Hum. Reprod. Advance Access first published online on May 12, 2009
This version published online on July 1, 2009
Human Reproduction, doi:10.1093/humrep/dep186
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Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome
1 Clinical Epidemiology Unit and Centre for Pharmacoepidemiology, Department of Medicine, Karolinska University Hospital and Institute, Stockholm, Sweden 2 Department of Woman and Child Health, Division of Obstetrics and Gynaecology, Karolinska University Hospital and Institute, Stockholm, Sweden
3 Correspondence address. Tel: +46-8-517-791-06; Fax: +46-8-517-793-04; E-mail: olof.stephansson{at}ki.se
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Abstract |
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BACKGROUND: Endometriosis, a common gynaecological disease, is characterized by local and systemic inflammation, which may cause infertility and consequently, increased utilization of assisted reproduction technology (ART). We aimed to estimate the risk for preterm birth, small-for-gestational-age (SGA) birth, stillbirth, Caesarean section, pre-eclampsia and antepartal haemorrhage among women with a previous diagnosis of endometriosis compared with women with no previous diagnosis of endometriosis.
METHODS: In a nationwide Swedish study including 1 442 675 singleton births we assessed the association between adverse pregnancy outcome, ART and a previous diagnosis of endometriosis. Information was obtained by linkage of data between 1992 and 2006 in the Medical Birth Register with the Patient Register between 1964 and 2006.
RESULTS: There were 13 090 singleton births among 8922 women diagnosed with endometriosis. Compared with women without endometriosis, women with endometriosis had higher risks of preterm birth [adjusted odds ratio 1.33, 95% confidence interval (CI), 1.23–1.44]. Among women with endometriosis 11.9% conceived after ART compared with 1.4% of women without endometriosis. The risk of preterm birth associated with endometriosis among women with ART was 1.24 (95% CI, 0.99–1.57), and among women without ART 1.37 (95% CI, 1.25–1.50). Women with endometriosis had higher risks of antepartal bleeding/placental complications, pre-eclampsia and Caesarean section. There was no association between endometriosis and risk of SGA-birth or stillbirth.
CONCLUSIONS: Endometriosis appears to be a risk factor for preterm birth, irrespective of ART. Women with endometriosis may be more likely to be delivered by Caesarean section and to suffer from antepartal haemorrhage/placental complications and pre-eclampsia.
Key words: endometriosis/pregnancy/preterm birth/assisted reproduction technology/reproductive epidemiology
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Introduction |
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Endometriosis is a chronic inflammatory disease defined as the presence of endometrial-like tissue outside the uterine cavity, and common symptoms include dysmenorrhoea, dyspareunia and subfertility (Kennedy et al., 2005
; Farquhar, 2007). The prevalence of endometriosis is estimated to be around 10–15% of all women of reproductive age (Nothnick and D’Hooghe, 2003; Hemmings et al., 2004), although recent data suggest that the prevalence may be lower (Pugsley and Ballard, 2007). Several factors are involved in the development of endometriosis (Farquhar, 2007), and the disease is sustained by aberrant expression of several pro-inflammatory cytokines (Akoum et al., 1996; Pizzo et al., 2002). Recent epidemiological studies suggest that women with certain forms of endometriosis may have an increased risk of preterm birth and small-for-gestational-age (SGA)-birth, and possible mechanisms include altered endometrial function and prostaglandin (PG) levels (Juang et al., 2007; Fernando et al., 2009). However, women with endometriosis are more likely to have difficulties to conceive, and to receive assisted reproduction technology (ART) which itself is a risk factor for adverse pregnancy outcome (Helmerhorst et al., 2004). Using a cohort of more than 1 400 000 births from the Swedish Medical Birth Register (MBR); we studied the association between endometriosis, ART and risk of adverse pregnancy outcome. |
Materials and Methods |
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Study design
We used the Swedish MBR to identify women giving birth between 1 January 1992 and 31 December 2006. The MBR recorded 1 442 675 singleton births and by means of each individual's unique personal registration number we linked data from this register with data from the Patient Register (PAR) to identify all women with a diagnosis of endometriosis (defined according to the relevant International Classification of Disease (ICD) codes ICD-8: 625.3; ICD-9: 617; and ICD-10: n80) between 1964 and 2006. In the Swedish PAR, the ICD-code is assigned to each individual patient when discharged from a hospital. The PAR started in 1964 and from 1987 the register covers all public, in-patient care in Sweden. Since 2001 the register also includes diagnoses from specialized outpatient clinics. There were 13 090 singleton births among women diagnosed with endometriosis prior to delivery during the study period.
Study population
The population-based MBR includes prospectively collected information including demographic data, reproductive history and complications during pregnancy, delivery and the neonatal period among more than 98% of all births in Sweden (Cnattingius et al., 1990). In Sweden, maternal characteristics are recorded in a standardized manner during a woman's first visit for antenatal care, which occurs before the 15th week of gestation in more than 95% of the pregnancies. From height and weight measurements at the first visit we calculated each woman's BMI. Women were categorized according to the BMI as lean (BMI < 20.0 kg/m2), normal (BMI 20.0–24.9), overweight (BMI 25.0–29.9) and obese (BMI of 30.0 or more). Women were categorized as non-smokers, moderate smokers (one to nine cigarettes per day), or heavy smokers (at least10 cigarettes per day). ART includes information on IVF treatment for the present pregnancy and was available from 1995 and onwards. 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 or 35 years and older. Parity was categorized into nulliparous or parous women. Antepartal haemorrhage/placental complications were defined as placental abruption, placenta praevia and other reasons for antepartal bleeding (ICD-9 code 641, or ICD-10 codes O44, O45 and O46). Pre-eclampsia was defined according to ICD-9 codes: 642E, 642F, 642G and 642H or ICD-10 codes: O14 and O15. Through linkage with the Education Register, information on the number of years of formal education completed as of 1 January 2008, was obtained and categorized as 11 or fewer years, or 12 or more years.
Ultrasound for determination of gestational length has been offered to all pregnant women in Sweden since 1990, 95% of whom accept it (Hogberg and Larsson, 1997). Accordingly, gestational age was primarily based on prenatal ultrasound measurement if present or otherwise estimated on the recorded date of the first day of the last menstrual period. Information about stillbirth at 28 weeks of gestation or later, birthweight, and infant sex was obtained from the standardized paediatric record, routinely filled out immediately after delivery. We defined preterm birth as live birth before 37 completed weeks of gestation. SGA birth was defined as one with a birthweight that was more than 2 SD below the mean for gestational age on the Swedish reference curve of estimated fetal growth (Marsal et al., 1996). The study was approved by one of the Regional Ethical Review Boards in Stockholm, Sweden. The board did not require the women to provide informed consent.
Statistical analysis
We used unconditional logistic-regression analysis to evaluate the association between diagnosis of endometriosis and preterm delivery and SGA birth. We also investigated the possible association between endometriosis and stillbirth, Caesarean section, pre-eclampsia and antepartal bleeding. Odds ratios (OR), presented with 95% confidence intervals (CI) were calculated before and after adjustments for maternal characteristics. The estimates were adjusted for maternal age, parity, education, BMI, smoking and calendar year of birth of the child. In order to adjust for the effect of repeated pregnancies, estimates were calculated using the generalized estimating equation (GEE) method with no major differences in the results (Appendix Table A1). Due to the large data set we used a random sample of deliveries among women with no endometriosis 10 times the size of the deliveries with endometriosis matched for year of birth. The data were analyzed using the SAS software (SAS Institute Inc., Cary, NC, USA).
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Results |
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Within the cohort of 1 442 675 singleton births, 8922 women with endometriosis diagnosed before birth delivered 13 090 infants. The median duration from first diagnosis of endometriosis until delivery was 4 years and 6 months. Among the 1 442 675 singleton births there were 4778 cases of stillbirth (rate 3.3 per 1000 births). For 6606 births in the cohort we did not have information on gestational age. The rate of preterm birth was higher among women with endometriosis compared with women without endometriosis. Women with low and high maternal age, with short education, with high or low BMI, nulliparous women and cigarette smokers also had higher rates of preterm birth (Table I). Compared with women without endometriosis, women with endometriosis were of higher maternal age and were more likely to be primiparous. There were no major differences in years of formal education, BMI and smoking habits between women with and without endometriosis (Table II). In the multivariable analysis we adjusted for confounders known to be associated with adverse pregnancy outcome, such as maternal age, parity, socioeconomic status measured by years of formal education, BMI and cigarette smoking. In the adjusted model, the OR for preterm birth was 1.33 (95% CI, 1.23–1.44). For preterm birth we also categorized deliveries into spontaneous and induced (elective Caesarean or induction of labour) preterm birth. The risk associated with endometriosis was higher for induced preterm birth, OR 1.61, 1.41–1.83, compared with spontaneous preterm birth, OR 1.22, 1.11–1.34. There were 9775 very preterm deliveries (before gestational week 32), 113 among women with endometriosis. The adjusted OR for very preterm birth was 1.15 with 95% CI 0.93–1.45. For moderate preterm birth (gestational week 32–36) the corresponding OR was 1.36, 1.25–1.47. In separate analyses where we restricted the cohort to primiparous and parous women, the estimates for preterm birth did not differ from the full model.
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In the multivariate analysis, endometriosis disease was not associated with risk for SGA birth or stillbirth (Table III). As compared with women without endometriosis, women with endometriosis were at increased risk of pre-eclampsia (Table III). Among women with endometriosis the risk of antepartal bleeding including placental disorders was increased by almost 80% (Table III). Caesarean section was more common among women with endometriosis compared with women without endometriosis, and the risk was highest for prelabour Caesarean section (adjusted OR 1.64, 95% CI, 1.54–1.75), whereas the OR for emergency Caesarean section was 1.18 (95% CI, 1.10–1.27). The use of ART was more prevalent in women with endometriosis compared with women without endometriosis (11.9 and 1.4%, respectively). In stratified analyses, the adjusted OR for preterm birth associated with endometriosis among women with ART was 1.24 (95% CI, 0.99–1.54), and 1.37 (95% CI, 1.25–1.50) among women without ART (Table IV).
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Discussion |
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In the present large cohort study we found an increased risk of preterm delivery among women with endometriosis. The relative risk of preterm birth remained relatively unchanged when stratified for the use of ART. We also found that women with endometriosis more frequently were affected by pre-eclampsia and antepartal haemorrhage. Moreover, delivery through Caesarean section was almost twice as common in this group as compared with women without endometriosis.
The biochemical events involved in parturition, both at term and preterm, include the activation of pro-inflammatory mediators such as PGE2, cyclo-oxygenase-2 and interleukin-8 (Smith, 2007). The resulting local and systemic inflammation stimulates myometrial contractility and facilitates cervical ripening. In women with endometriosis, increased levels of PGs and cytokines have been found in peritoneal fluid (Badawy et al., 1982; Pizzo et al., 2002). Chronic inflammation may comprise the biochemical background for preterm birth in women with endometriosis. Other diseases characterized by chronic inflammation, such as Crohn's disease and rheumatoid arthritis, are associated with preterm birth (Skomsvoll et al., 1998; Cornish et al., 2007; Norgard et al., 2007). Among women with Crohn's disease, adverse pregnancy outcome appears to be related to disease activity (Norgard et al., 2007). There is a lack of evidence regarding the degree of inflammation during pregnancy in women with endometriosis. Although a few reports claim beneficial effects of pregnancy on endometriosis in humans, several animal studies point in the opposite direction (D’Hooghe et al., 1997). In contrast to women with inflammatory bowel disease and rheumatoid arthritis, women with endometriosis rarely use disease modifying drugs during pregnancy. The majority of drugs used for endometriosis preclude conception and should not be used during pregnancy (Kennedy et al., 2005). A potential negative influence of disease-modifying drugs on pregnancy outcome in women with endometriosis is therefore unlikely.
The results from this study are to some extent in accordance with two recent studies. An association between adenomyosis and preterm delivery was reported in a case–control study from Taiwan (Juang et al., 2007). In a retrospective cohort study from Australia, a doubled risk for preterm birth and SGA birth was observed in women with ovarian endometriosis (endometrioma) undergoing ART (Fernando et al., 2009). Strangely, endometrioma turned out to be the only risk factor for preterm birth in this cohort, and the authors speculated that abnormalities in the endometrium may impair placentation. Several studies have shown that the endometrium from women with endometriosis differs from healthy controls (Lessey et al., 1994; Taylor et al., 1999) with aberrant expression of integrins and HOX-genes which may affect endometrial receptivity and subsequent placentation (Damsky et al., 1994). Abnormal placentation could provide a rationale for the increased risk of antepartal haemorrhage and placental complications observed in this study.
We had no information regarding the indications for Caesarean section. However, the strongest association with endometriosis was observed for prelabour Caesarean section. Preterm birth may be categorized into spontaneous preterm labour, premature rupture of the membranes or delivery because of maternal or fetal indications (Goldenberg et al., 2008). We observed that among women with endometriosis the risk was higher for induced compared with spontaneous preterm birth. Our findings imply that women with endometriosis more frequently are scheduled for preterm delivery through Caesarean section or induction of labour; possibly due to placental complications.
We observed an increased risk of pre-eclampsia among women with endometriosis. This finding is in contrast with a recent case–control study, where pre-eclampsia surprisingly was found to be reduced in women with endometriosis (Brosens et al., 2007). However, several methodological aspects, including low response rate and possible selection bias may account for this result. It has been proposed that pre-eclampsia arises from a defective remodelling of junctional zone myometrial spiral arteries in the placental bed (Brosens et al., 1972), and studies by Leyendecker and co-workers suggest a relationship between endometriosis and dysregulation of the junctional zone (Leyendecker et al., 2004). This finding implies an association between endometriosis and pre-eclampsia. Furthermore, studies by Lockwood and co-workers of sFlt-1 (soluble fms-like tyrosine kinase-1), suggest a link between endometriosis and pre-eclampsia which involves the inhibition of the proangiogenetic factor, vascular endothelial growth factor (Cho et al., 2007; Lockwood et al., 2008).
The present study is population-based and data on endometriosis is based on diagnosis of discharge or out-patient visits at hospitals in Sweden before delivery. The clinical routines in Sweden have changed through the years and laparoscopic surgery is now the most common diagnostic technique (Melin et al., 2006). A limitation of the study is that we did not know to what extent the diagnosis of endometriosis was based on histological verification after surgery. In a previous study of endometriosis and cancer risk based on the Swedish PAR the diagnosis of endometriosis was histologically confirmed in 81% of the patients (Melin et al., 2006). Furthermore we only have information on diagnosis of endometriosis for women who have been hospitalized between 1964 and 2006 or attended outpatient clinics at hospitals between 2001 and 2006. It is therefore likely that such data are limited to the more severe stages of endometriosis. However, if some women were misclassified according to diagnosis of endometriosis this would dilute the effect of endometriosis because we have no reason to assume that diagnosis misclassification is related to the outcome under study. On the other hand it may not be possible to generalize the findings of an increased risk of adverse pregnancy outcomes to women with mild endometriosis. Because women with infertility are more likely to have a laparoscopy they are more likely to be diagnosed with endometriosis. We therefore stratified the analysis by ART and found that the relative risk for preterm birth was lower among women with ART compared with women with no ART, suggesting effect modification. Another limitation of the study is that we have not been able to assess the influence of treatment of endometriosis on the risk of adverse pregnancy outcome. We were able to adjust for confounders i.e. maternal age, parity, socio-economic status measured by years of formal education and cigarette smoking, known to be associated with preterm birth and other adverse pregnancy outcomes, such as intrauterine growth restriction and pre-eclampsia (Slattery and Morrison, 2002). In contrast to the findings of increased risks for preterm delivery, women with endometriosis had no increased risks of giving birth to an infant with SGA or stillbirth. These findings may suggest a difference in the aetiology of SGA and stillbirth in relation to preterm delivery.
In the present study, women with endometriosis generally had a lower BMI compared with women with no endometriosis, which is supported by a laparoscopy cohort study by Hediger et al. (2005). Previous studies on risk factors for endometriosis reported smoking to have a protective effect, whereas in our data women with endometriosis were less likely to be cigarette smokers (Cramer and Missmer, 2002). However, this observation may be related to differences in fertility rates among cigarette smokers with and without endometriosis. The association between long time to pregnancy and risk of adverse pregnancy outcome may in part be mediated by an increased prevalence of endometriosis among these women irrespective of the use of ART (Reddy et al., 2007).
In the present study of endometriosis and adverse obstetric outcome, based on more than 1.4 million births in Sweden, we found that endometriosis is associated with preterm birth. Endometriosis is a complex trait with multiple pathophysiological mechanisms. Some of these, including increased levels of PGs and endometrial abnormalities, may be related to obstetric events such as preterm birth, antepartal haemorrhage due to placental complication and pre-eclampsia. Endometriosis is common among women of childbearing age and our results provide important information in the search for etiological factors in preterm birth. From a clinical perspective, a woman with endometriosis may need extra attention during pregnancy.
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Author's Role |
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All authors contributed to the study design and to drafting the paper. O.S. led the study together with H.F. and H.K. contributed knowledge on adverse pregnancy outcomes. F.G. provided statistical knowledge. All authors contributed to the drafting, revision and final approval of the manuscript.
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Funding |
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Supported by the Swedish Society of Medicine (postdoc scholarship No. 2008-20966).
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Appendix |
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Table A1 Adjusted ORs with 95% CI for the association between endometriosis and adverse pregnancy outcome analyzed by the GEE-method
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Analyzed using 10 controls, matched by year of birth, per case of endometriosis.
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Submitted on March 17, 2009; resubmitted on April 17, 2009; accepted on April 22, 2009.
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