Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
7
Placental dysfunction in obese women and antenatal surveillance strategies Yadava B. Jeve, MSc, MRCOG, Higher Specialty Doctor, Obstetrics and Gynecology *, Justin C. Konje, PhD, Professor Obstetrics and Gynecology, Anjum Doshani, MD, Consultant Obstetrics and Gynecology University Hospitals of Leicester, Leicester, UK
Keywords: obesity placental dysfunction antenatal
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. © 2014 Elsevier Ltd. All rights reserved.
Introduction Obesity has become a global epidemic. It is estimated that 205 million men and 297 million women were obese in 2008 [1]. Obesity in pregnancy is defined as a body mass index (BMI) of 30 kg/m2 at * Corresponding author. Maternity Department, Leicester Royal Infirmary, Leicester LE1 5WW, UK. Tel.: þ44 07594119742. E-mail address: [email protected] (Y.B. Jeve).
http://dx.doi.org/10.1016/j.bpobgyn.2014.09.007 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
351
booking. One in five women in the UK is obese at antenatal booking; this is a threefold increase since 1980 [2]. Body fat distribution differs with race. Asian populations have more fat and more comorbidity for any given BMI; therefore, it has been suggested to use lower BMI cut-off points for these populations [3]. 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 [4]. 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 [5,6]. 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 [5,6]. Maternal oestrogen and progesterone promote pancreatic ß-cell hyperplasia causing an increased insulin release [7]. During pregnancy, the insulin resistance of the whole body is increased to about three times the resistance in the non-pregnant state [6,8]. In 2e4% 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 [5]. Obesity, independent of maternal glycaemia, is associated with fetal hyperinsulinaemia, birthweight, and newborn adiposity [9]. 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 [10]. In addition to hyperinsulinaemia, obesity induces exaggerated inflammatory responses in the placenta. The low-grade inflammation contributes to cellular dysfunction promoting metabolic disease [11,12]. 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 (NFkB) and c-Jun N-terminal kinase (JNK) signalling pathways are the primary pathways of inflammatory responses [13]. The resulting inflammatory milieu in which the fetus develops may have critical consequences for short- and long-term programming of obesity [14]. The lipotoxic insults induce inflammation in placental cells via the activation of JNK/early growth response protein 1 (EGR-1) signalling [15]. The study shows gene expression for cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-a, 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 2.5e5-fold higher in the stromal cells of obese compared to lean women [16]. TLR4 has been implicated in the pathogenesis of FFA-induced insulin resistance. FFAs are ligands for the TLR4 receptor [17,18]. 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 (IkB)/NFkB pathways. Abnormal TLR4 expression and signalling contribute to the pathogenesis of insulin resistance in humans [18]. 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 [18e21]. Low-grade maternal endotoxaemia is associated with insulin resistance and systemic inflammation in pregnant women with pre-gravid obesity [16]. Maternal obesity and change in placental metabolism strongly impact fetal redox
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Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
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 [22]. Maternal obesity causes abnormalities in angiogenesis near term [23]. 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 [24]. 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 [25]. Maternal obesity has a linear relationship with adverse outcome by reduction in placental villous proliferation and apoptosis [26]. In addition to the hyperglycaemiaehyperinsulinaemia 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 [27]. 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 [27]. 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 [28]. Studies show that obese women have a higher prevalence of infertility, recurrent
Fig. 1. The vicious cycle of maternal obesity leading to a future epidemic of obesity.
Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
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Table 1 Clinical impact of obesity on pregnancy. Feto-maternal complications
Odds ratio after adjusting other variables
Reference
Type of the study
Miscarriage rates
OR 1.31 (CI 1.18e1.46)
[30]
Recurrent miscarriage
OR 1.71
[30]
Congenital malformation
Neural tube defects OR, 1.87 (CI 1.62e2.15), Spina bifida OR, 2.24 (CI, 1.86e2.69), Cardiovascular anomalies OR, 1.30 (CI, 1.12 e1.51) Neural tube defects OR 2.8 (CI 1.2e6.6)
[63]
Systematic review and meta-analysis Systematic review and meta-analysis Systematic review and meta-analysis
Down syndrome
Gestational diabetes mellitus
BMI 30e34.9, OR 1.31 (1.10e1.55), BMI 35e39.9 OR 1.12 (CI 0.82e1.53), BMI 40 OR 1.56 (CI 1.00e2.43). Overweight e OR 3.5, Obese e OR 7.7, Severely obese e OR 11.0
[100] [73]
[31]
Obese e OR 2.6, Morbidly obese e OR 4.0
[101]
Overweight e OR 1.68 (CI, 1.53e1.84), Obese e OR 3.6 (CI, 3.25e3.98)
[33]
OR 3.19 (CI, 2.36e4.30)
[28]
Obese e OR 2.5, Morbidly obese e OR 3.2
[101]
OR 3.47 (CI 2.95e4.08)
[10]
Overweight e OR 1.9, Obese e OR 3, Severely obese e OR 4.4
[31]
OR 14.14 (CI, 9.44e21.17)
[9]
OR 2.99 (CI, 1.88e4.73)
[28]
OR 5.51 (CI, 4.15e7.31)
[44]
Overweight e OR 1.6, Obese e OR 3.3
[101]
Overweight OR 1.44 (CI,1.28e1.62), Obese OR 2.14 (CI, 1.85e2.47)
[33]
Preterm labour
OR 1.5 (CI, 1.1e2.1)
[101]
IUGR Large for gestational age
OR 2.1 Birth weight >90th percentile for GDM alone OR 2.19 (CI, 1.93e2.47), for obesity alone OR 1.73 (CI 1.50e2.00), Combined both GDM and obesity OR 3.62 (CI, 3.04e4.32).
[78] [102]
For overweight OR 1.6, Obese OR 2.2, Severely obese OR 2.7
[31]
Birth weight >90th percentile OR 3.52 (CI, 2.48 e5.00)
[9]
Gestational hypertension
Pre-eclampsia
Retrospective study of 420,362 women. Nationwide cohort of 1,568,604 Swedish women Danish cohort study of 369,347 women Prospective study of 16,102 women Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 1661 women Prospective study of 16,102 women HAPO Study, 25,505 women Danish cohort study of 369,347 women Observational cohort study 23,316 women Cohort study of 1661 women Cohort study of 13,722 women Multi-centre study of 16,102 women Cohort of 287,213 completed singleton pregnancies in UK Multi-centre study of 16,102 women Cohort study Observational cohort study 25,505 women in 15 centres in nine participant countries (HAPO study) Danish cohort study of 369,347 women Observational cohort study 23,316 women (continued on next page)
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Table 1 (continued ) Feto-maternal complications
Odds ratio after adjusting other variables
Reference
Type of the study
Birth weight >4000 g, Overweight OR 1.7, Obese OR 1.9 >4500 g, Overweight OR 2.0, Obese OR 2.4 Overweight OR 1.57 (CI, 1.50e1.64), Obese OR 2.36 (CI, 2.23e2.50)
[101]
Shoulder dystocia
OR 1.51 (CI, 1.05e2.19)
[103]
Venous thromboembolism
OR 1.30 (CI, 1.01e1.67)
[104]
OR of 2.65 (CI, 1.09e6.45)
[105]
pulmonary embolism OR 14.9 (CI, 3.0e74.8) deep venous thrombosis OR 4.4 (CI, 1.6e11.9)
[106]
Overweight OR 1.16 (CI, 1.12e1.21), Obese OR 1.39 (CI 1.32e1.46)
[33]
PPH after vaginal delivery OR 2.11 (CI, 1.54 e2.89) Caesarean OR 1.73 (CI, 1.32e2.28) OR 1.84 (CI, 1.53e2.22)
[107] [108]
OR 1.46 (CI, 1.29e1.65)
[103]
OR 1.80 (1.60e2.03)
[10]
OR 2.1
[31]
OR 2.23 (CI, 1.66e2.99)
[9]
OR 1.63 (CI, 1.34e1.99)
[28]
CS rate 33.8% for BMI of 30e34.9, CS rate 47.7% for women with a BMI of 35e39.9
[101]
VABC success rate 54.6% for obese compared to normal-weight women rate of 70.5%
[109]
Overweight OR 1.30 (CI, 1.25e1.34), Obese OR 1.83 (CI, 1.74e1.93)
[33]
OR 2.77 (CI, 1.11e6.96)
[28]
OR 3.4 (CI, 1.4e8.0)
[110]
Overweight (1.27 (1.09e1.48), Obese 2.24 (1.91 e2.64)
[33]
Need neonatal admission
NICU admission OR 1.28 (CI, 1.07e1.52),
[103]
Low Apgar score at 5 min
Overweight OR 3.7 (CI 2.4e4.6) Obesity OR 13.4 (CI 9.7e14.1) Overweight OR 1.3, Obese OR 1.4, Severely obese OR 1.9
[111]
Prospective multicentre study of 16,102 women Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 5788 women Cohort study of 299,810 women UKOSS study of 143 women with PE Danish cohort study of 71,729 women Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 11,363 women Cohort study of 6558 women Cohort study of 5788 women 25,505 women (HAPO study) Danish cohort study of 369,347 women HAPO study 23,316 women independent of maternal glycaemia Cohort study of 1661 women Prospective multicentre study of 16,102 women Study of 510 women attempting a trial of labour Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 1661 women Cohort study of 585 women Cohort of 287,213 singleton pregnancies Cohort study of 5788 women Cohort study of 3120 women Danish cohort study of 369,347 women
Post-partum haemorrhage
Need of caesarean section
Wound infection
[33]
[31]
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Table 1 (continued ) Feto-maternal complications
Odds ratio after adjusting other variables
Reference
Type of the study
Neonatal death
Neonatal death, OR 1.15 (CI, 1.07e1.23), Absolute risk 102/10,000 for BMI 30 as compared with absolute risk 76 for BMI 20 Infant death OR 1.42 (CI, 1.24e1.63) OR 1.24 (CI, 1.18e1.30)
[38]
Systematic review and meta-analysis
[112] [38]
OR 1.68 (CI, 1.00e2.82)
[103]
For overweight OR 1.4, obese OR 1.6, Severely obese OR 1.9
[31]
Overweight OR 1.47 (CI, 1.08e1.94), Obese OR 2.07 (CI, 1.59e2.74) Overweight OR 1.10 (CI, 0.94e1.28), Obese OR 1.40 (CI, 1.14e1.71)
[37]
Maternal death
49% of the women who died and for whom the BMI was known were either overweight or obese.
[113]
Long-term maternal complications
Obesity in later life: abdominal obesity after 4 years OR 2.9 (CI, 1.6e5.1) Mortality rates for women who survived >15 years Hazard ratio 1.94 (CI, 1.42e2.67); HR adjusted for BMI, 1.65 (CI, 1.19e2.79) Obesity in adult life birthweight 7.1e8.5 versus >10 lb. OR 1.62 (95% CI, 1.38e1.90)
[50]
Meta-analysis. Systematic review and meta-analysis Cohort study of 5788 women Danish cohort study of 369,347 women Meta-analysis of nine studies Cohort of 287,213 completed singleton pregnancies in UK The Eighth Report of the Confidential Enquiries into Maternal Deaths UK Cohort study of 478 women Cohort study 13,722 women
Infant death Stillbirth
Long-term complications in baby
[33]
[44]
[114]
Birthweights
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
7
Placental dysfunction in obese women and antenatal surveillance strategies Yadava B. Jeve, MSc, MRCOG, Higher Specialty Doctor, Obstetrics and Gynecology *, Justin C. Konje, PhD, Professor Obstetrics and Gynecology, Anjum Doshani, MD, Consultant Obstetrics and Gynecology University Hospitals of Leicester, Leicester, UK
Keywords: obesity placental dysfunction antenatal
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. © 2014 Elsevier Ltd. All rights reserved.
Introduction Obesity has become a global epidemic. It is estimated that 205 million men and 297 million women were obese in 2008 [1]. Obesity in pregnancy is defined as a body mass index (BMI) of 30 kg/m2 at * Corresponding author. Maternity Department, Leicester Royal Infirmary, Leicester LE1 5WW, UK. Tel.: þ44 07594119742. E-mail address: [email protected] (Y.B. Jeve).
http://dx.doi.org/10.1016/j.bpobgyn.2014.09.007 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
351
booking. One in five women in the UK is obese at antenatal booking; this is a threefold increase since 1980 [2]. Body fat distribution differs with race. Asian populations have more fat and more comorbidity for any given BMI; therefore, it has been suggested to use lower BMI cut-off points for these populations [3]. 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 [4]. 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 [5,6]. 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 [5,6]. Maternal oestrogen and progesterone promote pancreatic ß-cell hyperplasia causing an increased insulin release [7]. During pregnancy, the insulin resistance of the whole body is increased to about three times the resistance in the non-pregnant state [6,8]. In 2e4% 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 [5]. Obesity, independent of maternal glycaemia, is associated with fetal hyperinsulinaemia, birthweight, and newborn adiposity [9]. 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 [10]. In addition to hyperinsulinaemia, obesity induces exaggerated inflammatory responses in the placenta. The low-grade inflammation contributes to cellular dysfunction promoting metabolic disease [11,12]. 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 (NFkB) and c-Jun N-terminal kinase (JNK) signalling pathways are the primary pathways of inflammatory responses [13]. The resulting inflammatory milieu in which the fetus develops may have critical consequences for short- and long-term programming of obesity [14]. The lipotoxic insults induce inflammation in placental cells via the activation of JNK/early growth response protein 1 (EGR-1) signalling [15]. The study shows gene expression for cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-a, 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 2.5e5-fold higher in the stromal cells of obese compared to lean women [16]. TLR4 has been implicated in the pathogenesis of FFA-induced insulin resistance. FFAs are ligands for the TLR4 receptor [17,18]. 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 (IkB)/NFkB pathways. Abnormal TLR4 expression and signalling contribute to the pathogenesis of insulin resistance in humans [18]. 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 [18e21]. Low-grade maternal endotoxaemia is associated with insulin resistance and systemic inflammation in pregnant women with pre-gravid obesity [16]. Maternal obesity and change in placental metabolism strongly impact fetal redox
352
Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
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 [22]. Maternal obesity causes abnormalities in angiogenesis near term [23]. 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 [24]. 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 [25]. Maternal obesity has a linear relationship with adverse outcome by reduction in placental villous proliferation and apoptosis [26]. In addition to the hyperglycaemiaehyperinsulinaemia 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 [27]. 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 [27]. 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 [28]. Studies show that obese women have a higher prevalence of infertility, recurrent
Fig. 1. The vicious cycle of maternal obesity leading to a future epidemic of obesity.
Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
353
Table 1 Clinical impact of obesity on pregnancy. Feto-maternal complications
Odds ratio after adjusting other variables
Reference
Type of the study
Miscarriage rates
OR 1.31 (CI 1.18e1.46)
[30]
Recurrent miscarriage
OR 1.71
[30]
Congenital malformation
Neural tube defects OR, 1.87 (CI 1.62e2.15), Spina bifida OR, 2.24 (CI, 1.86e2.69), Cardiovascular anomalies OR, 1.30 (CI, 1.12 e1.51) Neural tube defects OR 2.8 (CI 1.2e6.6)
[63]
Systematic review and meta-analysis Systematic review and meta-analysis Systematic review and meta-analysis
Down syndrome
Gestational diabetes mellitus
BMI 30e34.9, OR 1.31 (1.10e1.55), BMI 35e39.9 OR 1.12 (CI 0.82e1.53), BMI 40 OR 1.56 (CI 1.00e2.43). Overweight e OR 3.5, Obese e OR 7.7, Severely obese e OR 11.0
[100] [73]
[31]
Obese e OR 2.6, Morbidly obese e OR 4.0
[101]
Overweight e OR 1.68 (CI, 1.53e1.84), Obese e OR 3.6 (CI, 3.25e3.98)
[33]
OR 3.19 (CI, 2.36e4.30)
[28]
Obese e OR 2.5, Morbidly obese e OR 3.2
[101]
OR 3.47 (CI 2.95e4.08)
[10]
Overweight e OR 1.9, Obese e OR 3, Severely obese e OR 4.4
[31]
OR 14.14 (CI, 9.44e21.17)
[9]
OR 2.99 (CI, 1.88e4.73)
[28]
OR 5.51 (CI, 4.15e7.31)
[44]
Overweight e OR 1.6, Obese e OR 3.3
[101]
Overweight OR 1.44 (CI,1.28e1.62), Obese OR 2.14 (CI, 1.85e2.47)
[33]
Preterm labour
OR 1.5 (CI, 1.1e2.1)
[101]
IUGR Large for gestational age
OR 2.1 Birth weight >90th percentile for GDM alone OR 2.19 (CI, 1.93e2.47), for obesity alone OR 1.73 (CI 1.50e2.00), Combined both GDM and obesity OR 3.62 (CI, 3.04e4.32).
[78] [102]
For overweight OR 1.6, Obese OR 2.2, Severely obese OR 2.7
[31]
Birth weight >90th percentile OR 3.52 (CI, 2.48 e5.00)
[9]
Gestational hypertension
Pre-eclampsia
Retrospective study of 420,362 women. Nationwide cohort of 1,568,604 Swedish women Danish cohort study of 369,347 women Prospective study of 16,102 women Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 1661 women Prospective study of 16,102 women HAPO Study, 25,505 women Danish cohort study of 369,347 women Observational cohort study 23,316 women Cohort study of 1661 women Cohort study of 13,722 women Multi-centre study of 16,102 women Cohort of 287,213 completed singleton pregnancies in UK Multi-centre study of 16,102 women Cohort study Observational cohort study 25,505 women in 15 centres in nine participant countries (HAPO study) Danish cohort study of 369,347 women Observational cohort study 23,316 women (continued on next page)
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Table 1 (continued ) Feto-maternal complications
Odds ratio after adjusting other variables
Reference
Type of the study
Birth weight >4000 g, Overweight OR 1.7, Obese OR 1.9 >4500 g, Overweight OR 2.0, Obese OR 2.4 Overweight OR 1.57 (CI, 1.50e1.64), Obese OR 2.36 (CI, 2.23e2.50)
[101]
Shoulder dystocia
OR 1.51 (CI, 1.05e2.19)
[103]
Venous thromboembolism
OR 1.30 (CI, 1.01e1.67)
[104]
OR of 2.65 (CI, 1.09e6.45)
[105]
pulmonary embolism OR 14.9 (CI, 3.0e74.8) deep venous thrombosis OR 4.4 (CI, 1.6e11.9)
[106]
Overweight OR 1.16 (CI, 1.12e1.21), Obese OR 1.39 (CI 1.32e1.46)
[33]
PPH after vaginal delivery OR 2.11 (CI, 1.54 e2.89) Caesarean OR 1.73 (CI, 1.32e2.28) OR 1.84 (CI, 1.53e2.22)
[107] [108]
OR 1.46 (CI, 1.29e1.65)
[103]
OR 1.80 (1.60e2.03)
[10]
OR 2.1
[31]
OR 2.23 (CI, 1.66e2.99)
[9]
OR 1.63 (CI, 1.34e1.99)
[28]
CS rate 33.8% for BMI of 30e34.9, CS rate 47.7% for women with a BMI of 35e39.9
[101]
VABC success rate 54.6% for obese compared to normal-weight women rate of 70.5%
[109]
Overweight OR 1.30 (CI, 1.25e1.34), Obese OR 1.83 (CI, 1.74e1.93)
[33]
OR 2.77 (CI, 1.11e6.96)
[28]
OR 3.4 (CI, 1.4e8.0)
[110]
Overweight (1.27 (1.09e1.48), Obese 2.24 (1.91 e2.64)
[33]
Need neonatal admission
NICU admission OR 1.28 (CI, 1.07e1.52),
[103]
Low Apgar score at 5 min
Overweight OR 3.7 (CI 2.4e4.6) Obesity OR 13.4 (CI 9.7e14.1) Overweight OR 1.3, Obese OR 1.4, Severely obese OR 1.9
[111]
Prospective multicentre study of 16,102 women Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 5788 women Cohort study of 299,810 women UKOSS study of 143 women with PE Danish cohort study of 71,729 women Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 11,363 women Cohort study of 6558 women Cohort study of 5788 women 25,505 women (HAPO study) Danish cohort study of 369,347 women HAPO study 23,316 women independent of maternal glycaemia Cohort study of 1661 women Prospective multicentre study of 16,102 women Study of 510 women attempting a trial of labour Cohort of 287,213 completed singleton pregnancies in UK Cohort study of 1661 women Cohort study of 585 women Cohort of 287,213 singleton pregnancies Cohort study of 5788 women Cohort study of 3120 women Danish cohort study of 369,347 women
Post-partum haemorrhage
Need of caesarean section
Wound infection
[33]
[31]
Y.B. Jeve et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 350e364
355
Table 1 (continued ) Feto-maternal complications
Odds ratio after adjusting other variables
Reference
Type of the study
Neonatal death
Neonatal death, OR 1.15 (CI, 1.07e1.23), Absolute risk 102/10,000 for BMI 30 as compared with absolute risk 76 for BMI 20 Infant death OR 1.42 (CI, 1.24e1.63) OR 1.24 (CI, 1.18e1.30)
[38]
Systematic review and meta-analysis
[112] [38]
OR 1.68 (CI, 1.00e2.82)
[103]
For overweight OR 1.4, obese OR 1.6, Severely obese OR 1.9
[31]
Overweight OR 1.47 (CI, 1.08e1.94), Obese OR 2.07 (CI, 1.59e2.74) Overweight OR 1.10 (CI, 0.94e1.28), Obese OR 1.40 (CI, 1.14e1.71)
[37]
Maternal death
49% of the women who died and for whom the BMI was known were either overweight or obese.
[113]
Long-term maternal complications
Obesity in later life: abdominal obesity after 4 years OR 2.9 (CI, 1.6e5.1) Mortality rates for women who survived >15 years Hazard ratio 1.94 (CI, 1.42e2.67); HR adjusted for BMI, 1.65 (CI, 1.19e2.79) Obesity in adult life birthweight 7.1e8.5 versus >10 lb. OR 1.62 (95% CI, 1.38e1.90)
[50]
Meta-analysis. Systematic review and meta-analysis Cohort study of 5788 women Danish cohort study of 369,347 women Meta-analysis of nine studies Cohort of 287,213 completed singleton pregnancies in UK The Eighth Report of the Confidential Enquiries into Maternal Deaths UK Cohort study of 478 women Cohort study 13,722 women
Infant death Stillbirth
Long-term complications in baby
[33]
[44]
[114]
Birthweights
