Obstetrical Complications in Women with Endometriosis: A Cohort Study in Japan

Endometriosis is defined as the presence of endometrium-like tissue outside the uterus. The disease is common, affecting 10% of reproductive age women and 40% of women seeking infertility evaluation. Until recently, obstetricians and gynecologists had been unaware of the potential risks during pregnancy of patients with endometriosis. However, recent epidemiological studies reported an association between endometriosis and adverse pregnancy outcomes [ 1 , 2 ]. Some studies reported increased incidences of preterm birth, pregnancy-induced hypertension (PIH), and small for gestational age (SGA) babies in women with endometriosis, suggesting that endometriosis affects pregnancy outcomes [ 1 , 2 ]. Women with endometriosis are more likely to have difficulty conceiving and tend to receive infertility treatment, including assisted reproductive technology (ART) therapy, which in itself is a risk factor for preterm birth, PIH, and SGA babies [ 3 , 4 ]. No prospective cohort study has yet examined the effects of endometriosis on pregnancy outcomes in pregnant Japanese women. Furthermore, it is unclear whether pregnancy outcomes in women with endometriosis are affected by ART. The aim of this study was to determine the incidence of adverse pregnancy outcomes and the influence of endometriosis. The effects of endometriosis on pregnancy outcomes were examined by comparing women with or without endometriosis, using a cohort of 9,186 births from the first part of the data from the Japan Environment & Children’s Study (JECS).

The participants’ characteristics, age, smoking, passive smoking, and alcohol drinking were similar between women with and without endometriosis ( Table 1 ). A total of 9,186 pregnant women were enrolled whose pregnancy terminated between 1 February and 31 December 2011. Of the 9,186 participants, 330 reported a diagnosis of endometriosis before pregnancy; 266 conceived naturally (80.6%), 29 received ART therapy for infertility (8.8%), 13 pregnant women received intracytoplasmic sperm injection, and 16 patients underwent IVF. Twenty pregnant women answered that a blastocyst was transferred into the uterus at the time of ART. Data expressed as n (%). a, Chi-squared test b, Fisher's exact test c, Wilcoxon rank-sum test A total of 4,119 (44.8%) of the 9,186 JECS participants were diagnosed with obstetrical complications; 180 of 330 women with endometriosis had obstetrical complications (54.5%). Of 8,856 women without endometriosis, 3,939 (44.5%) had complications of pregnancy ( Table 2 ). a, Chi-squared test b, Fisher's exact test As shown in Table 3 , women with endometriosis were at increased risk for complications of pregnancy when compared with those without endometriosis (OR = 1.50; 95% CI = 1.20–1.87). Interestingly preterm PROM, placenta previa and placental abruption appeared to increase in women with endometriosis (OR = 2.17; 95% CI = 1.13–4.17, OR = 6.39; 95% CI = 3.38–12.09 and OR = 3.99; 95% CI = 1.55–10.27). The incidence of preeclampsia did not increase in the endometriosis group. OR, odds ratio; CI, confidence interval; n/a, not applicable a Multivariable-adjusted by age, smoking (Non-,Ex-,Current), passive smoking (< 3 days/week, ≥3 days/week), alcohol drinking (Non-,Ex-, Current) b P < .05 On multivariable analysis, adjustment for confounders known to be associated with adverse pregnancy outcomes, such as maternal age, smoking habits, and alcohol drinking, was performed. In the adjusted model, women with endometriosis were at increased risk of threatened preterm delivery (OR = 1.53; 95% CI, 1.16–2.03), placenta previa (OR = 6.42; 95% CI = 3.25–12.65), and placental abruption (OR = 3.45; 95% CI = 1.19–10.01). However, endometriosis did not change the risk for threatened abortion and preterm PROM. Furthermore, no significant difference was found in the incidence of fetal growth restriction and NRFS. To remove the influence of infertility treatment, logistic regression analyses were performed for the four combination groups by endometriosis and infertility treatment; the adjusted OR for obstetrical complications in pregnant women with endometriosis who conceived naturally (Group-A2) was 1.45 (95% CI = 1.11–1.90). Moreover, the adjusted ORs for preterm PROM, placenta previa, and placental abruption associated with endometriosis among women without infertility treatment were 2.51 (95% CI = 1.20–5.23), 3.31 (95% CI = 1.16–9.41), and 3.43 (95% CI = 1.03–11.48) ( S1 Table ). Among pregnant women with endometriosis, the ORs of preterm PROM and placenta previa were significantly higher compared with women never diagnosed with endometriosis who conceived naturally or conceived after infertility treatment, except for ART therapy ( S1 Table ).

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 [ 5 , 6 ]. A total of 100,000 children and their parents took part across 15 regions in Japan with follow-up programs to examine health periodically from the early stages of pregnancy until the participating child reaches 13 years of age. The present study is based on the dataset of jecs-ag-ai-20131008, which was released in October 2013. Enrollment started on 24 January 2011 and ended on 31 March 2014. All participants provided their written, informed consent. The current study is considered as a part of the JECS study. All adjunct studies are not required to have patient’s approval because it has been already written in the original consent. 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 jecs-ag-ai-20131008 dataset does not contain any patient identifying information. This study was conducted under the approval of the JECS as an adjunct study. It has obtained the written consent approved by MOE, ensuring that they do not interfere with the main study of the JECS. We sought an approval from the ethics committee of the national center for japan environmental and children’s study. The JECS is a national project which was designed to improve children’s health and development. The MOE instituted a general rule to open the jecs-ag-ai-20131008 dataset. Any researcher can use the dataset after seeking permission from the MOE. The email address is [email protected] to contact details for inquiries about JECS. The JECS participants were enrolled before delivery. A research coordinator described the JECS to the pregnant women after calculating the estimated date of delivery by ultrasound based on the crown lump length. In this study, each woman completed a questionnaire regarding her past history of endometriosis, reporting whether she had been diagnosed with endometriosis during the past year, ever had endometriosis, and ever received infertility treatment. This study did not take into account the period between diagnosis of endometriosis and the occurrence of pregnancy. Trained research coordinators collected data concerning obstetrical complications and neonatal outcomes from medical records in the obstetrics institutions. Included in this study were 9,186 pregnant women in the JECS with or without a history of endometriosis who gave birth, stillbirth, or whose pregnancy was terminated with abortion between February and December 2011. They were diagnosed with a single pregnancy in the first trimester by transvaginal ultrasound in the hospitals. Cases of multiple pregnancies were excluded. Maternal age was defined as age in completed years at the time of delivery and was categorized as <20, 20–24, 25–29, 30–34, 35–39, or 40 years and older. Women were classified as non-smokers, ex-smokers, current smokers, and those exposed to passive smoke, and they were sorted into < 3 days/week and ≥ 3 days/week. Alcohol drinking was defined as non-drinking, ex-drinking, and current drinking. ART therapy included information about in vitro fertilization (IVF) treatment, intracytoplasmic sperm injection (ICSI), frozen-thawed embryo transfer, and blastocyst embryo transfer for the present pregnancy. ART did not include artificial insemination with the husband’s semen (AIH). Complications of pregnancy were characterized as threatened abortion, threatened premature delivery, premature rupture of the membranes (PROM), gestational diabetes, preeclampsia, placenta previa, placental abruption, fetal growth restriction (FGR), and non-reassuring fetal status (NRFS). Neonatal outcomes were defined as livebirth, abortion, and stillbirth. Threatened abortion was diagnosed by clinical symptoms, such as genital bleeding, lower abdominal pain, a shortened cervix before 22 weeks’ gestation, and threatened premature delivery from 22 to 37 weeks’ gestation. Non-reassuring fetal status (NRFS) was defined by doctors as an abnormal fetal heartbeat monitored during labor, classified as an FHR pattern level of 3 to 5 (mild, moderate, and severe variant patterns) using a combination of three factors: the baseline variability, the baseline, and the presence of various decelerations [ 7 ]. Preeclampsia was defined as persistently raised blood pressure ≥140/90 mmHg, occurring after >20 weeks of pregnancy in an otherwise normotensive woman, including gestational hypertension (preeclampsia without proteinuria), and gestational proteinuria (preeclampsia with proteinuria of ≥300 mg protein in 24 h) [ 7 ]. Preeclampsia with severe features was defined as severe blood pressure elevation (systolic blood pressure ≥ 160 mmHg or diastolic ≥ 110 mm Hg) and severe proteinuria (≥ 2,000 mg protein in 24 h). The pregnant women with gestational diabetes (GD) were screened by the following stepwise method in Japan. Firstly, the random blood glucose levels were measured at early stage of pregnancy (each hospital should determine its own cut-off value). A 50-g glucose challenge test was given to the pregnant women (cut-off value ≥140 mg/dL) or the random glucose levels were measured for the second time (cut-off value ≥100 mg/dL) between 24 and 28 weeks. The pregnant women with a positive screening test result were tested for 75-g oral glucose tolerance test (OGTT). Gestational diabetes is defined as the pregnant woman having fulfilled one or more threshold values of a 75-g OGTT. Threshold values for 75-g OGTT are fasting plasma glucose (FPG) ≥ 92 mg/dL, 1-h PG ≥ 180 mg/dL, and 2-h PG ≥ 153 mg/dL [ 7 ]. FGR was defined as below the −1.5 SD value of the mean estimated fetal weight (EFW). Abortion was defined as termination of a pregnancy caused by spontaneous abortion or medical means prior to 22 weeks of gestation. Stillbirth is commonly defined as the death of a fetus at 22 or more weeks’ gestation that died before or during delivery. The Wilcoxon rank-sum test and the chi-squared test were used to evaluate whether there were significant differences in age, smoking, passive smoking, alcohol drinking, gestational age, and other clinical characteristics between women with and without endometriosis. To compare the incidence of complications of pregnancy in women with and without endometriosis, Fisher’s exact test and logistic regression analysis were used. To examine the interaction between endometriosis and fertility treatment, all women were grouped into one of four combination groups: Group-A1, as the reference group, women without a history of endometriosis and without infertility treatment group; Group-A2, women with endometriosis and without infertility treatment; Group-A3, women without endometriosis and with infertility treatment; and Group-A4, women with endometriosis and with infertility treatment. Unconditional logistic regression models were used to estimate age-adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). To examine the interaction between endometriosis and ART therapy, women were also grouped into four combination groups: Group-B1, as the reference group, women without a history of endometriosis who conceived naturally or conceived after infertility treatment, except for ART therapy; Group-B2, women with endometriosis and without ART therapy; Group-B3, women without endometriosis and with ART therapy; and Group-B4, women with both endometriosis and ART therapy. We restricted the analyses population to the pregnancies with complete covariate data. All analyses were performed using SAS V.9.4 (SAS Institute Inc., Cary, NC, USA). A value of p<0.05 was considered significant for every statistical analysis.

The present study demonstrated that preterm PROM and placenta previa are more frequent complications of pregnancy in women with a history of endometriosis. The present study is the first to show a significant impact of endometriosis, causing an increased incidence of preterm PROM and placenta previa after adjusting for the confounding of ART. One of the weak points of this study is the diagnosis of endometriosis was based on self-reporting by the participants. The authors did not have an access to the medical records of the participants. It was not feasible to know how many women had active endometriosis during their pregnancies.

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