{"paper_id":"505322b3-9899-4117-ab37-135b0479fd3e","body_text":"Archives of the Balkan Medical Union\nCopyright © 2024 Balkan Medical Union\nvol. 59, no. 2, pp. 167-173\nJune 2024\nRÉSUMÉ\nE n d o m é tri ose  e t  p lace n ta ti o n  al té r ée:  un e  é tu d e  \nprospective de cohorte comparant le PLGF dans les \ngrossesses de patients atteints et non atteints d’endo-\nmétriose\nIntroduction.  L’endométriose est une maladie chro-\nnique qui touche 10% des femmes en âge de procréer. \nLes grossesses associées à l’endométriose comportent \ndes risques supplémentaires, comme prééclampsie, ac-\ncouchement prématuré et restriction de la croissance \ndu fœtus.\nL’objectif de l’étude  a été d’examiner si l’endométriose \naffecte la fonction placentaire pendant la grossesse, me-\nsurée par PLGF par rapport aux patients non touchés.\nMatériel et méthodes.  Dans cette étude prospec-\ntive de cohorte, nous avons enregistré des femmes \nABSTRACT\n I ntroduction.  Endometriosis is a chronic condi-\ntion that affects 10% of women of childbearing age. \nPregnancies associated with endometriosis have addi-\ntional risks, such as preeclampsia, preterm birth, and \nfoetal growth restriction.\nT he objective of the study  was to investigate if en-\ndometriosis affects placental function during pregnan-\ncy, measured by placental growth factor (PLGF) when \ncompared to unaffected patients.\nMaterial and methods.  In this prospective cohort \nstudy , we enro lled pregnan t women wi th endome-\ntriosis according to laparoscopic findings, who were \nmatched for body mass index and parity in a 1:1 ratio \nwith healthy patients. Pregnant women with endome-\ntriosis were compared to non-endometriosis patients \nand assessed for PLGF and pregnancy-associated \n ORIGINAL PAPER\nENDOMETRIOSIS AND IMPAIRED PLACENTATION: \nA PROSPECTIVE COHORT STUDY COMPARING PLGF \nIN PREGNANCIES OF PATIENTS WITH AND WITHOUT \nENDOMETRIOSIS\n Cosmina R. COSTACHE1,2 , Draga M. MANDI1,3 , Mariana C. COSTACHE OUTAS2, \nTraean BURCOS1,3\n1 Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania\n 2  Integrated Ambulatory of Coltea Clinical Hospital, Bucharest, Romania\n3  General surgery Department of Coltea Clinical Hospital, Bucharest, Romania\nReceived 23th May, Accepted 07th June 2024\nhttps:/ / doi.org/10.3 1688/ ABMU.2024.59 .2.04\n Address for correspondence:   Cosmina R. COSTACHE\nBulevardul Ion C. Bratianu 1, Bucuresti 030167, Integrated \nAmbulatoryEmail: ralukacostache@gmail.com\nDraga M. MANDI\nBulevardul Ion C. Bratianu 1, Bucuresti 030167, General Surgery \nDepartament\nEmail: mandi.draga@gmail.com, Phone +40724636055\n\nEndometriosis and impaired placentation: a prospective cohort study comparing PLGF in… – COSTACHE et al\n168 / vol. 59, no. 2\nINTRODUCTION\nAround 10% of women of childbearing age have \nendometriosis, a chronic, hormone-dependent illness \nthat res  ults in infertility, painful periods, and pelvic \npain\n1. Research has also connected endometriosis to \nadverse pregnancy and delivery outcomes, including \nelevated risks of small for gestational age newborns, hy-\npertension, and pre-eclampsia as a result of decreased \ndeep placentation brought on by abnormalities in the \nuterus and surrounding tissues\n2. Over the last 20 years, \nresearch has highlighted that a combined screening test \ndeveloped by the Fetal Medicine Foundation (FMF) \nis the most effective at detecting these complications \nwhen compared to other tests. This screening includes \nanalyzing maternal demographic data and specific bio-\nmarkers, with the uterine artery Doppler measurement \nof the pulsatility index being particularly crucial\n3. This \nmethod has proven to be a reliable early detector of \npre-eclampsia, fetal growth restrictions, and small for \ngestational age infants, and is now integrated into \nstandard obstetric practice\n4.\nPrior research comparing pregnant women with \nand without endometriosis revealed no appreciable \nchanges in uterine artery Doppler readings or levels \nof pregnancy-associated plasma protein-A (PAPP-A), \nwith the exception of extreme instances. These stud-\nies, however, did not account for gestational age or \nenceintes atteintes d’endométriose selon les résultats \nlaparoscopiques et ont été comparés pour l’indice de \nmasse corporelle et la parité dans un rapport de 1:1 \navec les patients en bonne santé. Les femmes enceintes \natteintes d’endométriose ont été comparées à des pa-\ntients sans endométriose et évaluées pour le PLGF et le \nPAPP-A à 11-14 semaines de gestation. La prééclampsie \na été notée au troisième trimestre.\nRésultats.  L’étude a révélé que les patients atteints \nd’endométriose avaient des taux de PLGF significati-\nvement plus faibles que ceux des contrôles (p=0,003). \nDans notre étude, l’endométriose a été associée à une \ndiminution des taux de PLGF et à une prééclampsie \n(p=0.026).\nConclusions.  Selon ces résultats, l’endométriose est \nassociée à une perfusion placentaire tardive clinique-\nment mesurable altérée. Il est recommandé que les pa-\ntients atteints d’endométriose aient un suivi plus étroit \npour mieux prédire et prévenir les résultats périnatals \net de grossesse dus à une perfusion altérée du placenta.\nMots-clés:  endométriose, placenta, artère utérine, \nPLGF.\nplasma protein A (PAPP-A) at 11-14 weeks of gestation. \nPreeclampsia was noted in the third trimester.\nResults.  The study found that patients with endome-\ntriosis had significantly lower PLGF levels compared \nto control (p = 0.003). In our study, endometriosis was \nassociated with decreased PLGF levels and preeclamp-\nsia (p = 0.026).\nConclusions.  According to these results, endometriosis \nis associated with a clinically measurable impaired late \nplacental perfusion. It is recommended that patients \nwith endometriosis must have a closer follow up for bet-\nter prediction and prevention of perinatal and pregnan-\ncy outcomes due to impaired perfusion of the placenta.\nKeywords:  endometriosis, placenta, uterine arteries, \nPLGF.\nList of abbreviations:\nBeta HCG = -human chorionic gonadotrophin\nBMI = body mass index\nCRL = crown rump lenght\nDE = deep endometriosis\nFGR = fetal growth restriction\nFMF = Fetal Medicine Foundation\nGA = gestational age\nIQR = interquartile\nISUOG = International Society of Ultrasound in ob-\nstetrics and Gynecology\nIVF = in vitro fertilization\nLMP = last menstrual period\nMOM = multiples of median\nOMA = ovarian endometrioma\nPAPP-A = pregnancy-associated plasma protein A\nPLGF = placental growth factor\nPE = preeclampsia\nPTB = preterm birth\nSD = standard deviation\nUtA-PI = pulsatility index of uterine artery\nVEGF = vascular endothelial growth factor\n\nArchives of the Balkan Medical Union\nJune 2024 / 169\ntake into account additional influencing variables \nsuch as in vitro fertilization (IVF) conception 5,6.\nPLGF, a member of the vascular endothelial \ngrowth factor (VEGF) family, amplifies the angiogenic \neffects  of VEGF7. This protein, which is glycosylated \nand exists as a dimer, is well-known for its ability to \npromote the formation of new blood vessels and the \ndevelopment of trophoblasts in the maternal decidua. \nIt also plays a critical role in the differentiation and \ninvasion of trophoblasts. The PLGF gene is located \non chromosome 14q.14 and generates four PLGF \nisoforms. PLGF-1 and –2 are the main isoforms seen \nthroughout pregnancy and are highly expressed in vil-\nlous trophoblast cells. PLGF-2 and PLGF-4 vary from \nPLGF by possessing extra heparin-binding domains, \neven though PLGF still retains 53% of its structural \nsimilarity with VEGF-A\n8.\nThroughout pregnancy, a secondary phase of spi-\nral artery remodelling occurs between 16 and 18 weeks \nof gestation, which corresponds with an increase in \nPLGF expression in the placenta throughout the second \ntrimester. It is believed that PLGF causes angiogenesis \nto change from branching to non-branching starting in \nweek 25, which helps the placental capillary network \nthat is intended for low resistance to grow. PLGF levels \nstart to drop towards the end of pregnancy and peak \nbetween weeks 29 and 32. Placental hypoxia from uter-\noplacental ischemia specifically suppresses the produc-\ntion of PLGF in trophoblastic cells, whereas non-troph-\noblastic cells upregulate PLGF expression in response \nto damage.While non-trophoblastic cells respond to \ndamage by upregulating PLGF expression, uteroplacen-\ntal ischemia-induced placental hypoxia specifically sup-\npresses the production of PLGF by trophoblastic cells\n9.\nInstead of just treating preeclampsia (PE) pa-\ntients who show with late-onset clinical symptoms, \ndoctors can take proactive steps to prevent and screen \nfor PE by identifying high-risk patients early on. \nInterestingly, decreased PLGF levels can be seen as \nearly as 11–13 weeks of gestation, providing a window \nof opportunity for early first-trimester screening.\nTHE OBJECTIVE OF THE STUDY was to assess if there \nis any difference in PLGF levels in women with and \nwithout endometriosis throughout the first trimester. \nBy measuring alterations in late uterine perfusion, \nendometriosis raises the likelihood of placental mal-\nfunction; this understanding might assist elucidate this \ninvolvement.\nMATERIALS AND METHODS\nStudy design and setting\nThis was an observational, monocentric, pro-\nspective cohort study carried out from January 2019 \nto January 2022 in Bucharest, Romania.\nGroup of study\nThe study included only singleton pregnancies \nthat were diagnosed with endometriosis and verified \nwith laparoscopic surgery prior to pregnancy. The \nendometriotic lesions were classified according to \ntheir location as either ovarian endometriomas, deep \nendometriosis, or a mix of both. Patients with adeno-\nmyosis, numerous pregnancies, foetal abnormalities, \nuterine pathology, pre-existing maternal comorbidi-\nties such as cardiovascular, liver, or renal problems, \ndiabetes, coagulation disorders, and autoimmune dis-\neases were excluded\n10. Surgical and histological data \nwere examined during the inclusion of patients.\nThe control group consisted of randomly chosen \npregnant women who had no previous history of en-\ndometriosis. The criteria for selecting controls were \nthe absence of a previous diagnosis of endometriosis, \na normal transvaginal ultrasound before pregnancy, \nand no history of considerable menstrual discomfort, \npainful intercourse, or persistent severe pelvic pain. \nControls were paired with cases in a one-to-one ratio.\nData collection\nThe data gathering followed the ethical guide-\nlines outlined in the Declaration of Helsinki 8. The \ndetermin ation of pregnancy dates relied on the last \nmenstrual period (LMP) for natural conceptions, \nwhereas for IVF conceptions, it was determined as \n19 days before blastocyst transfer or 1 7 days before \ncleavage-stage embryo transfer. The gestational age \n(GA) was determined during the first trimester us-\ning ultrasound measurements of the crown-rump \nlength (CRL), following the recommendations set \nby the Foetal Medicine Foundation (FMF) and the \nInternational Society of Ultrasound in Obstetrics \nand Gynaecology (ISUOG)\n10.\nThe Doppler ultrasonography was used to meas-\nure the uterine artery pulsatility index (UtA-PI) \nthroughout the 11-14 weeks of pregnancy, following \nthe guidelines established by the FMF and ISUOG\n11. \nThe UtA-PI was determined by subtracting the peak \nsystolic velocity from the end diastolic velocity and \nt hen dividing the result by the time-averaged veloc-\nity. Measurements from both sides were averaged to \nprovide an overall mean, which was then compared \nto a reference value\n3,10 .\nAll Doppler ultrasound assessments were per-\nformed by certified experts using high-end Voluson \nE8 and Voluson E10, GE HealthCare Technologies, \nUSA devices fitted with multi-frequency convex \ntransabdominal transducers.\nThe data collection encompassed initial ma-\nternal parameters, such as age, BMI, parity, concep-\ntion technique, and smoking status\n6, first trimester \nultrasound characteristics and placental hormone \n\nEndometriosis and impaired placentation: a prospective cohort study comparing PLGF in… – COSTACHE et al\n170 / vol. 59, no. 2\nbiochemistry values. The collected data consisted of \nmeasurements of Crown-rump length (CRL), serum \nlevels of beta-hCG and PAPP-A, and PLGF translated \ninto multiples of the median (MoM)\n12.\nOutcome\nThe result of this study was the computation of \nthe risk of preeclampsia throughout the initial three \nmonths of pregnancy. The scores were calculated us-\ning reference equations based on previously published \nnormal ranges. This allows for the evaluation of aber-\nrations in placental hormone readings compared to \nrecognised norms throughout these pregnancies.\nStatistical analysis\nThe statistical analysis started by doing the \nShapiro-Wilk test to see if the continuous variables \nconformed to a normal distribution. Variables that \nwere normally distributed were presented as the \nmean ± standard deviation (SD), while variables that \ndid not follow a normal distribution were represented \nusing the median and interquartile range (IQR). The \ncategorical variables were shown as both absolute val-\nues and percentages (%).\nTo ensure comparability between the data from \ncases and controls, appropriate tests were utilised \nbased on the characteristics and distribution of the \ndata. The Student t-test was used for quantitative var-\niables that exhibited a normal distribution, whereas \nthe Wilcoxon signed-rank test was used for variables \nthat did not exhibit a normal distribution. The se-\nlection of either Pearson’s Chi-square test or Fisher’s \nexact test was determined by the anticipated frequen-\ncies for categorical variables.\nWe did a research to examine the relationship \nbetween endometriosis and PLGF Z-scores. We used \nminimal deviance analysis to identify the most precise \nconnection and variance functions. Subsequently, we \nemployed conventional goodness-of-fit tests to choose \nthe optimal multivariable model. The findings also \ndisplayed the mean marginal effects for all variables \nin the model, along with 95% confidence intervals.\nThe statistical analyses were conducted using \nSTATA version 17. For all studies, a p-value less than \n0.05 was considered to have statistical significance.\nRESULTS\nStudy population\nA total of 12 individuals diagnosed with en-\ndometriosis were included in the research. Out of \nthese cases, 10 (83.3%) had ovarian endometriomas \n(OMA), 6 (50%) had deep endometriosis (DE), and \n2 (16.6%) had both OMA and DE localizations. Out \nof the 12 patients who had ovarian involvement, \nbilateral endometriomas were seen in 2 cases, ac-\ncounting for 16.6% of the total.\nThe study cohort consisted of 12 cases of endo-\nmetriosis, which made up 50% of the overall group, \nand 12 controls, which accounted for the remaining \n50%. The control group exhibited no signs of the ill-\nness and were selected to match the patients in terms \nof parity and body mass index (BMI).\nBaseline characteristics and univariable analysis\nTable 1 presents the fundamental features of \nboth endometriosis patients and controls. Based on \nthe comparison with the matched controls, there \nwere no notable disparities seen in BMI and parity \n(specifically, nulliparous vs. parous). Moreover, the \nmother age, cigarette smoking status, and conception \ntechnique (spontaneous versus in vitro fertilisation) \nwere similar in both groups. 87.5% of cases were relat-\ned to IVF cycles that utilised frozen-thawed embryo \ntransfers (95% confidence interval of 74.4–94.4%).\nTable 2 provides a complete evaluation of ultra-\nsonography (US) factors throughout the first trimes-\nter for both patients and controls. T his table presents \na comprehensive comparison of several ultrasound \nmeasures obtained during the first trimester for both \ncases and controls, along with the statistical signifi-\ncance of the observed discrepancies. There were no \nnotable variations in the Z-scores of the uterine artery \npulsatility index (UtA-PI) between the two groups \nduring the first trimester. During the first trimester, \nthe MoM PlGF levels were substantially lower in the \ngroup with endometriosis (median 1.098, interquar-\ntile range 0.37 to 1.75) compared to the control group \n(median 1.56, interquartile range 1.01 to 1.85), with \na p-value of 0.003. No significant variations were seen \nin the serum biomarkers (MoM PAPP-A and MoM \nfree -hCG) or in the standardisation of crown-rump \nlength (CRL) throughout the first trimester. In ad-\ndition, there was a slightly increased occurrence of \nPE in the observed cases, but this difference was not \nstatistically significant.\nDISCUSSION\nThis study found that pregnant patients with en-\ndometriosis had a greater incidence of PE in the  third \ntrimester compared to patients without endometriosis. \nHowever, there were no changes in the UtA-PI Z-scores \nduring the first trimester between the two groups.\nWe would want to explore potential pathways \nbased on our findings. Typically, PLGF levels rise as \npregnancy advances, indicating the development of \nthe placenta and the conversion of spiral arteries into \nuteroplacental arteries. The increase in PLGF empha-\nsises the significance of ongoing maternal hemody-\nnamic adaptations throughout the third trimester.\n\nArchives of the Balkan Medical Union\nJune 2024 / 171\nEndometriosis-related fibrosis can impact the \nperformance of peripheral arteries by modifying en-\ndothelial function and raising vascular stiffness. The \nfibrotic entrapment of pelvic blood arteries may re-\nsult in the hardening of artery walls and decreased \nvascular flexibility, which might hinder the usual \nhemodynamic adaptations observed during the later \nstages of pregnancy. Therefore, it is only in the third \ntrimester that the increased resistance in uterine \narteries in endometriosis compared to controls be-\ncomes evident, as a result of concurrent alterations \nin maternal hemodynamics\n13.\nThe decrease in uterine artery pulsatility index \n(UtA-PI) during pregnancy is also affected by increas-\ning oestrogen levels, which typically encourage vasodi-\nlation. However, in cases of endometriosis, the pelvic \nregion frequently exhibits a condition of excessive oes-\ntrogen, which can lead to an abnormal reaction of the \nuterine blood vessels to oestrogen during pregnancy. \nThe hormonal activity, which involves the interac-\ntion between oestrogen and progesterone, is precisely \nregulated by the controlled expression of steroid re-\nceptors, chaperone proteins, and signalling pathways. \nDisruptions in these pathways in endometriosis might \nresult in incorrect interactions between the chorion \nand decidua in the latter stages of pregnancy\n13.\nRecent studies have also brought attention to \npossible problems associated with deep implantation \nof the pla centa in endometriosis, which is connected \nto structural and functional abnormalities in the \nlining of the uterus and the muscular layer of the \nuterus. The presence of endometrial tissue in abnor-\nmal locations in endometriosis results in the produc-\ntion of excessive amounts of cytokines that promote \ninflammation and fibrosis. This can interfere with \nthe normal functioning of the immune system and \nblood vessels, which are crucial for the healthy inter-\naction between the placenta and the uterine lining\n14. \nAs a consequence, complications such as PE, foetal \ngrowth restriction, and preterm birth may arise. \nDuring normal pregnancies, spiral arteries undergo \na process of remodelling, transforming into high-flow \nchannels with low resistance. These transformed ar-\nteries play a crucial role in supporting the growth of \nthe foetus\n15. Pregnancies impacted by endometriosis \nmay maintain the musculo-elastic composition of \nTable 1. Demographic characteristics of both cases of endometriosis and  controls\nVariable Cases (n=12) Controls (n=12) p-value\nMaternal age, years 33.5±4.9 34.08±3.9 0.157\nBMI, kg/m² 21.46 (15.8 to 28) 22.91 (19.1 to 26.7) 0.816\nSmoking, % 3 (25%) 3 (25%) 0.656\nNulliparous, % 10 (83.3%) 9 (75%) 0.969\nSpontaneous conception, % 3 (25%) 9 (75%) 0.738\nIVF, % 9 (75%) 3 (25%) 0.738\nNotes:\n– Data are presented as mean ± SD, median (IQR) or n (%).\n– Abbreviations: BMI – body mass index, IVF – in vitro fertilization.\nTable 2. Evaluation of ultrasonography and biochemical factors througho ut the first and third trimester in \nboth patients with endometriosis and controls.\n Measurement Cases (n = 12) Controls (n = 12) p-value\nFirst trimester\nCRL, mm1  56.75±17.89  59 .26±7.36 0.441\nIUGR- risk1 0.41±0.293 0.324±0.270 0.952\nUtA PI2 1.435 (0.9 to 1.875) 1.61 (1.24 to 2.19) 0.715\nMoM PLGF2 1.098 (0.37 to 1.75) 1,561(1.01 to 1.85) 0.003\nMoM free -hCG2 0.89 (0.328 to 4.365) 1.22 (0.235 to 2.38) 0.31\nMoM PAPP-A2 1.343 (0.271 to 2.129) 1.09 (0.25 to 2.12) 0.07\nThird trimester\nPE3 50 % 25% 0.640\nNotes: Data are 1 mean ± SD, 2 median (IQR) or 3 n (%).\nAbbreviations: CRL, crown-rump length; IUGR- intrauterine g rowth restriction; UtA PI, uterine artery pulsatility index; \nMoM, multiples of the normal median; free -hCG, free -human chorionic gonadotrophin; PAPP-A, pregnancy-associated \nplasma protein A; PLGF, placental growth factor, PE- preeclampsia\n\nEndometriosis and impaired placentation: a prospective cohort study comparing PLGF in… – COSTACHE et al\n172 / vol. 59, no. 2\nthese arteries, resulting in heightened resistance to \nblood flow and complications with the development \nof the placenta.\nThis study highlights the significance of in-\ncreased uterine artery impedance during the third tri-\nmester as an indicator of placentation issues in women \nwith endometriosis. This is associated with a higher \nlikelihood of negative outcomes for both mother and \nbaby. Although normal UtA-PI is observed in the first \ntrimester, placental malfunction can advance from \na subclinical stage to a clinically relevant condition \nthroughout the later stages of pregnancy.\nRecent meta-analyses and systematic reviews \nhave shown that endometriosis is linked to a range of \nadverse obstetric and neonatal outcomes. These diffi-\nculties encompass heightened chances of miscarriage, \npreterm birth (PTB), placenta previa, and newborns \nwith small-for-gestational-age, among other potential \nissues. The presence of robust evidence is hindered \nby the inconsistency in diagnostic criteria and catego-\nrization systems for endometriosis, making it difficult \nto interpret these findings consistently.\nThis research also confirms that increasing ma-\nternal age affects PLGF in the first trimester, with \nolder women facing multiple adverse pregnancy out-\ncomes due to generally decreased vascular compli-\nance and cardiovascular adaptations. Furthermore, \nin IVF, especially when using frozen-thawed embryo \ntransfers, has a considerable impact on third-trimes-\nter uterine artery pulsatility indices (UtA-PIs), which \nis consistent with findings from earlier studies.\nWhile this study’s conclusions are robust, some \nlimitations include the reliance on ultrasound for \ndiagnosing deep and ovarian endometriosis and \nthe generalizability of the results, primarily applica-\nble to advanced stages of the disease. Nonetheless, \nthe study’s strengths include stringent matching for \nknown confounders, high-quality and consistent ul-\ntrasound methodology, and a robust statistical analy-\nsis, enhancing the validity of our findings.\nCONCLUSIONS\nEndometriosis is associated with a significant \ndecrease in placental perfusion during the third tri-\nmester of pregnancy, as indicated by PLGF Z-scores \n(95% CI 0.01-3.56, OR 0.23) that are 30% lower com-\npared to unaffected individuals. This limitation may \narise from fibrosis associated with endometriosis, \nwhich alters the vascular response to oestrogen and \nprogesterone, as well as the inflammatory conditions \nin the pelvic area. Based on these discoveries, it is \nadvisable to suggest increased surveillance for these \nindividuals. This would need regular well-being and \ngrowth scans between weeks 28 and 36 of pregnancy, \nto identify or prevent problems that may occur be-\ncause of abnormal placental development. Additional \ninvestigation is required to elucidate the mechanism \nby which reduced blood flow in the placenta, which \nis linked to endometriosis, might result in difficulties \nduring pregnancy and childbirth. The ultimate goal \nis to improve the outcomes of pregnancy for women \naffected by this condition.\n Aknowledgements:\nWe would like to express our sincere gratitude to \nAlina Ursuleanu for her meticulous verification of the ob-\nstetrical outcomes, which was crucial for ensuring the rigor \nof this study. We would like to express our appreciation to \nValentin Vl ădescu for his exceptional ability to manage \nthe analytical data and conduct statistical analysis, which \nsignificantly enhanced our research findings. In addition, \nwe would like to recognize the group of anesthesiologists, \nheaded by Leti ția Coriu, whose specialized knowledge was \nessential in carrying out the surgeries that played a pivotal \nrole in this study. 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