This review is aimed at discussing placental dysfunction in obesity and its clinical implication in pregnancy as well as an antenatal surveillance strategy for these women. Maternal obesity is associated with adverse perinatal outcome. Obesity is an independent risk factor for fetal hyperinsulinaemia, birthweight and newborn adiposity. Maternal obesity is associated with childhood obesity and obesity in adult life. Obesity induces a low-grade inflammatory response in placenta, which results in short- and long-term programming of obesity in fetal life. Preconception and antenatal counselling on obstetrics risk in pregnancy, on diet and lifestyle in pregnancy and on gestational weight gain is associated with a better outcome. Fetal growth velocity is closely associated with maternal weight and gestational weight gain. Careful monitoring of gestational weight gain and fetal growth, and screening and management of obstetrical complications such as gestational diabetes and pre-eclampsia, improves perinatal outcome. The use of metformin in non-diabetic obese women is under investigation; further evidence is required before recommending it.
Highlights
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Obesity is associated with significant short-term and long-term feto-maternal complications.
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Excess gestational weight gain is associated with metabolic disorders.
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Placental dysfunction is mediated through inflammatory pathways.
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Antenatal surveillance, counselling on ideal weight gain and screening and management of complications are the key for good outcomes.
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Metformin is not recommended in non-diabetic obese women.
Introduction
Obesity has become a global epidemic. It is estimated that 205 million men and 297 million women were obese in 2008 . Obesity in pregnancy is defined as a body mass index (BMI) of ≥30 kg/m 2 at booking. One in five women in the UK is obese at antenatal booking; this is a threefold increase since 1980 . Body fat distribution differs with race. Asian populations have more fat and more co-morbidity for any given BMI; therefore, it has been suggested to use lower BMI cut-off points for these populations . Maternal obesity is associated with an increased risk of feto-maternal complications. Maternal obesity causes not only risks during the perinatal period but also long-term complications for the offspring. It creates a significant risk for the next generations with metabolic compromise already apparent at birth. The risks of developing adulthood obesity, hypertension, diabetes and metabolic syndromes are engineered in fetal life. The financial implications of obesity results in the rise in the health-care cost by 23% among overweight women and 37% among obese women after adjusting for maternal age, parity, ethnicity and co-morbidity, when compared with women with normal weight . The present review is aimed at providing a comprehensive view on placental dysfunction in obese women and the need for antenatal surveillance strategies.
Molecular basis of placental dysfunction in obesity
In pregnancy, the feto-placental unit is a major site of protein and steroid hormone production and secretion, which results in metabolic changes. During in utero development, the fetus relies primarily on glucose as an energy substrate. There is a steady supply of glucose even during maternal fasting by increased hepatic gluconeogenesis in normal pregnancy. During early pregnancy, glucose tolerance is normal as insulin sensitivity and hepatic basal glucose production are normal . In the second and third trimester, the feto-placental factors increase maternal insulin resistance, which is aimed at increasing the supply of glucose to the fetus . Maternal oestrogen and progesterone promote pancreatic ß-cell hyperplasia causing an increased insulin release . During pregnancy, the insulin resistance of the whole body is increased to about three times the resistance in the non-pregnant state . In 2–4% of women, the pancreatic insulin response is inadequate to counterbalance the insulin resistance and gestational diabetes ensues. Maternal insulin resistance during pregnancy results in increased lipolysis with increased availability of free fatty acids (FFAs) to be used as adipogenic substrates in the fetus. Increased fetal adiposity and fetal insulin resistance are closely associated . Obesity, independent of maternal glycaemia, is associated with fetal hyperinsulinaemia, birthweight, and newborn adiposity . Although obesity and gestational diabetes share common metabolic pathways such as increased insulin resistance, hyperglycaemia and hyperinsulinaemia, they are independently associated with adverse maternal and neonatal outcomes. Their combination has a greater impact than either one alone . In addition to hyperinsulinaemia, obesity induces exaggerated inflammatory responses in the placenta. The low-grade inflammation contributes to cellular dysfunction promoting metabolic disease . There are various pathways suggested to explain the inflammatory state. The accumulation of a heterogeneous macrophage population and pro-inflammatory mediators in the placenta are suggested mechanisms. Nuclear factor kappaB (NFκB) and c-Jun N-terminal kinase (JNK) signalling pathways are the primary pathways of inflammatory responses . The resulting inflammatory milieu in which the fetus develops may have critical consequences for short- and long-term programming of obesity . The lipotoxic insults induce inflammation in placental cells via the activation of JNK/early growth response protein 1 (EGR-1) signalling . The study shows gene expression for cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-8, and monocyte chemotactic protein 1 (MCP1); for lipopolysaccharide (LPS)-sensing CD14, Toll-like receptor 4 (TLR4), translocation associated membrane protein 2 (TRAM2) was 2.5–5-fold higher in the stromal cells of obese compared to lean women . TLR4 has been implicated in the pathogenesis of FFA-induced insulin resistance. FFAs are ligands for the TLR4 receptor . Excessive fatty acids in the fetal circulation due to maternal obesity are expected to activate TLR4, which results in inflammation by activating inhibitor of kappaB (IκB)/NFκB pathways. Abnormal TLR4 expression and signalling contribute to the pathogenesis of insulin resistance in humans . Excess adipose tissue combined with low-grade inflammation and impaired insulin action is a central feature of the metabolic dysregulation in adult obesity. Maternal obesity enhances the expression of fatty acid transport proteins (FATPs), which increases fatty acid uptake and results in fetal adiposity at midgestation. These excessive fatty acids induce inflammation through the TLR4 pathway . Low-grade maternal endotoxaemia is associated with insulin resistance and systemic inflammation in pregnant women with pre-gravid obesity . Maternal obesity and change in placental metabolism strongly impact fetal redox balance. It is associated with metabolic alterations and dysregulation of redox balance. Maternal malondialdehyde, carbonyl proteins, nitric oxide and superoxide anion levels were high, while reduced glutathione concentrations and superoxide dismutase activity were low in obesity. These insults lead to maternal and fetal complications. Oxidative stress is one of the key downstream mediators that initiate programming of the offspring . Maternal obesity causes abnormalities in angiogenesis near term . Thus, an increase in angiogenic and adhesion molecules released from adipose tissue affects angiogenesis, inflammation and/or lipid and glucose metabolism in mother and baby . Therefore, maternal obesity leads to a lipotoxic placental environment that is associated with decreased regulators of angiogenesis and increased markers of inflammation and oxidative stress . Maternal obesity has a linear relationship with adverse outcome by reduction in placental villous proliferation and apoptosis . In addition to the hyperglycaemia–hyperinsulinaemia theory, maternal obesity cause changes in fetal muscle development by shifting mesenchymal stem cell differentiation from myogenesis toward adipogenesis. This shift is expected to have permanent effects on offspring skeletal muscle properties . The effect of chronic inflammation caused by maternal obesity may alter fetal skeletal muscle development through the following three mechanisms: (1) down-regulation of WNT signalling, (2) inhibition of PRKA activity, and (3) induction of epigenetic modifications . Fig. 1 explains the vicious cycle of maternal obesity leading to childhood and adult obesity.
Molecular basis of placental dysfunction in obesity
In pregnancy, the feto-placental unit is a major site of protein and steroid hormone production and secretion, which results in metabolic changes. During in utero development, the fetus relies primarily on glucose as an energy substrate. There is a steady supply of glucose even during maternal fasting by increased hepatic gluconeogenesis in normal pregnancy. During early pregnancy, glucose tolerance is normal as insulin sensitivity and hepatic basal glucose production are normal . In the second and third trimester, the feto-placental factors increase maternal insulin resistance, which is aimed at increasing the supply of glucose to the fetus . Maternal oestrogen and progesterone promote pancreatic ß-cell hyperplasia causing an increased insulin release . During pregnancy, the insulin resistance of the whole body is increased to about three times the resistance in the non-pregnant state . In 2–4% of women, the pancreatic insulin response is inadequate to counterbalance the insulin resistance and gestational diabetes ensues. Maternal insulin resistance during pregnancy results in increased lipolysis with increased availability of free fatty acids (FFAs) to be used as adipogenic substrates in the fetus. Increased fetal adiposity and fetal insulin resistance are closely associated . Obesity, independent of maternal glycaemia, is associated with fetal hyperinsulinaemia, birthweight, and newborn adiposity . Although obesity and gestational diabetes share common metabolic pathways such as increased insulin resistance, hyperglycaemia and hyperinsulinaemia, they are independently associated with adverse maternal and neonatal outcomes. Their combination has a greater impact than either one alone . In addition to hyperinsulinaemia, obesity induces exaggerated inflammatory responses in the placenta. The low-grade inflammation contributes to cellular dysfunction promoting metabolic disease . There are various pathways suggested to explain the inflammatory state. The accumulation of a heterogeneous macrophage population and pro-inflammatory mediators in the placenta are suggested mechanisms. Nuclear factor kappaB (NFκB) and c-Jun N-terminal kinase (JNK) signalling pathways are the primary pathways of inflammatory responses . The resulting inflammatory milieu in which the fetus develops may have critical consequences for short- and long-term programming of obesity . The lipotoxic insults induce inflammation in placental cells via the activation of JNK/early growth response protein 1 (EGR-1) signalling . The study shows gene expression for cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-8, and monocyte chemotactic protein 1 (MCP1); for lipopolysaccharide (LPS)-sensing CD14, Toll-like receptor 4 (TLR4), translocation associated membrane protein 2 (TRAM2) was 2.5–5-fold higher in the stromal cells of obese compared to lean women . TLR4 has been implicated in the pathogenesis of FFA-induced insulin resistance. FFAs are ligands for the TLR4 receptor . Excessive fatty acids in the fetal circulation due to maternal obesity are expected to activate TLR4, which results in inflammation by activating inhibitor of kappaB (IκB)/NFκB pathways. Abnormal TLR4 expression and signalling contribute to the pathogenesis of insulin resistance in humans . Excess adipose tissue combined with low-grade inflammation and impaired insulin action is a central feature of the metabolic dysregulation in adult obesity. Maternal obesity enhances the expression of fatty acid transport proteins (FATPs), which increases fatty acid uptake and results in fetal adiposity at midgestation. These excessive fatty acids induce inflammation through the TLR4 pathway . Low-grade maternal endotoxaemia is associated with insulin resistance and systemic inflammation in pregnant women with pre-gravid obesity . Maternal obesity and change in placental metabolism strongly impact fetal redox balance. It is associated with metabolic alterations and dysregulation of redox balance. Maternal malondialdehyde, carbonyl proteins, nitric oxide and superoxide anion levels were high, while reduced glutathione concentrations and superoxide dismutase activity were low in obesity. These insults lead to maternal and fetal complications. Oxidative stress is one of the key downstream mediators that initiate programming of the offspring . Maternal obesity causes abnormalities in angiogenesis near term . Thus, an increase in angiogenic and adhesion molecules released from adipose tissue affects angiogenesis, inflammation and/or lipid and glucose metabolism in mother and baby . Therefore, maternal obesity leads to a lipotoxic placental environment that is associated with decreased regulators of angiogenesis and increased markers of inflammation and oxidative stress . Maternal obesity has a linear relationship with adverse outcome by reduction in placental villous proliferation and apoptosis . In addition to the hyperglycaemia–hyperinsulinaemia theory, maternal obesity cause changes in fetal muscle development by shifting mesenchymal stem cell differentiation from myogenesis toward adipogenesis. This shift is expected to have permanent effects on offspring skeletal muscle properties . The effect of chronic inflammation caused by maternal obesity may alter fetal skeletal muscle development through the following three mechanisms: (1) down-regulation of WNT signalling, (2) inhibition of PRKA activity, and (3) induction of epigenetic modifications . Fig. 1 explains the vicious cycle of maternal obesity leading to childhood and adult obesity.
Clinical impact of placental dysfunction in obesity
Overweight and obese women are at a high risk of immediate and late maternal and fetal complications . Studies show that obese women have a higher prevalence of infertility, recurrent miscarriage and congenital malformations . Pre-pregnancy obesity is a risk factor for gestational diabetes, pre-eclampsia, labour induction and caesarean section . Post-delivery maternal complications include low breastfeeding rates , caesarean wound infection , thromboembolism and post-partum weight retention . The risk of stillbirth and neonatal death are doubled with obesity . These complications were found to be independently associated with obesity when corrected for other variables. The risks of feto-maternal complications with maternal obesity are described in Table 1 . These complications have a linear relationship with BMI. Each one-unit increase in BMI among nulliparous women confers a 7% increase in the risk of pre-eclampsia and a 6% increase in the risk of early pre-eclampsia . The summary relative risk per five-unit increase in maternal BMI for fetal death is 1.21 for stillbirth, 1.24 for perinatal death, 1.16 and 1.15 for neonatal death . The fetuses of obese mothers had a greater amount of body fat. The long-term effects on babies born to overweight and obese women include increased newborn adiposity with either an enlarged or normal-weight fetus, which leads to an increased incidence of obesity and metabolic diseases of the offspring in later life . Maternal obesity has also been linked to impaired brain development and behavioural changes in children. Studies show that obese mothers were more likely to have a child with an autism spectrum disorder, diagnosed with standardized assessments, and twice as likely to have a child with a developmental delay . The long-term effects on maternal health include development of diabetes, thromboembolism, hypertension in later life and increased long-term maternal mortality rates .
| Feto-maternal complications | Odds ratio after adjusting other variables | Reference | Type of the study |
|---|---|---|---|
| Miscarriage rates | OR 1.31 (CI 1.18–1.46) | Systematic review and meta-analysis | |
| Recurrent miscarriage | OR 1.71 | Systematic review and meta-analysis | |
| Congenital malformation | Neural tube defects OR, 1.87 (CI 1.62–2.15), Spina bifida OR, 2.24 (CI, 1.86–2.69), Cardiovascular anomalies OR, 1.30 (CI, 1.12–1.51) | Systematic review and meta-analysis | |
| Neural tube defects OR 2.8 (CI 1.2–6.6) | Retrospective study of 420,362 women. | ||
| Down syndrome | BMI 30–34.9, OR 1.31 (1.10–1.55), BMI 35–39.9 OR 1.12 (CI 0.82–1.53), BMI ≥ 40 OR 1.56 (CI 1.00–2.43). | Nationwide cohort of 1,568,604 Swedish women | |
| Gestational diabetes mellitus | Overweight – OR 3.5, Obese – OR 7.7, Severely obese – OR 11.0 | Danish cohort study of 369,347 women | |
| Obese – OR 2.6, Morbidly obese – OR 4.0 | Prospective study of 16,102 women | ||
| Overweight – OR 1.68 (CI, 1.53–1.84), Obese – OR 3.6 (CI, 3.25–3.98) | Cohort of 287,213 completed singleton pregnancies in UK | ||
| Gestational hypertension | OR 3.19 (CI, 2.36–4.30) | Cohort study of 1661 women | |
| Obese – OR 2.5, Morbidly obese – OR 3.2 | Prospective study of 16,102 women | ||
| Pre-eclampsia | OR 3.47 (CI 2.95–4.08) | HAPO Study, 25,505 women | |
| Overweight – OR 1.9, Obese – OR 3, Severely obese – OR 4.4 | Danish cohort study of 369,347 women | ||
| OR 14.14 (CI, 9.44–21.17) | Observational cohort study 23,316 women | ||
| OR 2.99 (CI, 1.88–4.73) | Cohort study of 1661 women | ||
| OR 5.51 (CI, 4.15–7.31) | Cohort study of 13,722 women | ||
| Overweight – OR 1.6, Obese – OR 3.3 | Multi-centre study of 16,102 women | ||
| Overweight OR 1.44 (CI,1.28–1.62), Obese OR 2.14 (CI, 1.85–2.47) | Cohort of 287,213 completed singleton pregnancies in UK | ||
| Preterm labour | OR 1.5 (CI, 1.1–2.1) | Multi-centre study of 16,102 women | |
| IUGR | OR 2.1 | Cohort study | |
| Large for gestational age | Birth weight >90th percentile for GDM alone OR 2.19 (CI, 1.93–2.47), for obesity alone OR 1.73 (CI 1.50–2.00), Combined both GDM and obesity OR 3.62 (CI, 3.04–4.32). | Observational cohort study 25,505 women in 15 centres in nine participant countries (HAPO study) | |
| For overweight OR 1.6, Obese OR 2.2, Severely obese OR 2.7 | Danish cohort study of 369,347 women | ||
| Birth weight >90th percentile OR 3.52 (CI, 2.48–5.00) | Observational cohort study 23,316 women | ||
| Birth weight >4000 g, Overweight OR 1.7, Obese OR 1.9 >4500 g, Overweight OR 2.0, Obese OR 2.4 | Prospective multi-centre study of 16,102 women | ||
| Overweight OR 1.57 (CI, 1.50–1.64), Obese OR 2.36 (CI, 2.23–2.50) | Cohort of 287,213 completed singleton pregnancies in UK | ||
| Shoulder dystocia | OR 1.51 (CI, 1.05–2.19) | Cohort study of 5788 women | |
| Venous thromboembolism | OR 1.30 (CI, 1.01–1.67) | Cohort study of 299,810 women | |
| OR of 2.65 (CI, 1.09–6.45) | UKOSS study of 143 women with PE | ||
| pulmonary embolism OR 14.9 (CI, 3.0–74.8) deep venous thrombosis OR 4.4 (CI, 1.6–11.9) | Danish cohort study of 71,729 women | ||
| Post-partum haemorrhage | Overweight OR 1.16 (CI, 1.12–1.21), Obese OR 1.39 (CI 1.32–1.46) | Cohort of 287,213 completed singleton pregnancies in UK | |
| PPH after vaginal delivery OR 2.11 (CI, 1.54–2.89) Caesarean OR 1.73 (CI, 1.32–2.28) | Cohort study of 11,363 women | ||
| Need of caesarean section | OR 1.84 (CI, 1.53–2.22) | Cohort study of 6558 women | |
| OR 1.46 (CI, 1.29–1.65) | Cohort study of 5788 women | ||
| OR 1.80 (1.60–2.03) | 25,505 women (HAPO study) | ||
| OR 2.1 | Danish cohort study of 369,347 women | ||
| OR 2.23 (CI, 1.66–2.99) | HAPO study 23,316 women independent of maternal glycaemia | ||
| OR 1.63 (CI, 1.34–1.99) | Cohort study of 1661 women | ||
| CS rate 33.8% for BMI of 30–34.9, CS rate 47.7% for women with a BMI of 35–39.9 | Prospective multi-centre study of 16,102 women | ||
| VABC success rate 54.6% for obese compared to normal-weight women rate of 70.5% | Study of 510 women attempting a trial of labour | ||
| Overweight OR 1.30 (CI, 1.25–1.34), Obese OR 1.83 (CI, 1.74–1.93) | Cohort of 287,213 completed singleton pregnancies in UK | ||
| Wound infection | OR 2.77 (CI, 1.11–6.96) | Cohort study of 1661 women | |
| OR 3.4 (CI, 1.4–8.0) | Cohort study of 585 women | ||
| Overweight (1.27 (1.09–1.48), Obese 2.24 (1.91–2.64) | Cohort of 287,213 singleton pregnancies | ||
| Need neonatal admission | NICU admission OR 1.28 (CI, 1.07–1.52), | Cohort study of 5788 women | |
| Low Apgar score at 5 min | Overweight OR 3.7 (CI 2.4–4.6) Obesity OR 13.4 (CI 9.7–14.1) | Cohort study of 3120 women | |
| Overweight OR 1.3, Obese OR 1.4, Severely obese OR 1.9 | Danish cohort study of 369,347 women | ||
| Neonatal death | Neonatal death, OR 1.15 (CI, 1.07–1.23), Absolute risk 102/10,000 for BMI 30 as compared with absolute risk 76 for BMI 20 | Systematic review and meta-analysis | |
| Infant death | Infant death OR 1.42 (CI, 1.24–1.63) | Meta-analysis. | |
| Stillbirth | OR 1.24 (CI, 1.18–1.30) | Systematic review and meta-analysis | |
| OR 1.68 (CI, 1.00–2.82) | Cohort study of 5788 women | ||
| For overweight OR 1.4, obese OR 1.6, Severely obese OR 1.9 | Danish cohort study of 369,347 women | ||
| Overweight OR 1.47 (CI, 1.08–1.94), Obese OR 2.07 (CI, 1.59–2.74) | Meta-analysis of nine studies | ||
| Overweight OR 1.10 (CI, 0.94–1.28), Obese OR 1.40 (CI, 1.14–1.71) | Cohort of 287,213 completed singleton pregnancies in UK | ||
| Maternal death | 49% of the women who died and for whom the BMI was known were either overweight or obese. | The Eighth Report of the Confidential Enquiries into Maternal Deaths UK | |
| Long-term maternal complications | Obesity in later life: abdominal obesity after 4 years OR 2.9 (CI, 1.6–5.1) | Cohort study of 478 women | |
| Mortality rates for women who survived >15 years Hazard ratio 1.94 (CI, 1.42–2.67); HR adjusted for BMI, 1.65 (CI, 1.19–2.79) | Cohort study 13,722 women | ||
| Long-term complications in baby | Obesity in adult life birthweight 7.1–8.5 versus >10 lb. OR 1.62 (95% CI, 1.38–1.90) | Cohort study of 71,100 women (Nurses Health Study I) | |
| Birthweights <5.5 lb., Hypertension OR 1.43 (95% CI, 1.31–1.56) | Cohort study of 92,940 women (the Nurses’ Health Study II) | ||
| Birthweight <5.5 lb., Hypertension OR 1.26 (CI 1.11–1.44), Diabetes mellitus OR 1.75 (CI, 1.21–2.54) | Cohort study of 22,846 US men (Health Professionals Follow-up Study) | ||
| Childhood obesity: children who were born to obese mothers are twice as likely to be obese by 2 years of age | A study of 8400 children | ||
| Risk of obesity, hypertension, glucose intolerance and dyslipidaemia, LGA at birth OR 2.19 (CI: 1.25–3.82; P = 0.01) by 11 years of age. Children of obese women OR 1.81 (CI, 1.03–3.19) | A longitudinal cohort study of 179 children |
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