Clinical Opinion ajog.org

OBSTETRICS

The potential perinatal origin of placentationdisorders in the young primigravidaIvo Brosens, MD; Giuseppe Benagiano, MD; Jan J. Brosens, MD

The fetus is exposed to high plasma concentrations of unbound estrogens and pro-gesterone throughout pregnancy. However, secretory or decidual changes in the fetaluterus occur relatively infrequently before birth, suggesting a variable endometrialprogesterone response at the time of birth. Arguably, partial progesterone resistance thatpersists into adolescent years may compromise the physiological transformation of thespiral arteries and predispose for defective placentation in the case of pregnancy.Decidualization of the endometrial stromal compartment and junctional zone myome-trium precedes trophoblast invasion. It represents the first step in the process of spiralartery remodeling needed to establish effective uteroplacental blood flow by mid-pregnancy. The major obstetric syndromes caused by impaired placental bed spiralartery remodeling are prevalent in teenage pregnancies, including preeclampsia, fetalgrowth restriction, and spontaneous preterm labor. Preconditioning of the uterus inresponse to cyclic menstruation during adolescence may be critical to achieve full uterineresponsiveness to hormonal cues. Understanding the mechanisms of functional matu-ration of the uterus during the early reproductive years may yield novel insights into themajor obstetric syndromes.

Key words: decidua, obstetric syndromes, placentation, preconditioning, progesteroneresistance

he core of our knowledge on early

T uterine development dates back tothe middle part of the 20th century andis centered on the neonatal uterus. Amajor autopsy study entitled “Observa-tions on the endometrium and ovary inthe newborn” by the Harvard patholo-gists Ober and Bernstein was publishedin 1955.1 In their analysis of 169 neonataluteri, the authors found inactive orproliferative endometrium in two-thirdsof cases, whereas in the remaining in-fants, there was evidence of secretoryactivity in the glandular epithelium andeven decidualization of the stromalcompartment or menstrual changes.

From the Catholic University Leuven and Leuven InBelgium (Dr I. Brosens); Department of GynecologRome, Italy (Dr Benagiano); and Division of ReprodSciences Research Laboratories, University Hospit

Received Nov. 3, 2014; revised Dec. 21, 2014; ac

The authors report no conflict of interest.

Corresponding author: Ivo Brosens, MD. ivo.brose

0002-9378/free � ª 2015 Elsevier Inc. All rights reserved

580 American Journal of Obstetrics & Gynecology

An important feature of the physiologyof the newborn uterus is transient uterinebleeding, described in the French litera-ture as crise génitale du nouveau-né andin German literature as neugeborenen-blutung.2-5 Neonatal uterine bleeding(NUB) is classified as either overt oroccult. Although overt NUB is relativelyrare, affecting between 3.3% and 5.3% ofnewborns, biochemical evidence ofvaginal bleeding can be found in 25e61%of the neonates.In an intriguing study, Beri�c et al6

registered the incidence of overt uterine

stitute for Fertility and Embryology, Leuven,y, Obstetrics, and Urology, Sapienza University,uctive Health, Warwick Medical School, Clinicalal, Coventry, United Kingdom (Dr J. Brosens).

cepted Jan. 7, 2015.

ns@med.kuleuven.be

. � http://dx.doi.org/10.1016/j.ajog.2015.01.013

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bleeding in all female babies bornthroughout 1979 in Novi Sad, then theformer Yugoslavia. The study included2477 female newborns and reported anincidence of uterine bleeding in 0.8% inpremature neonates, 4.4% in term ba-bies, and 9.1% in infants born postterm.The overall frequency of NUB in thisstudy was 3.9%.

On the basis of a critical reinterpre-tation of the available literature, we haveargued that NUB is akin to menstrua-tion.7 Furthermore, anatomical aspectsof the neonate uterus render it likelythat retrograde menstruation be morepronounced than antegrade flow, thuspotentially contributing to the patho-genesis of early-onset and pre-menarcheal endometriosis.8-10 On theother hand, there is no evidence ofprogesterone response in the endome-trial stromal compartment in mostnewborns, raising the possibility thatthe endometrium, particularly in pre-term born girls, is still immature interms of progesterone responsiveness atthe onset of adolescence.

Pregnancy in the human is charac-terized by spontaneous perivasculardecidualization and deep placentationwith dramatic remodeling of the spiralarteries in the decidua and inner myo-metrium.11 Spiral artery remodelingdefects are most pronounced in early-onset preeclampsia and fetal growth re-striction.12,13 Although some studieshave reported an association betweenimpaired spiral artery remodeling andother obstetrical disorders, such as pre-term labor or preterm prematurerupture of the membranes, the severityand prevalence of the lesions are lesspronounced when compared with thosefound in severe preeclampsia.14-18

How the uterus is prepared for theintense tissue remodeling associatedwith deep hemochorial placentation isunknown. Arguably this process starts in

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the perinatal period, although a criticalinterpretation of uterine development interms of its subsequent function hasbeen overlooked.

In this communication, we attemptto interpret the available literature onhormonal responses in the uterus ofthe neonate in the context of subsequentpregnancy disorders, especially inadolescent girls. We argue that the neo-natal uterus exhibits intrinsic progester-one resistance and postulate thatpersistence of hormonal refractorinessinto the early reproductive years mayrestrict spiral artery remodeling and deepplacentation, leading to an increased riskof major pregnancy disorders in theyoung adolescent primigravida.

Strategy of searchAs detailed previously,8,9 we attemptedto retrieve every available scientificarticle on the presence and character-istics of neonatal uterine bleeding aswell as the characteristics of the fetaland neonatal endometrium. In addi-tion, we searched the internationalscientific literature for the following keywords: fetal uterus, fetal endometrium,neonatal uterine bleeding, endometri-osis, preeclampsia, fetal growth restric-tion and small for gestational age, andadolescent pregnancy.

Fetal and perinatal uterinematurationDevelopmental anatomy of the cervixand corpus uteriBased on intravaginal injection ofrapidly settling liquid silicon, Terruhn19

found that the fetal urethra, vagina,uterus, and Fallopian tubes have adefined lumen by the 14th week ofgestation. However, after the 26th weekof gestation, the cervical canal is nolonger patent, presumably because ofplugging by secretions of the cervicalepithelium that lines the canal.

Fluhmann20 documented a tremen-dous growth of the cervix during the last3 months of fetal life, a phenomenonalso apparent in the vagina but notshared by the uterine corpus. Conse-quently, the length of the cervix isapproximately 2- to 2.5-fold that of thecorpus in the newborn. In fact, the

length of the corpus increases propor-tionally with the fetal weight duringthe last 3 months of pregnancy, whereasthe length of the cervix increases at anaccelerated rate. Immediately after birth,there is a marked decrease in the lengthof the cervix and, much more modestly,in the length of the corpus. The differ-ence is likely explained by the ento-dermal (urogenital sinus) origin of thecervix with enhanced cellular activity,which is absent in the mesodermalMüllerian duct.Using real-time ultrasound, Hata

et al21 studied the morphology of thenormal uterus and cervix in neonatesdelivered at term. The uterus wasvisualized in 41 of the 46 neonates(89.1%), and the cervical volume wasfound to be approximately 3 timesthe corporeal volume (3.65 � 1.36cm3 vs 1.18 � 0.42 cm3, respectively;P < .001). Arguably, the anatomicalstructure of the cervix and uterus atthe time of birth could promote theretrograde flux of menstrual effluent,thus obscuring the true incidence ofNUB.

Plasma estrogens and progesterone inmaternal and fetal circulationThroughout pregnancy, the fetus isexposed to high concentrations of un-bound estrogens and progesterone.22-24

The mean concentrations of unboundestrone, estradiol, and estriol measuredby radioimmunoassay in the umbilicalvein are significantly greater than thosefound in the maternal circulation atterm. Furthermore, the mean concen-trations of total and unbound plasmaprogesterone at term are, respectively,5- and 7-fold higher in the umbilicalvein than in the peripheral maternalcirculation25 (Table).Hill et al26 suggested that placental

distribution of enzymes involved in ste-roidogenesis and metabolism accountfor the higher circulating progesteronelevels in the fetus compared with themother. For example, type 2 17b-hydroxysteroid dehydrogenase, whichoxidizes estradiol to estrone and 20a-dihydroprogesterone to progesterone, ishighly expressed in placental endothelialcells lining fetal vessels.

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Conversely, syncytium, which isdirectly in contact with maternal blood,produces higher amounts of estradioland 20a-dihydroprogesterone becauseof the expression of other steroid de-hydrogenases, including 17b-hydroxy-steroid dehydrogenase types 1, 5, and 7.Circulating progesterone levels in neo-nates drop rapidly after birth. Ferris andGreen27 found that the excretion ofpregnanediol, the major inactive pro-gesterone metabolite, in neonatal urinedisappeared after the fifth day of life.

The hormonal responsiveness of theendometrium in the fetus, newborn,and infantAs early as 1934, it was recognized thatproliferative activity in the fetal endo-metrium during the third trimester ofpregnancy could not reflect ovarian ac-tivity but must be caused by stimulationfrom placental hormones.28 As afore-mentioned, Ober and Bernstein1 de-scribed in detail the changes in theendometrium and ovaries in a series of169 autopsies, which included 68 infantsborn at term (38-42 weeks’ gestation).Among these infants, 57 died within thefirst 3 days of life and the remaining 11died before 14 days. The endometriumwas classified asproliferative in 116 (68%),secretory in 45 (27%), and progestationalin 8 (5%) cases. It should be noted that60 of 116 cases classified as proliferativeshowed a basal phenotype (resting phase),and 37 of 45 classified as secretory showedonly subnuclear vacuolation.

The group with progestational changesconsisted of the 8 cases with histologicalevidence of decidualization or menstrualtissue breakdown. Importantly, evidenceof ovarian follicular development to theantral stage was observed only in a singlecase, and none of the ovaries had aGraafian follicle or corpus luteum. Fromthese observations, the authors correctlyconcluded that the secretory and pro-gestational changes in the endometriumcould not be accounted for by fetal orneonatal ovarian activity.

The aforementioned study by Huberet al3 involved 82 uteri of fetuses, infants,and children. This study showed thatglandular formation is absent from thefetal endometrium before the 20th week

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TABLETotal and unbound plasma progesterone concentrations in maternal andfetal plasma

Variable

Total Unbound

n Measure, ng/mL % Measure, ng/mL

Luteal phase 5 17 � 3 4.83 � 0.1 0.82 � 0.14

End of first trimester 10 41 � 5 4.93 � 0.1 2.03 � 0.24

Term pregnancy 10 160 � 10 5.02 � 0.1 8.03 � 0.50

Umbilical vein at term 10 788 � 30 7.01 � 0.2 55.20 � 2.10

Adapted from Tulchinsky and Okada.25

Brosens. Potential perinatal placentation disorders in young primigravida. Am J Obstet Gynecol 2015.

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of gestation. Gradually proliferation be-comes apparent in both the epithelial andstromal compartments, and secretorychanges in the glands are increasinglyfound after 33 weeks, with activitypeaking at birth. Immediately after birth,tissue involution and regression areassociated with desquamation of theepithelial layer and discrete interstitialbleeding. Immediately after birth regres-sional changes of the endometrium set in,and after the eighth postnatal day, atransitional type of endometrium with-out glandular activity appears. Theepithelium is comparatively low, and noevidence of glycogen is found.

After the transitional phase, the endo-metrium consists of a very thin, nearly flatepithelial layer and remains in an atro-phic, inactive state. This seems a charac-teristic pattern during infancy and earlychildhood until the child shows the firstvisible signs of ovarian activity at aboutthe age of 7 or 8 years. Huber et al3

concluded that we have to assume thatfunctional changes in the fetal and in-fantile endometrium take place indepen-dently of any ovarian activity of the childitself and are brought about by the effectof maternal (placental) hormones. At thesame time, the fetal and infantile tissueshave not reached their full maturity andcan therefore not react like that of amature woman. These observations wereconfirmed byHiersche andMeinen29 andPryse-Davies and Dewhurst.30

Decidualization and progesteronesignalingOne of the most striking aspects of thefetal endometrium is the lack of decidual

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transformation of the stroma despiteprolonged exposure to estrogens and,more importantly, to progesterone.Decidualization is a progesterone-drivenprocess, characterized by the trans-formation of endometrial stromal fi-broblasts into specialized secretorydecidual cells. This transformation of thestroma is indispensable in pregnancybecause decidual cells provide a nutritiveand immunoprivileged matrix essentialfor embryo implantation and placentaldevelopment.31

Withdrawal of progesterone actionfrom a decidualizing endometrium isthe universal signal inducing menstru-ation. Refractoriness to progesterone inthe fetal endometrial stroma is also re-flected in the absence of CD56þ uterinenatural killer (uNK) cells. Different linesof evidence, including animal models,genetic investigations, and isolateddecidual leukocyte studies, have shownthat uNK cells are a rich source ofangiogenic and other factors necessaryfor the physiological transformationof spiral arteries at the maternal-fetalinterface.32

The most abundant endometrialleukocyte populations between the 19thweek of gestation and term are CD14þ

monocytes and CD68þ macrophages.Intriguingly, uNK cells appear in theendometrium of neonates, albeit at lowdensity.33 Combined with the increasedfrequency of overt NUB in postterm ba-bies,6 these observations seem to suggestthat the stromal compartment of thehuman endometrium becomes graduallyresponsive to progesterone signalingaround the very late stages of pregnancy.

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The mechanism accounting for pro-gesterone resistance in the stromalcompartment of the fetal endometriumis unknown. It has been shown that theestrogen receptor-a (ESR1) is expressedin the fetal uterus at the beginning of thesecond trimester of pregnancy.34 To thebest of our knowledge, there are nostudies on progesterone receptor (PGR)expression in the human fetal uterus.However, PGR expression was found tobe extremely scant in the fetal rhesusmacaque endometrium a little pastmidgestation.

The level of PGR expression increasedsignificantly at term, although only 15%of epithelial and stromal cells becameimmune positive. By comparison, 50%of nuclei in stromal and epithelial com-partments stained positive for ESR1, andthis level of expression did not changebetween midgestation and term.34

Hence, in contrast to adult endome-trium, PGR expression in fetal endo-metrium is uncoupled from ESR1activity.

Intriguingly, microarray analysis offetal rhesus macaque endometriumdemonstrated that the modest inductionof PGR at term coincided with enrich-ment of marker genes indicative of he-matopoietic cells.35

Taken together, these observationssuggest 2 very different models ofincreased progesterone responsivenessof the endometrial stromal compart-ment at term, or soon after birth. First,through some unknown mechanism,endometrial PGR expression is up-regulated, and once a threshold isreached, a decidual response will betriggered as long as circulated proges-terone levels have not yet dropped.An alternative and perhaps moreprovocative explanation is that theresponsiveness of the endometrium isconnected to the transition in late preg-nancy of the production of hematopoi-etic stem cells from the fetal liver to thebone marrow.

Recently several studies have shownthat the endometrium is dynamicallypopulated by bone marrowederivedmesenchymal stem cells (MSCs).36-39

Furthermore, a recent study has high-lighted the striking similarities between

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bone marrow and endometrial MSCs.39

Although entirely speculative, it is notinconceivable that the establishment ofa functional stem cell niche environ-ment in bone marrow bestows thenecessary competence on MSCs tomigrate to the uterus, populate thespace around the immature spiral ar-teries, and induce a progesterone-responsive microenvironment.

Defective endometrial maturationand risk of major obstetricsyndromesBased on the previously mentioned ob-servations, we propose that the humanendometrium must transit from fetal orontogenetic progesterone resistance tofull progesterone responsiveness in theadult uterus. The postmortem study byOber and Bernstein1 indicates that thistransition is not yet initiated in twothirds of term babies (68%); is in prog-ress in less than one third (27%); and isseemingly completed in approximately5% of newborns with histological evi-dence of decidual or menstrual changesin the stroma. The observation that overtNUB occurs less frequently in pretermbabies but more often in postdates in-fants fits the concept of a transitionalperiod around or soon after fullgestation.

The timing of this transition may havemajor ramifications for future repro-ductive performance. For example, thereis evidence in support of the hypothesisthat retrograde NUB may result inseeding of endometrial progenitor cellsin the pelvic cavity.9 These cells couldremain largely dormant until menarcheand then give rise to early-onset endo-metriosis. In an experimental model,surgically induced endometriosis hasbeen shown to reduce the engraftment ofbone marrow MSCs in the uterus.40

Extending these observations, it seemsplausible that early endometriotic le-sions in adolescent girls, over cumulativecycles, may diverge a sufficient numberof extrauterine MSCs away from theeutopic endometrium to have an impacton decidual responses and menstrualevents, thus establishing a feed-forwardmechanism that reinforces the disease.In a majority of babies, there is no

histological evidence that the switch to aprogesterone-responsive endometriumhas occurred prior to the rapid fall incirculating progesterone levels at birth.Given this situation, it is conceivable thatontogenic progesterone resistance per-sists until the menarche and that fullprogesterone responsiveness is onlygradually achieved after the onset of cy-clic menstruation.Al-Sabbagh et al41 recently surmised

that steroid hormone responses in theendometrium are likely to be muchmore dynamic and complex than previ-ously appreciated and modified by thecumulative effects of cyclic menstruationand other inflammatory signals. In thiscontext, it has been suggested that theemergence of cyclic menstruation maynot have been an evolutionary coinci-dence but serves to protect uterinetissues from the profound hyper-inflammation and oxidative stress asso-ciated with deep placentation, a processknown as preconditioning.42

This hypothesis proposes that cyclicendometrial decidualization and men-strual shedding is an example of physi-ological preconditioning that preparesuterine tissue for the dramatic vascularremodeling, reactive oxygen speciesproduction, and hyperinflammationassociated with deep hemochorialplacentation. The absence of adequatepreconditioning may explain why preg-nancy in the early teenage primigravidwoman is associated with a significantlyincreased risk of poor pregnancyoutcome (such as preterm delivery, fetalgrowth restriction, and preeclampsia) incomparison with primigravid women intheir early 20s.43

Other factors may also be at work: forinstance, it has been recently pointedout44 that an imbalance of angiogenesisis not a unique feature of preeclampsia,and it also occurs in spontaneous pre-term labor.44,45

An alternative, and not necessarilymutually exclusive, hypothesis is thatcyclic menstruations play a role inenhancing recruitment and/or activationof endometrial progenitor cells. TheseMSCs, defined by cell surface markerssuch as sushi domain containing 2(W5C5) or the coexpression of cluster of

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differentiation 140b (platelet-derivedgrowth factor receptor-b) and CD146(also known as melanoma cell adhesionmolecule), are highly enriched aroundthe spiral arteries.46-48 Furthermore, arecent study showed that perivascularstromal cells mount a decidual responsethat is highly distinct from non-perivascular cells and characterized byenhanced secretion of cytokines andchemokines involved in trophoblast andlymphocyte chemotaxis.49 Thus,repeated cycles of tissue regenerationand stem cell activation may well bestowfunctionality of the spiral arteries toaccommodate trophoblast invasion anddeep placentation.

Regardless of the underlying mecha-nisms, the predicted immaturity of theuterus at and soon after the menarche isan obvious risk factor for defectiveplacenta formation. In this respect, it iswell established that very young mothersare at increased risk of a spectrum ofpregnancy disorders linked to poorplacentation, independently of con-founding sociodemographic factors.

This was clearly illustrated in a studyof 134,088 white girls and women, aged13e24 years, in Utah who deliveredsingleton, first-born children between1970 and 1990.43 This trial comparedmarried mothers of 2 age groups (13e17and 20e24 years of age) with educa-tional levels appropriate for their ages.Both groups received adequate prenatalcare. Compared with mothers in their20s, younger women had a significantlyhigher risk (P < .001) than adultmothers of delivering an infant whohad the following: (1) had low birth-weight (relative risk [RR], 1.7; 95%confidence interval [CI], 1.5e2.0]; (2)was delivered prematurely (RR, 1.9; 95%CI, 1.7e2.1]; (3) was small for gesta-tional age (RR, 1.3; 95% CI, 1.2e1.4].

A recent Canadian study by Chenet al50 found that all teenage groups wereassociated with increased risks for pre-term delivery, low birthweight, andneonatal mortality. Infants born toteenage mothers aged 17 years oryounger had a higher risk for low Apgarscores at 5minutes. Further adjustmentfor weight gain during pregnancy did notchange the observed association, and

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restricting the analysis to white marriedmothers with age-appropriate educationlevel, adequate prenatal care, andwithout smoking and alcohol use duringpregnancy yielded similar results.

Interestingly, epidemiological studieshave shown that to be born prematurely,which is associated with a very lowincidence of NUB and possibly pro-nounced perinatal progesterone resis-tance, lowers the risk of subsequentendometriosis in adulthood.51 On theother hand, à Rogvi et al52 found in acohort of young Danish mothers thatbeing born prematurely was associatedwith an increased risk of preeclampsia.

For completeness, it should bementioned that the concept of primi-gravidity as a risk factor for preeclampsiahas been challenged by the alternativeprimipaternity model that may explainepidemiological descriptions that wouldotherwise be difficult to understand.53

This theory, also coined the genetic con-flict hypothesis, stems from the uniqueimmunogenic maternal-paternal rela-tionship specific of hemochorial placen-tation. It considers preeclampsia as adisease of an individual couple and notonly of the mother and fetus and leads toa consideration of several factors, such asthe following: (1) the length of the sexualrelationship; (2) the relevance of pri-mipaternity versus primigravidity; and(3) the existence of the so-calleddangerous father. It concludes that pro-longed exposure to paternal antigens inseminal fluid induces maternal toleranceto the allogeneic fetus, protecting it fromrejection and facilitating successful im-plantation and placentation.54,55

Such an alternative concept, however,needs to be supported by pathophysio-logical data. On the morphological side,the examination of hysterectomy speci-mens with the placenta in situ demon-strated that deep placentation in normalpregnancy involves the influx of immunecells and trophoblasts with vascularremodeling in the decidua and the innermyometrium except for the periphery.12

In preeclampsia and other relatedpregnancy disorders, interstitial tropho-blast invasion of the junctional zoneappears adequate, although impaireddecidualization of the myometrial spiral

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arteries predisposes for failed intravas-cular trophoblast invasion. Because thedecidualization process in humans iscontrolled by cross talk between sexsteroid hormones and locally releasedcytokines during the secretory phase,failure of subsequent deep placentationmay already have been determined in theconception cycle.56

This process suggests that in youngwomen, disruption of the decidual pro-cess in the secretory phase of the men-strual cycle may trigger a cascade ofevents, resulting in failed deep placen-tation, and that factors such as neonatalprogesterone resistance may play a pri-mary role in explaining adolescenthigher risk, the younger the age.

ConclusionsDuring pregnancy, high concentrationsof estradiol and unbound progesteronecirculate in the fetus. The morphologicalresponse of the fetal uterus, and inparticular of the endometrium, startsaround midpregnancy with proliferativechanges. It is only during the thirdtrimester that the endometrium occa-sionally displays secretory changes andin exceptional cases decidualization ofthe stromal compartment. In the firstfew days following delivery, estradiol andprogesterone levels in the mother fall tononpregnant values and become unde-tectable in neonates. This fall results inan overt withdrawal bleeding (ie, truemenstruation) in approximately 5% ofneonates, which suggests that ontogenicprogesterone resistance remains presentin most newborns.It seems reasonable to assume that

neonatal progesterone resistance willpersist until the menarche and then beprogressively relieved in response to cyclicmenstruation during adolescence. Thus,progesterone resistance associated withuterine immaturity may account for theincreased risk of major obstetric compli-cations in the adolescent primigravida.-

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