternal obesity as a risk factor for early childhood type 1 diabetes: a nationwide, prospective, population-based case—control study.
Open Access. First Online: 02 November Introduction Type 1 diabetes is one of the most common chronic diseases in children and young adults, and the incidence has increased worldwide in recent decades [ 1 , 2 ]. The pregnancy length and parity of the mothers did not significantly differ between the groups, nor did gestational weight gain Table 1. This finding remained when only mothers who delivered at term were included in the analysis data not shown.
Only one underweight mother with an inadequate weight gain had diabetes. Table 1 Maternal characteristics of children with and without type 1 diabetes. A subgroup analysis comparing offspring of non-diabetic mothers revealed that children who developed type 1 diabetes more often had obese mothers compared with control children 8. However, this increased risk was not seen in the offspring of diabetic mothers Table 2 , regardless of whether the mother had type 1 diabetes or gestational diabetes data not shown.
Table 2 Risk of type 1 diabetes in offspring in relation to maternal diabetes and BMI class. In the multivariate analysis Table 3 a child whose mother had been obese in early pregnancy had an increased risk of developing type 1 diabetes crude OR 1.
An inadequate gestational weight gain seemed to be a protective factor crude OR 0. Table 3 Logistic regression model with ORs for developing type 1 diabetes. As seen in Fig. On the other hand, in children diagnosed below this age there was a clear tendency of increasing incidence of type 1 diabetes with higher maternal BMI. For the oldest age group the pattern was reversed. These findings were the same for both boys and girls.
However, further analysis showed that the observed differences were only seen for non-diabetic mothers, whereas there was no significant difference if the mothers had diabetes data not shown. Open image in new window. Acknowledgements We thank M. Data availability Data are available from the corresponding author on request.
Duality of interest The authors declare that there are no conflicts of interest associated with this manuscript. Samuelsson U, Lindblad B, Carlsson A et al Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season. Hasham A, Tomer Y The recent rise in the frequency of type 1 diabetes: who pulled the trigger? Blomberg M Obesity during pregnancy increases the risk for both the woman and child.
Skilled care can reduce the increased risk. Lakartidningen [article in Swedish] Google Scholar. Developmental overnutrition—an old hypothesis with new importance?
Dabelea D, Crume T Maternal environment and the transgenerational cycle of obesity and diabetes. Dahlquist G, Kallen B Maternal—child blood group incompatibility and other perinatal events increase the risk for early-onset type 1 insulin-dependent diabetes mellitus. Arkkola T, Kautiainen S, Takkinen HM et al Relationship of maternal weight status and weight gain rate during pregnancy to the development of advanced beta cell autoimmunity in the offspring: a prospective birth cohort study. Robertson L, Harrild K Maternal and neonatal risk factors for childhood type 1 diabetes: a matched case—control study.
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