Recurrent pregnancy loss (RPL) was defined as two or more miscarriages. Antiphospholipid syndrome, uterine anomalies, and parental chromosomal abnormalities, particularly translocation and abnormal embryonic karyotype, are identifiable causes of RPL. Obesity may increase the risk of sporadic miscarriage in pregnancies conceived spontaneously. Obesity with body mass index (BMI) > 30 kg/m 2 is an independent risk factor for further miscarriage with odds ratio 1.7–3.5 in patients with early RPL.
Obesity is associated with euploid miscarriage. Unexplained RPL with euploid embryo might be a common disease caused by both polymorphisms of multiple susceptibility genes and lifestyle factors such as women’s age, obesity, and smoking. Patients with a history of RPL were found to have a higher risk of cardiovascular disease, celiac disease, gastric ulcer, gastritis, and atopic dermatitis. No study has examined the effect of weight loss on the prevention of further miscarriage in patients with RPL.
Highlights
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Obesity is an independent risk factor for further miscarriage in patients with recurrent pregnancy loss (RPL).
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Obesity is associated with euploid miscarriage.
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Subjects with a history of RPL were found to be at a higher risk of cardiovascular disease.
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No study has examined the effect of weight loss on the prevention of further miscarriage.
The cause of recurrent pregnancy loss
Miscarriage is the most common complication of pregnancy. The estimated incidence is about 15% and it mainly depends on women’s age . Recurrent miscarriage (RM) is classically defined as three or more consecutive pregnancy losses . However, many researchers have now revised the definition to two or more pregnancy losses, namely recurrent pregnancy loss (RPL), because of the recent increase in the prevalence of childless couples. The estimated incidence of RM and RPL are 1% and 5%, respectively .
Antiphospholipid syndrome (APS), uterine anomalies, and abnormal chromosomes in either partner are identifiable causes of RPL ( Fig. 1 a ) . Approximately 50–70% of sporadic early (<10 weeks of gestation) miscarriages are associated with lethal numeric chromosome errors, such as trisomy, monosomy, and polyploidy, of which trisomy increases dramatically with advancing maternal age. We found chromosomal abnormalities in the embryo as a causative factor of RPL . In our previous study, both live birth rate and abnormal rate of embryos decreased according to the number of previous miscarriages ( Fig. 2 ) . In addition, abnormal embryonic karyotype was found to be a predictor of subsequent live birth .
It is well known that the cause remains indeterminate in over a half of the cases ( Fig. 1 a) . It has not been established whether hypothyroidism, diabetes mellitus, polycystic ovary syndrome (PCOS), thrombophilia, or infection cause RPL . Branch et al. recommended the examination of antiphospholipid antibodies, uterine anomalies, chromosomes in both partners, and karyotype in aborted conceptuses in RM clinical practice. According to our recent study, the abnormal embryonic karyotype was found in 41.1% of subjects in whom no conventional causes of RPL could be identified ( Fig. 1 b) . Therefore, the percentage of cases with RPL of truly unexplained cause may not exceed 24.5%.
Regarding embryonic or fetal abnormality, Philipp et al. found lethal embryonic developmental defects with the use of embryoscopy in more than half of clinically recognized miscarriages, some of which have euploid chromosome results . Rajcan-Separovic et al. identified genomic submicroscopic deletions and duplications, copy number variants, with microarray comparative genomic hybridization in euploid miscarriages of couples with idiopathic RPL . Further studies may lead to the identification of embryonic or fetal causes in RPL.
Tests recommended for patients with RPL for clinical practice are shown in Table 1 . Lupus anticoagulant using both activated partial thromboplastin time and Russell’s viper venom time, anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies should be measured . Positive tests should be measured again after ≥12 weeks to diagnose APS. Branch et al. recommend blood tests for diabetes mellitus or hypothyroidism if suggested by history or physical examination .
| Recommended tests | |
|---|---|
| Antiphospholipid syndrome | Lupus anticoagulant using both activated partial thromboplastin time and Russell’s viper venom time, anticardiolipin antibodies, or anti-β2-glycoprotein I antibodies |
| Uterine anomaly | Ultrasonography and hysterosalpingography, or hysteroscopy |
| Abnormal chromosome | Chromosome analysis of both father and mother |
| Abnormal embryonic karyotype | Chromosome analysis of the products of conception |
| Endocrine abnormality | Other tests for diabetes or hypothyroidism if suggested by history or physical examination |
RPL and obesity
A recent systematic review by Boots and Stephenson including 24,738 women from four studies suggests that obesity may increase the risk of sporadic miscarriage in pregnancies conceived spontaneously . The percentage of women with one or more miscarriages rose from 10.7% in women with normal body mass index (BMI) to 11.8% in overweight women and 13.6% in obese women (odds ratio (OR) 1.11 and 1.31, 95% confidence interval (CI) 1.00–1.24 and 1.18–1.46). However, Boots and Stephenson stated that the heterogeneity among studies limits the reliability of the results in summary.
There were a limited number of manuscripts concerning the association between RPL and obesity, in which the World Health Organization (WHO) BMI classification was used and maternal age was considered an independent confounding factor. Obesity was found to be associated with RM in 2004 . Lashen et al. conducted a nested case–control study including 1644 obese women with BMI >30 kg/m 2 and 3288 age-matched primiparous women with normal BMI (19–24.9 kg/m 2 ) . Lashen et al. defined early RM as three or more miscarriages between 6 and 12 weeks. The risks of early miscarriage and early RM were significantly higher among the obese patients (OR 1.2 and 3.5, 95% CI 1.01–1.46 and 1.03–12.0).
Data collected prospectively including 844 pregnancies from 491 patients with RM were analyzed retrospectively to investigate the effect of underweight, overweight, and obesity on the risk of miscarriage in the subsequent pregnancy in women with RM . When compared to patients with a normal BMI, obese and underweight patients had a significantly higher odds of miscarriage in the subsequent pregnancy (OR 1.71 and 3.98, 95% CI 1.05–2.8 and 1.06–14.92), whereas there was no significantly increased odds of miscarriage in overweight women (OR 1.02, 95% CI 0.72–1.45). Logistic regression analysis showed that the most important factor predicting the occurrence of miscarriage was advanced maternal age ( P = 0.01) followed by an increased BMI ( P = 0.04). A small but significant increased risk of miscarriage in the subsequent pregnancy, and not a mild increase in BMI, was observed in obese and underweight women with RM.
Lo et al. determined the relationship between maternal BMI and the future outcomes of pregnancy in couples with “unexplained” RM . Logistic regression demonstrated that maternal obesity (BMI ≥ 30 kg/m 2 ), Asian ethnicity, age, and the number of previous miscarriages were independent risk factors in couples with unexplained RM (OR 1.73 vs. 2.87 vs. 1.99 vs. 2.08, 95% CI 1.06–2.83 vs. 1.52–5.39 vs. 1.45–2.73 vs. 1.42–3.06). Asian women with a BMI similar to Caucasian women had a higher risk of a further miscarriage (OR 2.87, 95% CI 1.52–5.39). However, there was no difference in the miscarriage rate among those who were overweight (OR 1.27, 95% CI 0.89–1.83) or underweight (OR 0.12, 95% CI 0.15–1.00). The reliability may be small because the sample size of underweight women was small, only 10 patients.
Obesity is an independent risk factor for further miscarriage in patients with RM. However, the OR is relatively small.
RPL and obesity
A recent systematic review by Boots and Stephenson including 24,738 women from four studies suggests that obesity may increase the risk of sporadic miscarriage in pregnancies conceived spontaneously . The percentage of women with one or more miscarriages rose from 10.7% in women with normal body mass index (BMI) to 11.8% in overweight women and 13.6% in obese women (odds ratio (OR) 1.11 and 1.31, 95% confidence interval (CI) 1.00–1.24 and 1.18–1.46). However, Boots and Stephenson stated that the heterogeneity among studies limits the reliability of the results in summary.
There were a limited number of manuscripts concerning the association between RPL and obesity, in which the World Health Organization (WHO) BMI classification was used and maternal age was considered an independent confounding factor. Obesity was found to be associated with RM in 2004 . Lashen et al. conducted a nested case–control study including 1644 obese women with BMI >30 kg/m 2 and 3288 age-matched primiparous women with normal BMI (19–24.9 kg/m 2 ) . Lashen et al. defined early RM as three or more miscarriages between 6 and 12 weeks. The risks of early miscarriage and early RM were significantly higher among the obese patients (OR 1.2 and 3.5, 95% CI 1.01–1.46 and 1.03–12.0).
Data collected prospectively including 844 pregnancies from 491 patients with RM were analyzed retrospectively to investigate the effect of underweight, overweight, and obesity on the risk of miscarriage in the subsequent pregnancy in women with RM . When compared to patients with a normal BMI, obese and underweight patients had a significantly higher odds of miscarriage in the subsequent pregnancy (OR 1.71 and 3.98, 95% CI 1.05–2.8 and 1.06–14.92), whereas there was no significantly increased odds of miscarriage in overweight women (OR 1.02, 95% CI 0.72–1.45). Logistic regression analysis showed that the most important factor predicting the occurrence of miscarriage was advanced maternal age ( P = 0.01) followed by an increased BMI ( P = 0.04). A small but significant increased risk of miscarriage in the subsequent pregnancy, and not a mild increase in BMI, was observed in obese and underweight women with RM.
Lo et al. determined the relationship between maternal BMI and the future outcomes of pregnancy in couples with “unexplained” RM . Logistic regression demonstrated that maternal obesity (BMI ≥ 30 kg/m 2 ), Asian ethnicity, age, and the number of previous miscarriages were independent risk factors in couples with unexplained RM (OR 1.73 vs. 2.87 vs. 1.99 vs. 2.08, 95% CI 1.06–2.83 vs. 1.52–5.39 vs. 1.45–2.73 vs. 1.42–3.06). Asian women with a BMI similar to Caucasian women had a higher risk of a further miscarriage (OR 2.87, 95% CI 1.52–5.39). However, there was no difference in the miscarriage rate among those who were overweight (OR 1.27, 95% CI 0.89–1.83) or underweight (OR 0.12, 95% CI 0.15–1.00). The reliability may be small because the sample size of underweight women was small, only 10 patients.
Obesity is an independent risk factor for further miscarriage in patients with RM. However, the OR is relatively small.
Obesity is associated with euploid miscarriage
Boots et al. conducted cytogenetic analysis and microsatellite analysis and/or comparative genomic hybridization in aborted conceptuses of 372 women with early RPL, defined as ≥2 pregnancy losses <10 weeks, and at least one ultrasound-documented miscarriage with chromosome results . There were 578 miscarriages with chromosome results. Of the subjects, 18% were obese at the time of miscarriage. The mean maternal age at miscarriage was similar between the obese and nonobese groups. Only 117 subsequent miscarriages with chromosome results were included in the primary analysis, due to the high rate of maternal cell contamination in the prior miscarriages. The frequency of a euploid miscarriage among obese women (BMI ≥ 30 kg/m 2 ) was 58% compared with 37% of nonobese women (BMI < 30 kg/m 2 ) (relative risk 1.63, 95% CI 1.08–2.47).
Obese women have an increased frequency of euploid miscarriage. The frequency of truly unexplained miscarriages with embryonic euploidy may be 25% in our previous study . Embryonic euploidy is a risk factor for subsequent miscarriage when compared with embryonic aneuploidy (see Table 2 ).
