Adverse obstetrical outcomes for women with endometriosis and adenomyosis: A large cohort of the Japan Environment and Children's Study

Endometriosis is a chronic inflammatory disease characterized by the presence of extrauterine endometrial-like tissue. Prevalence of endometriosis has increased up to 50% in women with infertility [ 1 ]. Various pathogenetic mechanisms of infertility due to the presence of endometriosis have been indicated [ 2 ]. As a possible etiology, the abnormal eutopic endometrium of women with endometriosis may play an important role by exhibiting subtle but biologically important molecular abnormalities, such as an enhanced production of estrogen, cytokines, prostaglandins, and metalloproteinases [ 3 , 4 ]. Adenomyosis is a benign uterine disorder, characterized by the presence of endometrial glands and stroma deep within the myometrium. Adenomyosis has peak prevalence during reproductive ages [ 5 ]. Until recently, it was considered that adenomyosis is associated with multiparity, but not impaired implantation during in vitro fertilization (IVF) treatment [ 6 ]. In contrast, Dueholm demonstrated that the presence of adenomyosis is associated with a significant reduction in implantation of ‘good quality’ embryos in women undergoing IVF treatment [ 7 ]. It appears that women with endometriosis or adenomyosis are more likely to struggle with achieving pregnancy and to undergo infertility treatments, including assisted reproductive technology [ 8 ]. In addition, it is well established that singleton pregnancies conceived by ART are at a higher risk of complications than those conceived naturally [ 9 ]. In the present study, we assessed the pregnancy outcomes of women with or without gynecological disorders after excluding the age adjusted influence of ART therapy.

A total of 96,655 pregnant women were enrolled between January 2011 and March 2014 ( Table 2 ). Data expressed as n (%) a , Chi-squared test b , Wilcoxon rank-sum test The number of women diagnosed with endometriosis and adenomyosis were 3,517 and 325, respectively. There were 3,381 women with a history of endometriosis, 189 of adenomyosis and 136 with that of both disorders. The frequency of spontaneous abortions in women with adenomyosis was greater than that in pregnant women without adenomyosis (1.9% vs. 0.6%). The rate of preterm delivery between 22 and 36 weeks of gestational age in women with endometriosis or adenomyosis was higher than that in women without these diseases (6.7% vs. 4.8%, and 15.1% vs. 4.8%, respectively). The rate of cesarean delivery was higher in women who were diagnosed with either disease. Of the 3,517 pregnant women with a reported diagnosis of endometriosis before pregnancy, 2,705 conceived naturally (77.1%) and 411 conceived following ART therapy (11.7%). On the other hand, of the 325 women with a reported diagnosis of adenomyosis before pregnancy, 209 conceived naturally (64.7%) and 59 received ART therapy (18.2%). Table 3 shows the number of obstetrical complications in patients with endometriosis or adenomyosis. The frequency of obstetric complications was 53.6% (1,884/3,517) in women with endometriosis and 60.0% (195/325) in women with adenomyosis. The incidence rates of preterm PROM, gestational diabetes, and placenta previa were higher in women diagnosed with endometriosis or adenomyosis. Only pregnant women with a medical history of adenomyosis experienced adverse events of mild preeclampsia, placental abruption, FGR, and fetal death. Data expressed as n (%) a , Fisher’s exact test In multivariable analysis, maternal age, smoking habits, passive smoking and alcohol consumption were included as potential risk factors for adverse pregnancy outcomes. As shown in Table 4 , women with endometriosis were at a higher risk of obstetrical complications relative to those without endometriosis, following adjustment for the confounding characteristics (adjusted odds ratio: aOR = 1.32; 95% confidence interval: CI = 1.23–1.41). Particularly, the rates of extremely preterm birth, preterm birth, preterm PROM, and placenta previa were higher in women with endometriosis (aOR = 1.97, aOR = 1.32, aOR = 1.62, and aOR = 2.87, respectively). The aOR for GDM was 1.11 (CI = 0.92–1.35). Note: aOR, adjusted odds ratio; CI, confidence interval Multivariable-adjusted by age, smoking, passive smoking, alcohol drinking On the other hand, women with adenomyosis had increased risk of obstetrical complications compared to those without adenomyosis (aOR = 1.72; 95% CI = 1.37–2.16) ( Table 5 ). The odds of extremely preterm birth, preterm birth, and preterm PROM appeared to increase in women with either endometriosis or adenomyosis. Interestingly, pregnant women with adenomyosis, but not endometriosis, had a high risk of preeclampsia (mild), placental abruption and FGR compared to those without adenomyosis (aOR = 1.86, aOR = 2.62, and aOR = 2.72, respectively). The GDM and placenta previa rates were not higher for women with adenomyosis after adjustment for the confounding characteristics. The OR for spontaneous abortion was 2.51 (CI = 0.93–6.79). Note: aOR, adjusted odds ratio; CI, confidence interval Multivariable-adjusted by age, smoking, passive smoking, alcohol drinking To separate the influences of gynecological disorders from the effects of infertility treatment on the analysis, two combined groups were evaluated using a logistic regression analysis. A summary of the groups for analyzing the interactions between gynecological disorders and fertility treatment is shown in Table 1 . Among the pregnant women who conceived naturally, the aORs of extremely preterm birth, preterm birth, preterm PROM, and placenta previa in women diagnosed with endometriosis (Group-A2) were higher than those in women without endometriosis (Group-A1) ( Table 6 ). In women with endometriosis who conceived naturally or after infertility treatment without ART therapy (Group-B2), the aOR for obstetrical complications was 1.26 (95% CI = 1.17–1.35), and the aORs for extremely preterm birth, preterm birth, preterm PROM, and placenta previa associated with endometriosis were 2.15 (95% CI = 1.35–3.44), 1.28 (95% CI = 1.10–1.49), 1.52 (95% CI = 1.16–2.00), and 2.11 (95% CI = 1.51–2.94), respectively. Estimates are based on models adjusted for age. Note: aOR, adjusted odds ratio CI, confidence interval; n/a, not applicable In terms of adenomyosis, the aOR for obstetrical complications in pregnant women with adenomyosis who conceived naturally or after infertility treatment without ART therapy (Group-B2) was 1.52 (95% CI = 1.19–1.94) ( Table 7 ). In addition, our data showed that group B2 had higher frequencies of extremely preterm birth, preterm birth, preterm PROM, placental abruption, and FGR: odds ratio = 4.76 (95% CI = 1.75–12.91), 2.57 (95% CI = 1.77–3.75), 2.80 (95% CI = 1.43–5.46), 3.29 (95% CI = 1.22–8.89), and 2.88 (95% CI = 1.70–4.86), respectively. The aOR for mild preeclampsia was not higher for women with adenomyosis who conceived naturally or underwent infertility treatment without ART therapy (group B2). Estimates are based on models adjusted for age. Note: aOR, adjusted odds ratio CI, confidence interval; n/a, not applicable

The present study demonstrated that obstetrical complications such as preterm birth and preterm PROM were more frequent in women with a medical history of endometriosis or adenomyosis. Women who had been diagnosed with endometriosis also had a high incidence of placenta previa. Adenomyosis affected spontaneous abortion, placental abruption and FGR. This study is the first report on obstetrical complications based on the analysis of common factors that show an impact of endometriosis and adenomyosis after adjusting for the confounding influence of ART.

The Japan Environment and Children’s Study (JECS) is a national project, designed to improve children’s health and development. A total of 100,000 children and their parents across 15 regions in Japan have participated in it [ 10 ]. The purpose of the JECS, an ongoing prospective birth cohort study that began in 2011, is to evaluate the impact of various environmental factors on children’s health and development [ 11 , 12 ]. The JECS protocol was approved by the Institutional Review Board (IRB) on epidemiological studies of the Ministry of the Environment (MOE) and the Ethics Committees of all participating institutions. The present study was based on a dataset released in June 2016 that did not contain patient-identifying information. Enrollment of participants was conducted between January 2011 and March 2014. As stated above, the jecs-ag-20160424 dataset does not contain any patient identifying information. All participants provided their written informed consent. In this study, each woman completed a questionnaire regarding her history of gynecological disorders, recording whether she had been diagnosed during the past year and/or had undergone infertility treatment. The gynecological diseases described in the questionnaire included endometriosis, adenomyosis, uterine myoma, ovarian tumor, and congenital uterine anomaly. This study did not consider the time period between diagnosis of the gynecological disorder and pregnancy. Further data concerning obstetrical complications and neonatal outcomes were collected from medical records at the institutions that provided obstetric care to these patients. Women who gave birth, experienced stillbirth, or whose pregnancy was terminated through abortion were included in the JECS, with participants enrolled before delivery (or termination). A total of 103,099 pregnancies were reported. The exclusion criteria included multiple pregnancies, as well as pregnant women who could not clearly articulate their gynecological history. This study contained a total of 96,655 women. The presence of endometriosis or adenomyosis was based on the responses to a self-reported questionnaire. Women’s age was recorded at the time of delivery or pregnancy outcome and categorized as <20, 20–24, 25–29, 30–34, 35–39, or ≥40 years. The women were also classified as smokers, ex-smokers, and non-smokers. Their smoking habits were classified as <3 days/week and ≥3 days/week. Based on alcohol consumption, women were classified as non-drinkers, ex-drinkers, and current drinkers. ART therapy included IVF, intracytoplasmic sperm injection (ICSI), frozen-thawed embryo transfer, and blastocyst embryo transfer. ART did not include intra-uterine insemination. Complications of pregnancy were characterized as spontaneous abortion, extremely preterm birth (22–27 weeks gestation), preterm birth (28–36 weeks gestation), premature rupture of the membranes (PROM), gestational diabetes, preeclampsia, placenta previa, placental abruption, fetal growth restriction (FGR), and non-reassuring fetal status (NRFS). Perinatal mortality was defined as live-birth, abortion, and stillbirth. The medical definitions and diagnostic criteria of obstetrical complications have been described previously [ 13 , 14 ]. The Wilcoxon rank-sum test or the chi-squared test was used to evaluate significant differences in age, smoking status, passive smoking, alcohol consumption, gestational age, and other clinical characteristics between women who had been diagnosed with a gynecological disorder and those with no such diagnosis. A chi-squared test, Fisher’s exact test, or logistic regression analysis was used to compare the incidences of pregnancy complications between the two groups. To examine the associations between gynecological disorders and fertility treatment, all women were classified into the following two groups: group A1 (the reference group), which included women with no history of gynecological disorders and group A2, which included women with gynecological disorders who had not undergone infertility treatment ( Table 1 ). Unconditional logistic regression models were used to estimate age-adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). To examine the interactions between gynecological disorders and ART therapy, women were also grouped into the following two groups: group B1 (the reference group), which included women without a history of gynecological disorders who had conceived naturally or through infertility treatment but without ART therapy, and group B2, which included women with gynecological disorders who had not undergone ART therapy. These analyses were restricted to pregnancies with complete covariate data. All analyses were performed using SAS V.9.4 (SAS Institute Inc., Cary, NC USA.) A P value of <0.05 was considered significant for all statistical analyses.

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