Maternal and fetal outcomes among pregnant women with endometriosis

Introduction

Endometriosis is a chronic disorder characterized by the presence of endometrial-like tissue located outside of the uterus [1], 2], which is manifested as a collection of distressing symptoms including profound pelvic pain, fatigue, depressive affect, and gastrointestinal perturbations [3]. This gynecological condition assumes a considerable prevalence within the cohort of reproductive-aged women, affecting up to 10 % of this demographic [4]. Despite its prevalence and significant impact on the quality of life of patients, the etiology of endometriosis is still not fully understood. A few theories have been proposed to explain the progression of this disorder such as retrograde menstruation, genetic predisposition, immune dysfunction, and environmental factors [5].

There is evidence that pregnancies to individuals with endometriosis may be fraught with an increased risk of various adverse pregnancy and fetal outcomes, including preterm birth, placenta previa, placental abruption, and low birth weight [6], 7]. Nevertheless, conflicting findings have emerged, with some studies indicating that complications stemming from endometriosis are infrequent and do not confer substantial detrimental effects on pregnancy outcomes [8], 9]. It is important to acknowledge that these studies are frequently limited by their small sample sizes and often conducted within specialized infertility clinic settings, resulting in discordant and less generalizable findings. The objective of this study was to examine the maternal and newborn outcomes of pregnancies to women diagnosed with endometriosis using a large population-based cohort.

Materials and methods

Results

This study included a total of 16, 926, 453 delivery and maternal death admissions in US hospitals between the years of 1999 and 2019. Of these, we identified 14,956 pregnant individuals diagnosed with endometriosis, resulting in an overall rate of 88.4 per 100,000 pregnant individuals. There was a significant upward trend in the prevalence of endometriosis among births, rising from 34.9 to 160.6 per 100,000 births, over the 20-year period, as shown in Figure 1.

Figure 1:

Prevalence of endometriosis per 100,000 delivery admissions.

The baseline demographic and clinical characteristics between pregnant individuals with and without endometriosis is shown in Table 1. As compared with women without endometriosis, women with a confirmed diagnosis of endometriosis were more likely to be older, Caucasian, to belong to a higher income quartile, to be privately insured, to smoke and to be treated in urban teaching hospitals. They were also more likely to have pre-existing hypertension, gestational diabetes, and to be obese and morbidly obese.

The associations between a confirmed diagnosis of endometriosis and obstetrical outcomes are shown in Table 2. Individuals with endometriosis were at an increased risk of pre-eclampsia (adjusted OR [aOR] 1.54, 95 % CI 1.43–1.65), placenta previa (aOR 5.62, 95 % CI 5.14–6.14), and placenta abruption (aOR 1.93, 95 % CI 1.71–2.17) compared to women without endometriosis. Women with endometriosis were also at an increased risk of PPROM (aOR 1.30, 95 % CI 1.19–1.42), preterm birth (aOR 1.62, 95 % CI, 1.54–1.71), preterm labour (aOR 1.79, 95 % CI, 1.06–3.02), sepsis (aOR 5.01, 95 % CI, 4.08–6.16), DIC (aOR 4.58, 95 % CI, 3.41–6.17), chorioamnionitis (aOR 1.82, 95 % CI, 1.66–2.01), postpartum hemorrhage (aOR1.72, 95 % CI, 1.59–1.86), blood transfusions (aOR 3.09, 95 % CI, 2.78–3.43), and VTE (aOR1.90, 95 % CI, 1.44–2.52). In terms of modes of delivery, individuals with endometriosis were more likely to deliver via caesarean section (aOR 6.90, 95 % CI, 6.61–7.21). There was no significant difference for eclampsia, instrumental vaginal delivery, and maternal death between the two groups.

Table 3 presents the associations between a diagnosis of endometriosis and fetal/neonatal outcomes. A diagnosis of endometriosis was associated with a significantly higher prevalence of congenital anomalies in pregnancies (aOR 3.45, 95 % CI, 3.06–3.89) and IUGR (aOR 1.62, 95 % CI, 1.48–1.78). There was no significant difference for IUFD between the two groups.

Discussion

In this cohort study, encompassing a dataset of over 16 million deliveries in US hospitals over two decades, we examined the associations between endometriosis and maternal and fetal/neonatal outcomes. Our findings shed light on the impact of endometriosis on pregnancy, revealing significant associations with several adverse obstetrical events, including pre-eclampsia, placenta abruption, placenta previa, PPROM, preterm birth, preterm labour, sepsis, DIC, chorioamnionitis, postpartum hemorrhage, VTE, and blood transfusions. Endometriosis was also associated with congenital anomalies and IUGR.

Our study identified a total of 14,956 pregnant women diagnosed with endometriosis, translating to an overall rate of 88.4 per 100,000 pregnant individuals. A significant upward trend in endometriosis prevalence among pregnancies was observed over the 20-year study period. This trend may demonstrate the evolving recognition and diagnosis of endometriosis within the obstetric population, potentially reflecting improved patient and physician awareness over time, improved treatment, and the use of nonsurgical diagnostic methods with an emphasis on presentation of symptoms [11], 12]. Further, this upward trend in endometriosis prevalence may also be an indication of rising numbers of women with endometriosis conceiving via assisted reproductive technologies [13].

The demographic and clinical characteristics of women with a confirmed diagnosis of endometriosis demonstrated distinct differences from those without the condition. Individuals with endometriosis were more likely to be older, Caucasian, belong to a higher income quartile, be privately insured, obese, smokers, and treated in urban teaching hospitals. These results align with previous studies, including the Nurses’ Health Study which reported that African-American and Hispanic women had a 40 % lower likelihood of being diagnosed with endometriosis compared to Caucasians, when accounting for differences in healthcare access [14]. Furthermore, in a retrospective study conducted using Kaiser Permanente Washington electronic health records, which included 332,056 eligible women, researchers also demonstrated that women with endometriosis were more likely to be Caucasian, but this finding did not reach statistical significance [15]. Additionally, women with endometriosis in our study exhibited a higher prevalence of pre-existing hypertension, gestational diabetes mellitus, and obesity. This suggests that endometriosis may intersect with various sociodemographic and clinical factors, warranting further investigation into potential mechanisms underlying these associations. Our analyses considered these pre-existing conditions and patient demographic characteristics to be confounders and, as such, adjusted for them within the regression analyses in order to interpret our findings in isolation of these factors.

Our analysis of obstetrical outcomes revealed several significant associations between endometriosis and adverse maternal events, including pre-eclampsia. It has been suggested that the abnormal uterine junctional zone present in women with endometriosis may lead to defects in remodeling of the myometrial spiral arteries resulting in an increased risk of pre-eclampsia among women with endometriosis [8]. Despite this mechanistic theory, the association between endometriosis and risk of pre-eclampsia remains controversial. Indeed, some studies have demonstrated a strong link between these two conditions, while others have not. For example, using a national cohort consisting of 19,331 deliveries in Denmark between 1997 and 2014, Berlac et al. found that women with endometriosis had a 40–50 % higher risk of pre-eclampsia [16]. The researchers speculated that this increased risk might be influenced by the greater occurrence of twin pregnancies in their dataset due to more frequent use of assisted reproductive technologies (ART). On the contrary, a study by Brosens et al., which involved a survey of infertile women with endometriosis, found the incidence of pre-eclampsia to be lower among individuals with endometriosis compared with those without endometriosis (0.8 vs. 5.8 %, respectively), although it was based on a small sample [17]. Furthermore, other studies have demonstrated no association between endometriosis and pre-eclampsia [18], [19], [20]. However, a meta-analysis of 13 studies observed a greater risk of pre-eclampsia among individuals with endometriosis (OR 1.18, 95 % CI 1.01–1.39) [6]. This is in concordance with the findings of our study that also found a positive association between endometriosis and pre-eclampsia. Researchers proposed that pre-eclampsia risk might vary between pregnancies conceived spontaneously and those that used ART. However, this theory was not substantiated by a meta-analysis conducted by Lalani et al. They found no association between endometriosis and pre-eclampsia when the analysis was limited to women who conceived via ART (7 studies, OR 0.89, 0.48–1.67) or when limited to women who spontaneously conceived (2 studies, OR 1.21, 95 % CI 0.94–1.56) [6].

Placental abnormalities, specifically, placenta previa and placental abruption, were observed to be of greater likelihood among women with endometriosis in our study. This is in concordance with other studies that also found a positive association between endometriosis and placental abruption [16], 21] and placenta previa [18], [21], [22], [23]. A meta-analysis of 8 studies found a 4-fold greater risk of placenta previa among individuals with endometriosis [24]. It has been hypothesized that the abnormal uterine contractions that are characteristic of women with endometriosis leads to anomalous blastocyst implantation [8]. Further, over 50 % of women with endometriosis are diagnosed with chronic inflammation [25], which may impair the process of decidualization; hence, negatively impacting placental development [26].

Preterm birth [6], 7], 16], 27], 28] and PPROM [6], 29] were found to be associated with endometriosis in our study and others. Preterm birth may in part be attributed to the greater incidence of pre-eclampsia, placenta previa, chorioamnionitis, and IUGR associated with endometriosis. Studies have also found that greater levels of local and systemic inflammatory cytokines, progesterone resistance, reactive oxygen species and changes to the uterine junctional zone, which characterize endometriosis, may result in preterm birth [ 8,13].

Postpartum hemorrhage was found to be more common among women with endometriosis than among women without this condition; a finding that has been previously observed [30], 31]. The higher observed risk of postpartum hemorrhage, and resulting blood transfusions, among the endometriosis cases is most likely attributable to the greater observed frequency of placental abnormalities, such as placenta previa and abruption, in this group [32], 33]. Further, it has been proposed that the uterine blood vessels have been rendered exceedingly fragile due to the inflammatory environment characteristic of endometriosis.

Chorioamnionitis occurred more frequently among pregnancies complicated by endometriosis in our study, which may be linked with the incidence of sepsis development in this group. A recent cohort study consisting of livebirths that were conceived by IVF also found a greater risk of chorioamnionitis among women with endometriosis [34]. A study by Ni et al. that did not consider endometriosis, found that chorioamnionitis was associated with pregnancies conceived via ART but not among spontaneously conceived pregnancies [35]. Whether the association between endometriosis and chorioamnionitis observed in our study is also found in spontaneously conceived pregnancies needs to be explored in other studies.

Caesarean section emerged as the main mode of delivery associated with endometriosis, with women diagnosed with the condition being almost seven-fold more likely to undergo a caesarean section than women without endometriosis. This finding may possibly be attributed to various factors, including the potential impact of endometriosis on pelvic anatomy, adhesions, and the overall management of obstetric care in this patient population. The heightened risk of caesarean section among this group aligns with findings from previous studies that have highlighted an association between endometriosis and increased rates of surgical delivery [7], 22]. Evidently, Stephansson et al. illustrated that the occurrence of caesarean section delivery was nearly two-fold higher in women with endometriosis in comparison to those without the condition. They proposed that this disparity could be attributed to elevated rates of placental complications within the group affected by endometriosis [36], which is in accordance with the greater frequency of placenta previa and abruption observed in our study.

The neonatal outcomes assessed in this present study revealed that pregnancies complicated by endometriosis were associated with higher risks of congenital anomalies and IUGR. The risk of neonatal complications has been debated in the literature. Some previous studies have demonstrated an increased risk of complications, while others have demonstrated no significant difference in risk of neonatal complications between women with and without endometriosis. For example, Shmueli et al. observed no difference in risk of neonatal complications, such as neonatal intensive care admissions, asphyxia, and seizures, when comparing mothers with and without endometriosis [30]. These findings, according to the authors, were attributed to the study’s execution within a tertiary medical center, featuring highly skilled medical professionals and an available operating room on standby [30]. Berlac et al., in contrast, demonstrated that newborns had increased risk of being born prematurely, being small for gestational age, and having birth defects [16]. These results, overall, showcase the importance of enhanced prenatal monitoring for expectant mothers diagnosed with endometriosis.

This study, which was based on a large comprehensive population-wide dataset consisting of numerous variables, contributes to the existing literature on endometriosis and its impact on maternal and fetal/neonatal health. However, some limitations warrant consideration. The reliance on administrative data may have led to potential data misclassification and underestimation of endometriosis prevalence in pregnancy. Further, we were unable to review clinical charts to confirm the accuracy of the data provided. However, it should also be noted that the HCUP-NIS data undergoes regular quality control checks in order to ensure data are valid, internally consistent, and align with established norms [37]. Hence, we have a high degree of confidence in the quality of data provided by the HCUP-NIS. In addition, although regression models were adjusted for potential confounders, residual confounding bias may exist. With the discharge diagnosis and procedure coding system, our findings may have been underestimated as less clinically significant presentations of endometriosis and undiagnosed cases may have potentially been excluded. Although the HCUP-NIS database is very comprehensive, it did lack some important clinical information such as disease severity and subtype, timeline of disease diagnosis, and specific treatments, which would have provided deeper insights into the associations observed. Further, data pertaining to the method of conception-spontaneous or via ART, were not available.

The findings of this study underscore the complex relationship between endometriosis and pregnancy and neonatal outcomes. The significant associations observed between endometriosis and adverse maternal and neonatal events emphasize the importance of recognizing and managing this condition in the context of obstetric care. Further research is warranted to elucidate the underlying mechanisms linking endometriosis to these outcomes and to guide clinical practice in optimizing care for pregnant individuals with endometriosis. Prospective studies that include disease severity, treatment approaches, and mode of conception will provide a more exhaustive understanding of the relationships between endometriosis and pregnancy or fetal/neonatal outcomes.