{"paper_id":"a9047719-9a3e-41be-a7fb-028b643b94c0","body_text":"Journal of Endometriosis and Pelvic Pain Disorders 2015; 7(2): 51-55\nJEPPD\nISSN 2035-9969\n© 2015 The Authors. This article is published by Wichtig Publishing and licensed under Creative Commons Attribution-NC-ND 4.0 International  \n(CC BY-NC-ND 4.0). Any commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.wichtig.com\nReview\nfound that conclusive evidence is as yet lacking (1). At the \nsame time, data have been accumulating supporting the hy -\npothesis that – over and above toxic compounds – the risk \nof endometriosis can be influenced by a number of other \nfactors, including dietary habits (2-6).\nFollowing the emerging evidence that different in utero \nconditions, whether hormonal, nutritional or those caused \nby pregnancy complications, may influence the risk of en-\ndometriosis, we focused our attention on the hormonal re-\nsponsiveness of the neonatal endometrium. To this end, we \nelaborated a new theory to explain premenarcheal and early-\nonset endometriosis based on the observation that endome-\ntrium exhibits different degrees of progesterone resistance \nat birth (7). Indeed, the neonatal endometrium can display a \nnumber of cellular responses, varying from full progesterone \n resistance, to secretory activity in the glandular compartment \nand, in approximately 3%-5% of cases, changes akin to those \nDOI: 10.5301/je.5000218\nNeonatal menstruation explains epidemiological links \nbetween fetomaternal conditions and adolescent \nendometriosis\nivo Brosens 1, Caroline Gargett2, Stephan Gordts1, Jan Brosens3, Giuseppe Benagiano4\n1 Leuven Institute for Fertility and Embryology, Leuven - Belgium\n2  The Ritchie Centre, Hudson Institute of Medical Research and Department of Obstetrics and Gynecology, Monash University, Clayton -  \nAustralia\n3 The Division of Translational and Systems Medicine, Warwick Medical School, Coventry - UK\n4 Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome, Rome - Italy\nIntroduction\nIncreasing experimental evidence suggests that expo-\nsure to environmental pollutants during the early stages of \ndevelopment can disrupt endocrine and reproductive func-\ntions, thereby increasing the risk of endometriosis later in \nlife. We have recently reviewed the potential link between \nin utero conditions or exposures and endometriosis and \nABstRA ct\nBackground: Different fetomaternal conditions may influence the risk of endometriosis during adolescence and \nin adult life; here we focus on the hormonal maturation of the fetal endometrium in the final stages of pregnancy \nand on the theory that neonatal menstruation should be considered, similar to cyclic menstruation in the adult, \nas a risk factor for adolescent endometriosis.\nMethods: The literature on neonatal menstruation and associated factors was systematically searched, and 19 \nrelevant articles, published in different languages between 1950 and 1984, were retrieved. After closer scrutiny, \n11 publications were selected as relevant.\nResults: At birth, the neonatal endometrium displays different degrees of progesterone resistance, varying from \na complete absence of progesterone responses, to secretory activity, decidualization and menstrual-like shed-\nding. A temporal relationship exists between endometrial maturation and the incidence of neonatal menstrua-\ntion, supporting the hypothesis that vaginal bleeding at birth is triggered by progesterone withdrawal. Neonatal \nmenstruation occurs rarely in preterm babies, increases in those born at term and is a relatively frequent event \nin postmature infants. Analysis of archival clinical studies indicates that being born postterm or to a preeclamptic \nmother increases the risk of neonatal menstruation. Low birthweight may also enhance the likelihood of neonatal \nmenstruation, whereas prematurity could be protective, although the available data are inconclusive.\nConclusions: The available data suggest that fetomaternal risk factors associated with neonatal menstruation \ncould also potentially be useful in identifying women at risk of endometriosis. However, archival clinical studies \nhave important limitations, including lack of accurate dating of pregnancy, therefore necessitating prospective \nstudies and systematic registration of neonatal menstruation.\nKeywords: Endometriosis, Low birth weight, Neonatal menstruation, Postmaturity, Preeclampsia, Prematurity\nAccepted: June 4, 2015\nPublished online: July 15, 2015\nCorresponding author:\nProf. Dr . Ivo Brosens\nOud-Heverleestraat 83\nB-3001 Leuven, Belgium\nivo.brosens@med.kuleuven.be\n\nNeonatal menstruation\n52 \n© 2015 The Authors. Published by Wichtig Publishing\nseen prior and during menstruation in adults (8, 9). Thus, \nlike menstruation during reproductive years, neonatal uter -\nine bleeding is triggered by partial shedding of the endome-\ntrium in response to withdrawal of placental progesterone; \nhence the term neonatal menstruation. An integral part of \nthis theory is the conjecture that retrograde transplantation \nof endometrial stem/progenitor cells in response to neonatal \nmenstruation plays a critical role in the pathogenesis of early-\nonset endometriosis (10).\nIt seems therefore that the origin of endometriosis, at \nleast in premenarcheal and adolescent girls, may be linked \nto the presence or absence of physiological neonatal men-\nstruation. It has been argued that the likelihood of retrograde \nbleeding is particularly high at birth because of the structure \nof the neonatal cervical canal, which is twice as long as the \nuterine corpus and functionally blocked by thick endocervical \nmucus (11-13). Indeed, a unique case report described the \npresence of epithelial deposits of endometrial origin on the \nserosal surface of the sigmoid colon in a newborn (14).\nClinical and scientific interest in neonatal menstruation \nhas been largely confined to 1960s and 1970s, and relevant \nstudies were reported mainly in the French and German \n literature (15-19). Intriguingly, although there are no original \nstudies on neonatal uterine bleeding in the more recent med-\nical literature, a lively discussion on this topic can be found on \nthe internet. For instance, the WebMD site explains clearly:\nYour newborn girl’s genitals have been exposed to \nmany hormones in the uterus. Among other things, \nthese hormones may have made the outside of the \nvagina (“labia majora” and the “clitoris”) a little swol -\nlen and prominent and caused a thick, milky discharge \nin the vagina. Most dramatically, at 2 or 3 days of age, \nyour daughter may have a little bit of bleeding from \nher vagina. This is perfectly normal – it is caused by \nthe withdrawal of the hormones she was exposed to \nin the womb. It will be her first and last menstrual pe-\nriod for another decade or so (20).\nHaving identified 2 novel intrauterine variables that may \ninfluence the risk of endometriosis later in life – i.e., the de-\ngree of neonatal endometrial progesterone responsiveness \nand the incidence of retrograde bleeding soon after birth – \nwe reexamined the available literature in search of fetoma-\nternal factors relevant to both neonatal menstruation and \nendometriosis.\nSearch strategy and analysis\nTo develop our hypothesis on the neonatal origins of \nendometriosis, we started with the more recent litera-\nture (1980-2014) and identified a single study on neonatal \nmenstruation, published in 1985 in the Yugoslav Journal of  \nGynecology and Perinatology, a medical journal from the for-\nmer Yugoslavia (18). In addition, in our attempt to identify pu-\ntative fetomaternal markers of endometriosis, we searched \nfor neonatal endometrium, or endometrium in the neonate  \nin combination with preeclampsia or adolescent pregnancy; \nhowever, among the 33,971 publications on preeclampsia \nand 78,736 publications on adolescent pregnancy, not a \n single publication linked these subjects. Therefore, we manu-\nally but systematically searched the literature on neonatal \nmenstruation between 1950 and 1984 in the Library of the \nRoyal Society of Medicine in London. The references listed in \nthese publications were then used for a further search of rel-\nevant articles. We identified 19 articles and, after scrutiny of \nthe data, retained 11 publications relevant to our hypothesis. \nFor obvious reasons, our search cannot be considered “sys-\ntematic” in its full meaning, since a manual search is subject \nto involuntary omission. Another drawback of our approach \nis that a comprehensive understanding of the possible impact \nof neonatal menstruation on reproductive events later in life \nemerged progressively as we were able to obtain and analyze \nthe full text of these old publications. This step-wise approach \nled to a series of publications that developed an increasingly \nmore detailed theory (8, 9, 10, 21). Therefore, the hypothesis \nwe present here on a possible relationship between neonatal \nmenstruation, preeclampsia, adolescent pregnancy and en-\ndometriosis is probably still incomplete, and should therefore \nbe considered as a clinical opinion. Methodologically, the in -\ncidence of neonatal menstruation in various clinical cohorts \nwas compared using either the chi-square or Fisher’s exact \ntest with a p value <0.05 considered significant.\nThe first menstruation\nThe criterion used to determine the incidence of neonatal \nmenstruation in most studies is based on the presence of vis-\nible vaginal bleeding starting a few days after birth and lasting \nfor several days (Tab. I). We identified 5 informative studies, \nencompassing 5,163 babies. The overall incidence of overt \nmenstruation was very consistent across studies, ranging from \n3.0% to 5.2% (median 3.9%); which is entirely commensurate \nwith the frequency of full progesterone responsiveness of the \nneonatal endometrium when defined on histological evidence \nof decidual transformation of the stroma or menstruation-like \ntABLe i - Incidence of overt and occult neonatal menstruation\n Newborns \n(no.)\nNUB cases \n(no.)\nIncidence \nOvert\n Rosa et al (1955) (19) 976 29 3%\n Lévy et al (1964) (15) 1,207 57 4.7%\n Kaiser et al (1974) (16) 153 8 5.2%\n Huber et al (1976) (17) 350 12 3.4%\n  Berić et al (1985) (18) 2,477 96 3.9%\nOccult\n Rosa et al (1955) (19)* 50 13 26%\n Kaiser et al (1974) (16)† 153 93 61%\n Huber et al (1976) (17)‡ 350 89 24%\nNUB = Neonatal uterine bleeding. \n*Detection method: cytology.\n†Detection method: hemoglobin.\n‡Detection method: perox-ortho-toluidine.\n\nBrosens et al\n 53\n© 2015 The Authors. Published by Wichtig Publishing\ntissue breakdown. Three studies also reported the incidence \nof occult uterine bleeding, defined as “the  presence of blood \ndetected by cytology or biochemical tests” in the absence of \nvisible vaginal bleeding (Tab. I). By contrast to overt uterine \nbleeding, the reported incidence of occult uterine bleeding \nvaried widely, from 25% to 61%, which likely reflects the sen-\nsitivity of different methods used in these studies. Neonatal \nmenstruation is a transient phenomenon that is typically de -\ntectable between postpartum days 3 and 7.\nFetomaternal determinants of neonatal menstruation\nLow birthweight\nLévy et al (15) investigated the incidence of neonatal \nmenstruation in 3 groups of neonates. The first cohort con -\nsisted of 1,207 female neonates born at the Maternité de \nStrasbourg between the 12\nth of February 1961 and 12 th of \nFebruary 1962. The incidence of neonatal menstruation \nin this control group from the maternity hospital was 4.7% \n(57/1,207). The frequency of neonatal menstruation was also \nexamined in 2 study groups, consisting of newborns admit -\nted to the neonatal unit. The first study group included 584 \nso-called premature newborns, defined by a low birthweight \n(<2,500 g),  admitted to the neonatal unit over a 69-month \nperiod, starting on the 1\nst of January 1957. The second study \ngroup involved 272 term or postterm babies admitted over \na 32-month period. Interestingly, the incidence of neonatal \nmenstruation in the low birthweight group was 6.2% (36/584), \nhigher than the control group, although not significantly so \n(p = 0.22). Unfortunately, gestation length was not recorded \nin this study, rendering it impossible to separate premature \nfrom small-for-gestational-age newborns. By contrast, the in-\ncidence of neonatal menstruation in the second study group \nwas 14% (38/272), significantly higher when compared with \nthe control group (p<0.0001). Two tentative conclusions can \nbe drawn from this study. First, the data on birthweight and \nthe risk of menstruation are inconclusive and require further \ninvestigation. Second, the data also suggest that pregnancy \ndisorders that impact neonatal well-being may increase the \nrisk of neonatal menstruation.\nPrematurity and postmaturity\nA study by Berić et al (18) included all female babies born \nat the Department of Obstetrics and Gynaecology in Novi \nSad, Serbia, throughout 1979. The incidence of visible vagi-\nnal bleeding in term babies was 3.9% (96/2,241). In preterm \nnewborns, the incidence was 0.8% (1/126) and in postterm \n9.1% (10/110). Statistical analysis of this data confirmed that \nthe incidence of neonatal menstruation was significantly \ndifferent between preterm and postterm babies (p = 0.004) \nand between term and postterm babies (p = 0.009). By con -\ntrast, the difference between preterm and term babies did \nnot reach statistical significance (p>0.05). In an earlier study, \nRosa et al (19) reported 3 cases of menstruation in 206 girls \nborn before 36 weeks of gestation (1.5%) compared with 23 \ncases in 770 term babies (3%; p = 0.24). The authors also stat-\ned that these 3 preterm babies were almost mature as their \nbirthweights were between 2,750 and 2,900 g. As mentioned \nabove, the study of Lévy et al (15) defined term and preterm \non the basis of birthweight and not on length of gestation. \nNevertheless, the authors also recorded menstruation in 7 \nout of 13 (54%) newborns with clinical evidence of postmatu-\nrity, as defined by the criteria of Clifford and Reid (22). Taken \ntogether, these observations demonstrate that postmaturity \nis a strong risk factor for neonatal menstruation. Prematurity \nis likely protective, although the evidence is inconclusive. In \nany case, the incidence of menstruation illustrates the tem -\nporal relationship between endometrial maturation in late \ngestation and the incidence of uterine bleeding at birth; fur -\nther supporting the notion that neonatal uterine bleeding, \nlike adult menstruation, is caused by withdrawal of proges-\nterone actions on a responsive endometrium.\nPreeclampsia\nIn the study of Lévy et al (15), 65 babies were born to moth-\ners with preeclampsia. Preeclampsia was defined as severe, \nin the presence of hypertension, albuminuria and edema, \nand as mild, in the presence 2 of 2 symptoms. The incidence \nof menstruation associated with mild preeclampsia was 32% \n(8/25) and with severe preeclampsia 47.5% (19/40). Thus the \noverall incidence of neonatal uterine bleeding in babies born \nto preeclamptic mothers, irrespective of the severity, was \n42% (27/65), which is significantly higher than the overall in-\ncidence in the control or either study group (p<0.001). \nFetomaternal blood incompatibility\nA well-defined subgroup in the study of Lévy and col -\nleagues (15) consisted of 49 females at term or postterm \n babies admitted to the neonatal unit because of Rhesus or \nABO incompatibility. This subgroup is of interest as hemoly -\nsis and increased hematopoiesis could theoretically increase \nmobilization and trafficking of bone marrow–derived pro-\ngenitor cells to the uterus, which has been proposed as one \npossible explanation for increased progesterone responsive-\nness of the endometrium at term (23). However, the inci -\ndence of neonatal menstruation in this subgroup was 14.3% \n(7/49), which is greater than in the control group, but not sig-\nnificantly different from the overall incidence of in the term/ \npostterm study group (p>0.05).\nDiscussion\nThe role of the in utero environment in the pathogenesis \nof endometriosis is an emerging but controversial topic. Epi-\ndemiological studies have largely focused on adult endome-\ntriosis and the mothers’ lifestyle during the index pregnancy. \nWe recently highlighted that neonatal menstruation, a physi-\nological but entirely neglected phenomenon, not only ex -\ntends Sampson’s theory on the origins of endometriosis but \ncould potentially explain early-onset endometriosis. In this \nstudy, we investigated the putative fetomaternal risk factors \nof neonatal menstruation to determine the overlap, if any, \nwith those implicated in endometriosis. This exercise has im-\nportant limitations especially as all informative clinical stud-\nies predate the introduction of ultrasound and fetal growth \ncharts in clinical practice. Moreover, several putative risk \n\nNeonatal menstruation\n54 \n© 2015 The Authors. Published by Wichtig Publishing\n factors, such as low birthweight and prematurity, are interde-\npendent but their relative importance cannot be ascertained \nfrom the available data.\nNevertheless, our exercise yielded a number of intriguing \nobservations relevant to our understanding of pelvic endome-\ntriosis and confirmed by recent epidemiological studies (Tab. II).  \nFor example, the Nurses’ Health Study II reported a linear in-\ncrease in the incidence rate of laparoscopically confirmed en-\ndometriosis with decreasing birthweight. This observation was \nnot corroborated by the more recent Endometriosis, Natural \nHistory, Disease, Outcome (ENDO) Study (24). However, this \nstudy reported that preterm birth decreases the odds of find-\ning endometriosis at the time of surgery. This finding caused \nsome consternation at the time of publication, as there was \nno obvious explanation. However, the equivocal data on birth-\nweight and the protection conferred by preterm birth are in \nkeeping with the incidence of neonatal menstruation reported \nmany decades ago. Intriguingly, while several recent studies \nhave tried to assess the impact of endometriosis on obstetri-\ncal disorders, including preeclampsia (25), there are to our \nknowledge no studies that have examined the link between \npreeclampsia and the risk of the child developing endometrio-\nsis in adulthood or beyond.\nThe current interest in in utero exposures and risk of en-\ndometriosis is predicated on the early origins of health and \ndisease hypothesis, first proposed by David Barker in 1990 \n(26). This hypothesis posits that maternal signals or expo-\nsures may permanently reprogram the developing fetus in \na manner that determines the likelihood of developing dis-\nease later in life. In the  context of endometriosis, the data \nare ambiguous and inconclusive, reflecting the inherent bi-\nases associated with retrospective transgenerational stud-\nies. Furthermore, reprogramming of fetal organs is widely \nspeculated to involve an epigenetic mechanism, although \na  validated pathway has yet to emerge. Arguably, neonatal \nmenstruation and pelvic seeding of endometrial progeni-\ntor cells constitute a compelling and direct mechanism that \ncould link in utero events to the risk of endometriosis, espe-\ncially early-onset disease.\nFinally, the fact that neonatal menstruation is related to \nprogesterone sensitivity and represents a risk factor for en-\ndometriosis later in life, whereas endometriosis has been \nlinked to progesterone resistance, may be seen as a paradox. \nIn this respect, it has been argued that the term progesterone \n resistance within the context of endometriosis is a misnomer \nsince endometriotic cells, especially stromal cells, are also \nresistant to other signals, such as cyclic AMP or hCG (27). \nHence, it is far from clear whether “progesterone resistance” \nin the context of endometriosis is related or comparable to \nthe fetal situation.\nThe challenge now is to test this hypothesis prospective -\nly, which could be easily achieved if the presence or absence \nof neonatal uterine bleeding is systematically recorded as a \nputative clinical marker of future reproductive health. In this \nrespect, agreement should be sought on how to determine \nthe presence of vaginal blood in the neonate. Clearly this is \neasy in the event of overt bleeding but more cumbersome if \noccult bleeding is included since – as shown in the Table I – \ndifferent methods have different sensitivities. Furthermore, \nit remains to be established if occult bleeding reflects focal \ndisintegration of the neonatal endometrium that is other -\nwise still largely resistant to progesterone withdrawal.\nAcknowledgement\nWe are grateful to Dr. Bee Tan for advice. \nDisclosures\nFinancial support: This work was supported in part by the Biomedi -\ncal Research Unit in Reproductive Health, a joint initiative between \nthe University Hospitals Coventry and Warwickshire NHS Trust and \nWarwick Medical School, the National Health and Medical Research \nCouncil of Australia (1042298) and the Victorian Government’s  \nOperational Infrastructure Support Program.\nConflict of interest: All authors report no conflict of interest.\nReferences\n1. Benagiano G, Brosens I. In utero exposure and endometriosis. \nJ Matern Fetal Neonatal Med. 2014;27(3):303-308.\n2. Newbold R. Cellular and molecular effects of developmental \nexposure to diethylstilbestrol: implications for other environ -\nmental estrogens. 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Potential role of endometrial stem/progenitor cells \ntABLe ii  -  Fetomaternal conditions linked with endometriosis, as \nconfirmed by epidemiological studies\nFetomaternal condition Epidemiological confirmation\nNeonatal menstruation is very \nrare in preterm newborns  \n(Berić et al, 1985 (18))\nThe ENDO study found that, \nfor \nan unknown reason, endome-\ntriosis is rare in preterm born \nwomen (Wolff et al, 2013 (23))\nLow birth weight (<2,500 g)* is \nassociated with increased fre -\nquency of neonatal menstrua -\ntion (Lévy et al, 1964 (15))\nLow birth weight (<2,500 g)* is \nindependently associated with \nthe risk of deep endometriosis in \nadults (Borghese et al, 2015 (24))\n*Includes both premature and small-for-gestational-age newborns.\n\nBrosens et al\n 55\n© 2015 The Authors. Published by Wichtig Publishing\nin the pathogenesis of early-onset endometriosis. Mol Hum \nReprod. 2014;20(7):591-598.\n11. Fluhmann CF. The developmental anatomy of the cervix uteri. \nObstet Gynecol. 1960;15:62-69.\n12. Terruhn V. Formwandel und Epithelentwicklung der Portio \nvaginalis Uteri von der Geburst bis zur Adoleszenz. Eine vagi-\nnoskopische Untersuchung [Changes in the shape of the uter -\nine cervix and the development of its epithelium from birth to \nadolescence. A vaginoscopic study] [article in German]. Arch \nGynakol. 1980;229:123.\n13. Terruhn V. A study of impression moulds of the genital tract of \nfemale fetuses. Arch Gynecol. 1980;229(3):207-217.\n14. Arcellana RC, Robinson TW, Tyson RW, Joyce MR. Neonatal \nfellowship. McKusick-Kaufman syndrome with legal compli -\ncations of hydrometrocolpos and congenital endometriosis. J \nPerinatol. 1996;16(3 Pt 1):220-223.\n15. Lévy JM, Rosenthal R, Dellenbach P , Pequenot JP . Crise gé -\nnitale du nouveau-né. Répercussion de certains facteurs \nmaternels ou gravidiques sur la fréquence des métrorragies \nnéonatales. [Genital crisis in the newborn: repercussion of \ncertain  maternal or pregnancy factors on the frequency of \nneonatal metrorrhagia] [article in French]. Arch Fr Pediatr. \n1964;21:819.\n16. Kaiser R, Grässel G. Frequenz und Stärke der uterinen Neuge-\nborenenblutung. [Incidence and intensity of uterine bleeding \nin the neonate] [article in German]. Geburtshilfe Frauenheilkd. \n1974;34(8):644-648.\n17. Huber A. Häufigkeit der physiologischen vaginalen Neuge -\nborenenblutung. [Frequency of physiological vaginal hemorrhage \nin the newborn] [article in German]. Zentralbl Gynakol. 1976;  \n98(16):1017-1020.\n18. Berić BM, Prodanović Z, Mitrović M, Curcić O. Uterino krvavljen-\nje u novorodene dece. [Uterine hemorrhage in newborn] [ar -\nticle in Serbian]. Jugosl Ginekol Perinatol. 1985;25(3-4):89-91.\n19. Rosa P . Endocrinologie sexuelle du foetus feminin. Vol. 1. Paris: \nMasson et Cie; 1955:262.\n20. Web MD. Health and baby. http://www.webmd.com/parent -\ning/baby/your-newborn-girls-genitals-bleeding. Retrieved on \n15 June 2015.\n21. Brosens I, Benagiano G, Brosens JJ. The potential perinatal ori-\ngin of placentation disorders in the young primigravida. Am J \nObstet Gynecol. 2015;212(5):580-5.\n22. Clifford SH, Reid DE. Postmaturity. AMA Am J Dis Child. \n1951;82(2):232-235.\n23. Wolff EF, Sun L, Hediger ML, et al. In utero exposures and  \nendometriosis: the Endometriosis, Natural History, Disease, \nOutcome (ENDO) Study. Fertil Steril. 2013;99(3):790-795.\n24. Borghese B, Sibiude J, Santulli P , et al. Low birth weight is strongly \nassociated with the risk of deep infiltrating endometriosis: results \nof a 743 case-control study. PLoS ONE. 2015;10(2):e0117387.\n25. Falconer H. Pregnancy outcomes in women with endometrio-\nsis. Semin Reprod Med. 2013;31(2):178-182.\n26. Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placen -\ntal size and risk of hypertension in adult life. BMJ. 1990;301  \n(6746):259-262.\n27. Al-Sabbagh M, Lam EW, Brosens JJ. Mechanisms of endo -\nmetrial progesterone resistance. Mol Cell Endocrinol. 2012;  \n358(2):208-215.","source_license":"CC0","license_restricted":false}