This study aimed to investigate the effects of endometriosis on maternal and neonatal outcomes and to demonstrate whether pre-pregnancy treatments, including surgical treatment and hormone therapies for infertility, ovarian endometriosis, and chronic pain due to endometriosis, affect perinatal outcomes. The main finding of our study was that endometriosis was an independent risk factor for placenta previa after the adjustment of several confounding factors such as fertility treatment, pre-pregnancy BMI, maternal age, and parity. In patients with endometriosis, we found that patients with a history of surgical treatment before pregnancy were associated with an increased risk of placenta previa; on the contrary, patients without pre-pregnancy surgical treatment such as patients who only received hormone therapies or patients coincidentally diagnosed with ovarian endometriosis in the first trimester of pregnancy were not associated with an increased risk.
Our findings are consistent with that of the previous studies that found an association between endometriosis and placenta previa [22,23,24]. Compared to the recent systematic reviews [17, 25, 26], endometriosis did not increase the risks of preterm birth, HDP, PPH, placental abruption, and SGA in this study. This discrepancy might have been caused by a difference in sample size, patients’ backgrounds, and study designs. Because our hospital specializes in high-risk pregnancies, in the present study, women in the control group may have higher risks for these complications compared to the control groups of the previous studies [12, 13, 15], indicating that it might have been underpowered to show significant difference in maternal and neonatal outcomes.
The underlying mechanisms associating endometriosis to pregnancy complications remain largely unclear. However, several published papers have suggested that chronic inflammation (e.g., cyclooxygenase-2, interleukin-8, prostaglandin E2), adhesions, progesterone-resistant endometrium, and vascularized environment due to endometriosis could lead to various complications during pregnancy [16, 27, 28]. With regard to placenta previa, it has been hypothesized that hyperperistalsis of the uterus may be implicated in abnormal blastocyst implantation [29, 30], and dense pelvic adhesions may inhibit the migration of the placenta away from the internal ostium of uterus. Vercellini et al. reported that a higher incidence of placenta previa was observed in patients with rectovaginal lesions than in patients with peritoneal or ovarian lesions [30]. Additionally, severe cases such as deep infiltrating endometriosis (DIE) and revised American Society for Reproductive Medicine (rASRM) stage IV were significantly associated with a higher risk of placenta previa in subsequent pregnancies [31, 32].
Presently, data on the efficacy of endometriosis treatments such as surgical treatment and hormone therapies on perinatal outcomes in subsequent pregnancies are limited and unclear. To the best of our knowledge, only a few studies have demonstrated an association between pre-pregnancy surgery for endometriosis and the risk of placenta previa [12, 31]. Berlac et al. showed that gynecological surgery for endometriosis before pregnancy had an increased risk for placenta previa in a singleton pregnancy using a national cohort in Denmark (endometriosis, 2.2%; endometriosis with surgery, 3.4%; no endometriosis, 0.4%) [12]. Nirgianakis et al. demonstrated that patients with a history of surgical treatment for DIE presented a higher risk for placenta previa in subsequent pregnancies (endometriosis with surgery, 6.5%; no endometriosis, 0%) [31]. Although the exact reason why the risk for placenta previa increased despite a previous surgery for endometriosis remains unclear, it is possible that patients previously operated on before pregnancy might have exhibited severe endometriosis such as DIE, rASRM stage IV, and uncontrolled pain due to adhesion or ruptured ovarian endometriosis. Consistent with these previous reports [12, 31], patients with a previous surgery in this study were likely to have higher score of rASRM based on limited patients’ data (data not shown). Previous report demonstrated that the recurrence rate of endometriosis after surgery is relatively high, estimated to be 21.5% at 2 years and 40–50% at 5 years [11], and was associated with the duration of follow-up after surgery and the rASRM stage of endometriosis at surgery [33]. In the present study, patients who had a gap of more than 5 years between an surgical treatment and pregnancy had a higher risk of placenta previa. Therefore, increased risk of placenta previa in patients with endometriosis with pre-pregnancy surgical treatment might be due to the higher rate of severe stage of endometriosis or a recurrence of endometriosis. Another possible explanation is that additional adhesions by operative manipulation might have some pathological role in a placenta previa. Additionally, the majority of patients with endometriosis in the non-surgical treatment group were treated conservatively; therefore, they may have had a milder variety of endometriosis compared to patients in the surgical treatment group.
Several limitations of this study should be acknowledged. First, the diagnosis of endometriosis in the non-surgical treatment group was based on ultrasound, MRI, and presence of symptoms, which are less reliable methods than laparoscopy (gold standard). Specifically, symptom-based diagnosis is associated with high risk of misclassification bias and can introduce bias in results especially with a small sample size of 80 patients. Second, the sample size of this single-center retrospective study was smaller than the previous studies; therefore, further studies are required to test our findings in different populations (e.g., races, and regions) [12, 15]. Third, we could not collect sufficient data on the rASRM stage or the presence of DIE for patients with a history of surgical treatment because some patients were operated on at another hospital. Thus, we could not identify the association between placenta previa, pre-pregnancy treatments, and rASRM stage of the patients. Finally, the increased risk of placenta previa in the surgical treatment group may be partly due to the severity of endometriosis rather than surgical treatment itself. However, to determine the effect of surgery itself on pregnancy complications associated with endometriosis, a further study comparing another control group of women who have not been diagnosed with endometriosis but have had an abdominal surgery (e.g., appendectomy) is required.