http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–4 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.968843
ORIGINAL ARTICLE
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Women with endometriosis at first pregnancy have an increased risk of adverse obstetric outcome Nathalie Conti1, Gabriele Cevenini2, Silvia Vannuccini1, Cinzia Orlandini1, Herbert Valensise3, Maria Teresa Gervasi4, Fabio Ghezzi5,6, Mariarosaria Di Tommaso5,6, Filiberto Maria Severi1, and Felice Petraglia1 1
Department of Molecular and Developmental Medicine, 2Department of Medical Biotechnology, University of Siena, Siena, Italy, 3Department of Biomedicine, Obstetrics and Gynecology, Tor Vergata University, Rome, Italy, 4Obstetrics and Gynecology Unit, Department of Women and Children Health, AOP, Padova, Italy, 5Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy, and 6Department of Health Sciences, University of Florence, Florence, Italy Abstract
Keywords
Objective: To evaluate pregnancy, delivery and neonatal outcome in singleton primiparous versus multiparous women with/without endometriosis. Methods: Multicentric, observational and cohort study on a group of Caucasian pregnant women (n ¼ 2239) interviewed during their hospitalization for delivery in five Italian Gynecologic and Obstetric Units (Siena, Rome, Padua, Varese and Florence). Results: Primiparous women with endometriosis (n ¼ 219) showed significantly higher risk of small for gestational age fetuses (OR: 2.72, 95% CI 1.46–5.06), gestational diabetes (OR: 2.13, 95% CI 1.32–3.44), preterm premature rupture of membranes (OR: 2.93, 95% CI 1.24–6.87) and preterm birth (OR: 2.24, 95% CI 1.46–3.44), and were hospitalized for a longer period of time (p50.0001) comparing with control group (n ¼ 1331). Multiparous women with endometriosis (n ¼ 97) delivered significantly more often small for gestational age fetuses (OR: 2.93, 95% CI 1.28–6.67) than control group (n ¼ 592). Newborns of primiparous women with endometriosis needed more frequently intensive care (p ¼ 0.05) and were hospitalized for a longer period of time (p50.0001). Conclusions: Women with endometriosis at first pregnancy have an increased risk of impaired obstetric outcome, while a reduced number of complications occur in the successive gestation. Therefore, it is worthy for obstetricians to increase the surveillance in nulliparous women with endometriosis during pregnancy.
Endometriosis, gestational diabetes, neonatal complications, pPROM, pregnancy outcome, preterm birth, small for gestational age
Introduction Endometriosis is a benign gynecologic disease, affecting up to 10% of the women during their reproductive life, with an increasing incidence [1]. The ectopic localization of endometrial tissue outside uterus causes two main symptoms, pain and infertility, but endometriosis is associated with significant deterioration of quality of life and represents a significant public health issue [2]. Indeed, women with endometriosis show an increased incidence of gastrointestinal, urinary and psychiatric disorders with long-term implications on autoimmune or cancer risk [3]. It is well accepted that endometrium of women with endometriosis is abnormal [4] while the debate is open
Address for correspondence: Felice Petraglia, MD, FRCOG, Obstetrics and Gynecology Unit, Department of Molecular and Developmental Medicine, University of Siena, S. Maria alle Scotte, viale Bracci 53100, Siena, Italy. Tel: +39 0577 233.453. Fax: +39 0577 233.454. E-mail: [email protected]
History Received 3 July 2014 Revised 13 September 2014 Accepted 21 September 2014 Published online 9 October 2014
whether these abnormalities may impair decidualization and placentation during pregnancy [5]. Since these processes may be crucial for pregnancy implantation and development, it was hypothesized that pregnancy outcome may be affected in women with endometriosis [6]. Nevertheless, studies on the relationship between endometriosis and pregnancy outcome are conflicting, with some studies reporting an increased risk of complications (preterm birth, preeclampsia and antepartal bleeding/placental complications) [6–10] and others showing some (placenta previa) [11] or no association [12–15]. However, these studies followed different criteria, mostly evaluating retrospectively large databases from birth register [6] or from infertile women undergoing pregnancy with or without assisted reproductive technology (ART) [8,10,12,13]. No studies distinguished the parity of these women. The present study aimed to evaluate, during the time of hospitalization, pregnancy, delivery and neonatal complications in women with endometriosis achieving first or second pregnancy.
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N. Conti et al.
J Matern Fetal Neonatal Med, Early Online: 1–4
Methods
Results
This is a multicentric, observational and cohort study, including a group of Caucasian singleton pregnant women (n ¼ 2239) attending five Italian Gynecologic and Obstetric Units: Siena, Rome, Padua, Florence and Varese. The permission of the Local Human Investigation Committee was granted for the study. All women were studied after delivery during the post-partum hospitalization, collecting informations about gynecological and reproductive history and data on the ongoing pregnancy, delivery and neonatal outcome. The study group consisted of women who presented a history of endometriosis (n ¼ 316), distinguishing primiparas (n ¼ 219) and multiparas (n ¼ 97). The diagnosis of endometriosis had been confirmed before first pregnancy by pathology following surgical removal of the lesions, resulting ovarian (35%), mixed ovarian and peritoneal (25%), mixed ovarian and deep (21%) and deep endometriosis (19%). Data on the time interval between surgery and pregnancy and between first and second pregnancy, as well as the other medical treatment, were not collected. As control group (n ¼ 1923) all other women were included, subdivided into primiparas (n ¼ 1331) and multiparas (n ¼ 592) according to the present state. Exclusion criteria were endocrine, autoimmune, systemic diseases such as hypertension or diabetes and uterine disorders for both groups. Obstetric complications were: small for gestational age fetuses (SGA) (condition in which the fetus fails to reach his potential growth and birth weight is below the 10th centile for gestational age), gestational hypertension (systolic blood pressure over 140 mmHg or diastolic blood pressure over 90 mmHg, developing after 20 weeks of gestation), preeclampsia (hypertension developing after 20 weeks of gestation with proteinuria), gestational diabetes (carbohydrate intolerance with onset or recognition in pregnancy, with positive oral glucose tolerance test), premature rupture of membranes (pPROM) (rupture of membranes before 37 weeks of gestation) and spontaneous preterm birth (PTB) (live birth before 37 completed weeks of gestation after spontaneous labor). At delivery data were collected on gestational age, prelabor rupture of membranes (PROM), mode of delivery (spontaneous vaginal delivery, operative vaginal delivery and caesarean section), post-partum hemorrhage (blood loss estimated to be 4500 ml within 24 h of vaginal delivery or 4750 ml after caesarean section) and days of maternal hospitalization. Data collected on neonates were: weight at birth, sex, neonatal intensive care unit (NICU) admission and days of hospitalization.
Cases and controls had no statistically significant differences in terms of age, pregravidic and gravidic BMI both in primiparous and multiparous women. Undergoing ART was more common in women with endometriosis versus controls both at first gestation (35.0% versus 5.8%) and subsequent gestations (15% versus 4.1%) (p50.01). Multivariate analysis did not show any influences of ART on pregnancy, delivery and neonatal outcome. Women with endometriosis at first pregnancy showed significantly higher incidence of SGA (p ¼ 0.002), with 10.6% versus 4.1% and OR of 2.72. Pregnant women affected by endometriosis at first pregnancy showed a rate of 13.3% of gestational diabetes versus 6.7% in healthy ones (p ¼ 0.002) with OR 2.13. The OR for pPROM and PTB in primiparas affected by endometriosis was 2.93 (p ¼ 0.001) and 2.24 (p ¼ 0.0005), respectively. Compared with women without endometriosis, women at first pregnancy delivered approximately one week before healthy controls, with a median of 39 weeks of gestation (p ¼ 0.0002) and were hospitalized for a longer period of time (p50.0001) (Table 1). Newborns of women with endometriosis at first pregnancy needed more frequently NICU (p ¼ 0.05), with a OR 1.86 and were hospitalized for a longer period of time (p50.0001) (Table 1), because of a high incidence of prematurity (35%) and defective fetal growth (28%). Multiparous women with endometriosis showed significantly more often SGA (p ¼ 0.001) with a OR 2.93 (Table 1).
Statistical analysis Analysis of data was performed using MedCalcÕ Package (Version 12.4.0.0). Statistically significant differences were determinated using Student’s t-test, Mann–Whitney U test or Fisher’s exact test as appropriate. Logistic regression was used to calculate odds ratio (OR), presented with 95% confidence intervals (CI) to evaluate the association between endometriosis and obstetrics complications, before and after adjustment for infertility and use of ART. p values less than 0.05 were considered to indicate statistical significance.
Discussion The present study showed that women with endometriosis at first pregnancy have more complications than in the subsequent gestations, with greater risk of SGA babies, gestational diabetes, pPROM and PTB, with longer hospitalization both for mother and neonate. When women with endometriosis had a second pregnancy they showed a reduced risk, however, with prolonged maternal and neonatal hospitalization. Therefore, in case of endometriosis at first pregnancy should require more surveillance: an information which may be useful to the endometriosis patients and to the obstetricians to do a better counselling and make clinical decisions. An increased incidence of adverse pregnancy outcome fits with previous retrospective cohort study from a Swedish Register showing that women with endometriosis showed an increased incidence of PTB, preeclampsia and antepartal bleeding/placental complications [7]. Also in agreement with our data are the ART patients who showed that women with ovarian endometriosis had an increased rate of PTB and SGA babies [8]. Conversely, other studies have shown no association with adverse obstetric outcomes both in pregnancies achieved with IVF [13] and in those with spontaneous conception [14] or mix population [11,12]. Our study neither observed the decrease in risk of preeclampsia [15,16], nor the increased incidence of hypertensive disorders [7]. The possible explanation for the different results are: (1) the different methods (database versus interviews) and (2) the distinction between first and second pregnancy after a history of endometriosis.
Endometriosis and obstetric outcome
DOI: 10.3109/14767058.2014.968843
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Table 1. Pregnancy, delivery and neonatal outcomes in first pregnancy and subsequent pregnancies, in women with or without endometriosis, including percentage, for binary variables, median, for quantitative variables and odds ratio (OR) and related confidence intervals (CI) of statistically significant (p50.05) variables. First pregnancy
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Endometriosis (n ¼ 219) Selected conditions in pregnancy Small for gestational age fetus (SGA) (%) Gestational hypertension (%) Preeclampsia (%) Gestational diabetes (%) Premature rupture of membranes (pPROM) (%) Preterm birth (%) Delivery Induction of labour (%) Prelabor rupture of membranes (PROM) (%) Caesarean section (%) Gestational age at delivery (ws) Operative vaginal delivery (%) Post-partum haemorrage (%) Days of hospitalization (days) Neonatal outcome Neonatal gender (Male versus Female) (%) Neonatal weight (g) NICU admission (%) Days of hospitalization (days)
No endometriosis (n ¼ 1331)
Subsequent pregnancy Endometriosis (n ¼ 97)
No endometriosis (n ¼ 592)
OR
95% CI
2.72
1.46–5.06
10.5
3.8 4.2 0.5 9.7 1.5
10.6
4.1
3.7 2.2 13.3 3.6
5.8 1.2 6.7 1.2
2.13 2.93
1.32–3.44 1.24–6.87
1.1 1 11.6 2.5
17.8
8.8
2.24
1.46–3.44
8.2
8.8
16.0 32.2
19.9 28.2
7.2 20.0
11.5 27.3
29.1 39 3.4% 9.4 4
25.3 40 3.0% 7.8 3
17.8 39 2.7% 9.3 3.3
16.9 39 2.5% 10.2 3.0
47.4 versus 49.6 2905 ± 317 7.7 4
52.6 versus 47.4 3150 ± 320 4.9 3
49.5 versus 50.5 3240 ± 614 6.1 3.2
50.5 versus 49.5 3240 ± 552 5.1 3
The mechanism of action of endometriosis in determining an adverse pregnancy outcome may be an abnormal endometrium, resulting in suboptimal endometrial receptivity and impaired placentation during first pregnancy, even though no study has yet been performed on placenta from women with endometriosis [5]. However, this hypothesis of defective placentation is valid for explaining reduced fetal growth and an increased risk of SGA [8]. The increased incidence of PTB related to endometriosis may be explained by a chronic inflammation state, which is common in endometriosis and PTB [17]. Increased expression of inflammatory pathways in the endometrium of endometriosis (corticotropin-releasing hormone [18], growth factors and cytokines [19]) are the same factors implicated in decidua and trophoblast of PTB [20]. A major hormonal change common in endometriosis and PTB is progesterone receptor (PR) isoforms A more expressed than PR-B [21,22]. In endometriosis, the promoter of PR-B is hypermethylated in concomitance with reduced PR-B expression [23] as well as in PTB [24]. The increased incidence of pPROM in women with endometriosis at first pregnancy is related to a physical/ microbial inflammatory event weakening fetal membranes and increasing prostaglandins (PGs), causing collagen degradation within fetal membranes, also through the action of metalloproteinases (MMP-9) and collagenase [25]; in women with endometriosis increased levels of PGs and inflammatory cytokines locally activate MMP-9 and matrixdegrading enzymes and are responsible for the invasiveness of lesions [26,27]. The state of chronic, low-grade subclinical inflammation may also explain the increased incidence of gestational diabetes in primiparous women with endometriosis [28].
1.86
1.06–3.28
OR
95% CI
2.93
1.28–6.67
Women with endometriosis at first pregnancy and their neonates had a longer hospitalization. The higher need for NICU admission and the longer hospitalization are related to a higher incidence of prematurity and defective fetal growth. Previous studies showed an increased incidence of postpartum hemorrhage in endometriosis, even though adjusting for confounding factor such as IVF [11,29]. Aberrant expression of integrins and HOX-genes [30–32] provide a rationale for the increased risk of placental complications observed [11,29]. Pregnancy, delivery and neonatal complications showed in women with endometriosis at first pregnancy disappear in the successive one, suggesting an important role of pregnancy in inducing hormonal and immunological modifications. All women at first pregnancy showed higher rates of maternal, obstetrical and neonatal complications, with a higher tendency to gestational hypertension/preeclampsia, intrauterine growth retardation and preterm birth [33]. The beneficial effect of a natural pregnancy on endometriosis has been well established for a long time [34] and this is the first study to show an effect of pregnancy in endometriosis influencing positively the outcome of subsequent gestations. Specific local or systemic antepartum hormonal changes including steadily rising serum levels of progesterone during pregnancy may be the cause of an improvement of most cases of endometriosis [35], probably reducing the hyperinflammatory state at the basis of pregnancy complications endometriosis-induced. However, because of the low number of women and the lack of information on the management of endometriotic patients between surgery and pregnancy, a prospective large study will be necessary to confirm our observations.
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In conclusion, the rate of obstetrics disorders was significantly higher during first pregnancy, while these conditions did not occur in second pregnancy of multiparous women. This observation suggests a protective role of pregnancy in endometriosis towards subsequent pregnancies, probably through hormonal and immunological modification. As consequence, the patient with endometriosis achieving first pregnancy should be considered at increased risk. Further studies will elaborate the possible measures to suggest to these patients in order to reduce the risk. The clear message is that a link between endometriosis and current pregnancy exists, and that these gynecological patients require an accurate obstetric care.
Declaration of interest This study was in part supported by MIUR Grant entitled ‘‘Preterm birth: molecular, biochemical and biophysical markers of the feto-placental unit’’ (prot.20102CHST5).
References 1. Buck Louis GM1, Hediger ML, Peterson CM, et al. ENDO Study Working Group. Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertil Steril 2011;96: 360–5. 2. Fourquet J, Ba´ez L, Figueroa M, et al. Quantification of the impact of endometriosis symptoms on health-related quality of life and work productivity. Fertil Steril 2011;1:107–12. 3. Statton P, Barkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update 2011;17:327–46. 4. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update 2011;17:637–53. 5. Brosens I, Pijnenborg R, Benagiano G. Defective myometrial spiral artery remodelling as a cause of major obstetrical syndromes in endometriosis and adenomyosis. Placenta 2013;34:100–5. 6. Brosens I, Brosens JJ, Fusi L, et al. Risks of adverse pregnancy outcome in endometriosis. Fertil Steril 2012;98:30–5. 7. Stephansson O, Kieler H, Granath F, Falconer H. Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome. Hum Reprod 2009;24:2341–7. 8. Fernando S, Breheny S, Jaques AM, et al. Preterm birth, ovarian endometrioma and assisted reproduction technologies. Fertil Steril 2009;91:325–30. 9. Juang CM, Chou P, Yen MS, et al. Adenomyosis and risk of preterm delivery. BJOG 2007;114:165–9. 10. Omland AK, Abyholm T, Fedorcsa´k P, et al. Pregnancy outcome after IVF and ICSI in unexplained, endometriosis-associated and tubal factor infertility. Hum Reprod 2005;20:722–7. 11. Vercellini P, Parazzini F, Pietropaolo G, et al. Pregnancy outcome in women with peritoneal, ovarian and rectovaginal endometriosis: a retrospective cohort study. BJOG 2012;119:1538–43. 12. Kortelahti M, Anttila MA, Hippela¨inen MI, Heinonen ST. Obstetric outcome in women with endometriosis – a matched case-control study. Gynecol Obstet Invest 2003;56:207–12. 13. Benaglia L, Bermejo A, Somigliana E, et al. Pregnancy outcome in women with endometriomas achieving pregnancy through IVF. Hum Reprod 2012;27:1663–7.
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14. Mekaru K, Masamoto H, Sugiyama H, et al. Endometriosis and pregnancy outcome: are pregnancies complicated by endometriosis a high-risk group? Eur J Obstet Gynecol 2014;172:36–9. 15. Brosens I, Hamerlynck T, Imeraj L, et al. Endometriosis is associated with a decreased risk of pre-eclampsia. Hum Reprod 2007;22:1725–9. 16. Hadfield RM, Lain SJ, Raynes-Greenow CH, et al. Is there an association between endometriosis and the risk of pre-eclampsia? A population based study. Hum Reprod 2009;24:2348–52. 17. Petraglia F, Arcuri F, de Ziegler D, Chapron C. Inflammation: a link between endometriosis and preterm birth. Feril Steril 2012; 98:36–40. 18. Novembri R, Borges LE, Carrarelli P, et al. Impaired CRH and urocortin expression and function in eutopic endometrium of women with endometriosis. J Clin Endocrinol Metab 2011;96: 1145–50. 19. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update 2013;19:406–18. 20. Petraglia F, Imperatore A, Challis JR. Neuroendocrine mechanisms in pregnancy and parturition. Endocr Rev 2010;31:783–816. 21. Attia GR, Zeitoun K, Edwards D, et al. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab 2000;85:2897–902. 22. Mesiano S, Chan EC, Fitter JT, et al. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J Clin Endocrinol Metab 2002;87:2924–30. 23. Guo SW. Epigenetics of endometriosis. Mol Hum Reprod 2009;15: 587–607. 24. Li X, Chen C, Luo H, et al. Decreased DNA methylations at the progesterone receptor promoter A induce functional progesterone withdrawal in human parturition. Reprod Sci 2014;21:898–905. 25. Vadillo-Ortega F1, Estrada-Gutie´rrez G. Role of matrix metalloproteinases in preterm labour. BJOG 2005;112:19–22. 26. Rakhila H, Carli C, Daris M, et al. Identification of multiple and distinct defects in prostaglandin biosynthetic pathways in eutopic and ectopic endometrium of women with endometriosis. Fertil Steril 2013;100:1650–9. 27. Pitsos M, Kanakas N. The role of matrix metalloproteinases in the pathogenesis of endometriosis. Reprod Sci 2009;16:717–26. 28. Gomes CP, Torloni MR, Gueuvoghlanian-Silva BY, et al. Cytokine levels in gestational diabetes mellitus: a systematic review of the literature. Am J Reprod Immunol 2013;69:545–57. 29. Healy DL, Breheny S, Halliday J, et al. Prevalence and risk factors for obstetric hemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia. Hum Reprod 2010; 25:265–74. 30. Kim JJ, Taylor HS, Lu Z, et al. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod 2007;13:323–32. 31. Taylor HS, Bagot C, Kardana A, et al. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod 1999;14:1328–31. 32. Lessey BA, Young SL. Integrins and other cell adhesion molecules in endometrium and endometriosis. Semin Reprod Endocrinol 1997;15:291–9. 33. Bai J, Wong FW, Bauman A, Mohsin M. Parity and pregnancy outcomes. Am J Obstet Gynecol 2002;186:274–8. 34. McArthur JW, Ulfelder H. The effect of pregnancy upon endometriosis. Obstet Gynecol Surv 1965;20:709–33. 35. Ueda Y, Enomoto T, Miyatake T, et al. A retrospective analysis of ovarian endometriosis during pregnancy. Fertil Steril 2010;94: 78–84.
ORIGINAL ARTICLE
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Women with endometriosis at first pregnancy have an increased risk of adverse obstetric outcome Nathalie Conti1, Gabriele Cevenini2, Silvia Vannuccini1, Cinzia Orlandini1, Herbert Valensise3, Maria Teresa Gervasi4, Fabio Ghezzi5,6, Mariarosaria Di Tommaso5,6, Filiberto Maria Severi1, and Felice Petraglia1 1
Department of Molecular and Developmental Medicine, 2Department of Medical Biotechnology, University of Siena, Siena, Italy, 3Department of Biomedicine, Obstetrics and Gynecology, Tor Vergata University, Rome, Italy, 4Obstetrics and Gynecology Unit, Department of Women and Children Health, AOP, Padova, Italy, 5Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy, and 6Department of Health Sciences, University of Florence, Florence, Italy Abstract
Keywords
Objective: To evaluate pregnancy, delivery and neonatal outcome in singleton primiparous versus multiparous women with/without endometriosis. Methods: Multicentric, observational and cohort study on a group of Caucasian pregnant women (n ¼ 2239) interviewed during their hospitalization for delivery in five Italian Gynecologic and Obstetric Units (Siena, Rome, Padua, Varese and Florence). Results: Primiparous women with endometriosis (n ¼ 219) showed significantly higher risk of small for gestational age fetuses (OR: 2.72, 95% CI 1.46–5.06), gestational diabetes (OR: 2.13, 95% CI 1.32–3.44), preterm premature rupture of membranes (OR: 2.93, 95% CI 1.24–6.87) and preterm birth (OR: 2.24, 95% CI 1.46–3.44), and were hospitalized for a longer period of time (p50.0001) comparing with control group (n ¼ 1331). Multiparous women with endometriosis (n ¼ 97) delivered significantly more often small for gestational age fetuses (OR: 2.93, 95% CI 1.28–6.67) than control group (n ¼ 592). Newborns of primiparous women with endometriosis needed more frequently intensive care (p ¼ 0.05) and were hospitalized for a longer period of time (p50.0001). Conclusions: Women with endometriosis at first pregnancy have an increased risk of impaired obstetric outcome, while a reduced number of complications occur in the successive gestation. Therefore, it is worthy for obstetricians to increase the surveillance in nulliparous women with endometriosis during pregnancy.
Endometriosis, gestational diabetes, neonatal complications, pPROM, pregnancy outcome, preterm birth, small for gestational age
Introduction Endometriosis is a benign gynecologic disease, affecting up to 10% of the women during their reproductive life, with an increasing incidence [1]. The ectopic localization of endometrial tissue outside uterus causes two main symptoms, pain and infertility, but endometriosis is associated with significant deterioration of quality of life and represents a significant public health issue [2]. Indeed, women with endometriosis show an increased incidence of gastrointestinal, urinary and psychiatric disorders with long-term implications on autoimmune or cancer risk [3]. It is well accepted that endometrium of women with endometriosis is abnormal [4] while the debate is open
Address for correspondence: Felice Petraglia, MD, FRCOG, Obstetrics and Gynecology Unit, Department of Molecular and Developmental Medicine, University of Siena, S. Maria alle Scotte, viale Bracci 53100, Siena, Italy. Tel: +39 0577 233.453. Fax: +39 0577 233.454. E-mail: [email protected]
History Received 3 July 2014 Revised 13 September 2014 Accepted 21 September 2014 Published online 9 October 2014
whether these abnormalities may impair decidualization and placentation during pregnancy [5]. Since these processes may be crucial for pregnancy implantation and development, it was hypothesized that pregnancy outcome may be affected in women with endometriosis [6]. Nevertheless, studies on the relationship between endometriosis and pregnancy outcome are conflicting, with some studies reporting an increased risk of complications (preterm birth, preeclampsia and antepartal bleeding/placental complications) [6–10] and others showing some (placenta previa) [11] or no association [12–15]. However, these studies followed different criteria, mostly evaluating retrospectively large databases from birth register [6] or from infertile women undergoing pregnancy with or without assisted reproductive technology (ART) [8,10,12,13]. No studies distinguished the parity of these women. The present study aimed to evaluate, during the time of hospitalization, pregnancy, delivery and neonatal complications in women with endometriosis achieving first or second pregnancy.
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2
N. Conti et al.
J Matern Fetal Neonatal Med, Early Online: 1–4
Methods
Results
This is a multicentric, observational and cohort study, including a group of Caucasian singleton pregnant women (n ¼ 2239) attending five Italian Gynecologic and Obstetric Units: Siena, Rome, Padua, Florence and Varese. The permission of the Local Human Investigation Committee was granted for the study. All women were studied after delivery during the post-partum hospitalization, collecting informations about gynecological and reproductive history and data on the ongoing pregnancy, delivery and neonatal outcome. The study group consisted of women who presented a history of endometriosis (n ¼ 316), distinguishing primiparas (n ¼ 219) and multiparas (n ¼ 97). The diagnosis of endometriosis had been confirmed before first pregnancy by pathology following surgical removal of the lesions, resulting ovarian (35%), mixed ovarian and peritoneal (25%), mixed ovarian and deep (21%) and deep endometriosis (19%). Data on the time interval between surgery and pregnancy and between first and second pregnancy, as well as the other medical treatment, were not collected. As control group (n ¼ 1923) all other women were included, subdivided into primiparas (n ¼ 1331) and multiparas (n ¼ 592) according to the present state. Exclusion criteria were endocrine, autoimmune, systemic diseases such as hypertension or diabetes and uterine disorders for both groups. Obstetric complications were: small for gestational age fetuses (SGA) (condition in which the fetus fails to reach his potential growth and birth weight is below the 10th centile for gestational age), gestational hypertension (systolic blood pressure over 140 mmHg or diastolic blood pressure over 90 mmHg, developing after 20 weeks of gestation), preeclampsia (hypertension developing after 20 weeks of gestation with proteinuria), gestational diabetes (carbohydrate intolerance with onset or recognition in pregnancy, with positive oral glucose tolerance test), premature rupture of membranes (pPROM) (rupture of membranes before 37 weeks of gestation) and spontaneous preterm birth (PTB) (live birth before 37 completed weeks of gestation after spontaneous labor). At delivery data were collected on gestational age, prelabor rupture of membranes (PROM), mode of delivery (spontaneous vaginal delivery, operative vaginal delivery and caesarean section), post-partum hemorrhage (blood loss estimated to be 4500 ml within 24 h of vaginal delivery or 4750 ml after caesarean section) and days of maternal hospitalization. Data collected on neonates were: weight at birth, sex, neonatal intensive care unit (NICU) admission and days of hospitalization.
Cases and controls had no statistically significant differences in terms of age, pregravidic and gravidic BMI both in primiparous and multiparous women. Undergoing ART was more common in women with endometriosis versus controls both at first gestation (35.0% versus 5.8%) and subsequent gestations (15% versus 4.1%) (p50.01). Multivariate analysis did not show any influences of ART on pregnancy, delivery and neonatal outcome. Women with endometriosis at first pregnancy showed significantly higher incidence of SGA (p ¼ 0.002), with 10.6% versus 4.1% and OR of 2.72. Pregnant women affected by endometriosis at first pregnancy showed a rate of 13.3% of gestational diabetes versus 6.7% in healthy ones (p ¼ 0.002) with OR 2.13. The OR for pPROM and PTB in primiparas affected by endometriosis was 2.93 (p ¼ 0.001) and 2.24 (p ¼ 0.0005), respectively. Compared with women without endometriosis, women at first pregnancy delivered approximately one week before healthy controls, with a median of 39 weeks of gestation (p ¼ 0.0002) and were hospitalized for a longer period of time (p50.0001) (Table 1). Newborns of women with endometriosis at first pregnancy needed more frequently NICU (p ¼ 0.05), with a OR 1.86 and were hospitalized for a longer period of time (p50.0001) (Table 1), because of a high incidence of prematurity (35%) and defective fetal growth (28%). Multiparous women with endometriosis showed significantly more often SGA (p ¼ 0.001) with a OR 2.93 (Table 1).
Statistical analysis Analysis of data was performed using MedCalcÕ Package (Version 12.4.0.0). Statistically significant differences were determinated using Student’s t-test, Mann–Whitney U test or Fisher’s exact test as appropriate. Logistic regression was used to calculate odds ratio (OR), presented with 95% confidence intervals (CI) to evaluate the association between endometriosis and obstetrics complications, before and after adjustment for infertility and use of ART. p values less than 0.05 were considered to indicate statistical significance.
Discussion The present study showed that women with endometriosis at first pregnancy have more complications than in the subsequent gestations, with greater risk of SGA babies, gestational diabetes, pPROM and PTB, with longer hospitalization both for mother and neonate. When women with endometriosis had a second pregnancy they showed a reduced risk, however, with prolonged maternal and neonatal hospitalization. Therefore, in case of endometriosis at first pregnancy should require more surveillance: an information which may be useful to the endometriosis patients and to the obstetricians to do a better counselling and make clinical decisions. An increased incidence of adverse pregnancy outcome fits with previous retrospective cohort study from a Swedish Register showing that women with endometriosis showed an increased incidence of PTB, preeclampsia and antepartal bleeding/placental complications [7]. Also in agreement with our data are the ART patients who showed that women with ovarian endometriosis had an increased rate of PTB and SGA babies [8]. Conversely, other studies have shown no association with adverse obstetric outcomes both in pregnancies achieved with IVF [13] and in those with spontaneous conception [14] or mix population [11,12]. Our study neither observed the decrease in risk of preeclampsia [15,16], nor the increased incidence of hypertensive disorders [7]. The possible explanation for the different results are: (1) the different methods (database versus interviews) and (2) the distinction between first and second pregnancy after a history of endometriosis.
Endometriosis and obstetric outcome
DOI: 10.3109/14767058.2014.968843
3
Table 1. Pregnancy, delivery and neonatal outcomes in first pregnancy and subsequent pregnancies, in women with or without endometriosis, including percentage, for binary variables, median, for quantitative variables and odds ratio (OR) and related confidence intervals (CI) of statistically significant (p50.05) variables. First pregnancy
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Endometriosis (n ¼ 219) Selected conditions in pregnancy Small for gestational age fetus (SGA) (%) Gestational hypertension (%) Preeclampsia (%) Gestational diabetes (%) Premature rupture of membranes (pPROM) (%) Preterm birth (%) Delivery Induction of labour (%) Prelabor rupture of membranes (PROM) (%) Caesarean section (%) Gestational age at delivery (ws) Operative vaginal delivery (%) Post-partum haemorrage (%) Days of hospitalization (days) Neonatal outcome Neonatal gender (Male versus Female) (%) Neonatal weight (g) NICU admission (%) Days of hospitalization (days)
No endometriosis (n ¼ 1331)
Subsequent pregnancy Endometriosis (n ¼ 97)
No endometriosis (n ¼ 592)
OR
95% CI
2.72
1.46–5.06
10.5
3.8 4.2 0.5 9.7 1.5
10.6
4.1
3.7 2.2 13.3 3.6
5.8 1.2 6.7 1.2
2.13 2.93
1.32–3.44 1.24–6.87
1.1 1 11.6 2.5
17.8
8.8
2.24
1.46–3.44
8.2
8.8
16.0 32.2
19.9 28.2
7.2 20.0
11.5 27.3
29.1 39 3.4% 9.4 4
25.3 40 3.0% 7.8 3
17.8 39 2.7% 9.3 3.3
16.9 39 2.5% 10.2 3.0
47.4 versus 49.6 2905 ± 317 7.7 4
52.6 versus 47.4 3150 ± 320 4.9 3
49.5 versus 50.5 3240 ± 614 6.1 3.2
50.5 versus 49.5 3240 ± 552 5.1 3
The mechanism of action of endometriosis in determining an adverse pregnancy outcome may be an abnormal endometrium, resulting in suboptimal endometrial receptivity and impaired placentation during first pregnancy, even though no study has yet been performed on placenta from women with endometriosis [5]. However, this hypothesis of defective placentation is valid for explaining reduced fetal growth and an increased risk of SGA [8]. The increased incidence of PTB related to endometriosis may be explained by a chronic inflammation state, which is common in endometriosis and PTB [17]. Increased expression of inflammatory pathways in the endometrium of endometriosis (corticotropin-releasing hormone [18], growth factors and cytokines [19]) are the same factors implicated in decidua and trophoblast of PTB [20]. A major hormonal change common in endometriosis and PTB is progesterone receptor (PR) isoforms A more expressed than PR-B [21,22]. In endometriosis, the promoter of PR-B is hypermethylated in concomitance with reduced PR-B expression [23] as well as in PTB [24]. The increased incidence of pPROM in women with endometriosis at first pregnancy is related to a physical/ microbial inflammatory event weakening fetal membranes and increasing prostaglandins (PGs), causing collagen degradation within fetal membranes, also through the action of metalloproteinases (MMP-9) and collagenase [25]; in women with endometriosis increased levels of PGs and inflammatory cytokines locally activate MMP-9 and matrixdegrading enzymes and are responsible for the invasiveness of lesions [26,27]. The state of chronic, low-grade subclinical inflammation may also explain the increased incidence of gestational diabetes in primiparous women with endometriosis [28].
1.86
1.06–3.28
OR
95% CI
2.93
1.28–6.67
Women with endometriosis at first pregnancy and their neonates had a longer hospitalization. The higher need for NICU admission and the longer hospitalization are related to a higher incidence of prematurity and defective fetal growth. Previous studies showed an increased incidence of postpartum hemorrhage in endometriosis, even though adjusting for confounding factor such as IVF [11,29]. Aberrant expression of integrins and HOX-genes [30–32] provide a rationale for the increased risk of placental complications observed [11,29]. Pregnancy, delivery and neonatal complications showed in women with endometriosis at first pregnancy disappear in the successive one, suggesting an important role of pregnancy in inducing hormonal and immunological modifications. All women at first pregnancy showed higher rates of maternal, obstetrical and neonatal complications, with a higher tendency to gestational hypertension/preeclampsia, intrauterine growth retardation and preterm birth [33]. The beneficial effect of a natural pregnancy on endometriosis has been well established for a long time [34] and this is the first study to show an effect of pregnancy in endometriosis influencing positively the outcome of subsequent gestations. Specific local or systemic antepartum hormonal changes including steadily rising serum levels of progesterone during pregnancy may be the cause of an improvement of most cases of endometriosis [35], probably reducing the hyperinflammatory state at the basis of pregnancy complications endometriosis-induced. However, because of the low number of women and the lack of information on the management of endometriotic patients between surgery and pregnancy, a prospective large study will be necessary to confirm our observations.
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N. Conti et al.
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In conclusion, the rate of obstetrics disorders was significantly higher during first pregnancy, while these conditions did not occur in second pregnancy of multiparous women. This observation suggests a protective role of pregnancy in endometriosis towards subsequent pregnancies, probably through hormonal and immunological modification. As consequence, the patient with endometriosis achieving first pregnancy should be considered at increased risk. Further studies will elaborate the possible measures to suggest to these patients in order to reduce the risk. The clear message is that a link between endometriosis and current pregnancy exists, and that these gynecological patients require an accurate obstetric care.
Declaration of interest This study was in part supported by MIUR Grant entitled ‘‘Preterm birth: molecular, biochemical and biophysical markers of the feto-placental unit’’ (prot.20102CHST5).
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