Pathology Research and Practice 208 (2012) 458 461

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Pathology Research and Practice

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Original article

Sponta Foc

Jzsef G .Semmelweis Un ary

a r t i c l

Article history:Received 29 OReceived in reAccepted 8 Ma

Keywords:Spontaneous aMultiple pregnMonochorioniPerinatal autoDevelopmentaIntrauterine in

ay of

49 ca

nancireproh ass

Monrriagein 8 cconce

Our study conrms that spontaneous abortion is more common in multiple than in singleton pregnan-cies. Monochorial placentation predicted a higher fetal morbidity and mortality. In pregnancies where allfetuses were of male gender, miscarriage was more common than in pregnancies where all fetuses werefemale. Assisted reproductive techniques do not predispose to the development of fetal malformations.

2012 Elsevier GmbH. All rights reserved.

Introductio

Multipleposes an imof this is fuductive tecfrequency o[6,8,18,23].every 85 preand 1 quadwith the apthe incidenpregnanciecies approxHellin formuresearchersmoderatelyof natural crm this [1

Corresponogy and Obstefax: +36 1 317

E-mail add

0344-0338/$ http://dx.doi.on

pregnancy with its wide array of medical consequencesportant condition during pregnancy. The signicance

rther increased by the recent spread of assisted repro-hniques. In classic obstetric literature, the expectedf multiple pregnancy is calculated by the Hellin formula

This formula predicts a ratio of 1 twin pregnancy ingnancies, 1 triplet pregnancy in every 852 pregnancies,

ruplet pregnancy in every 853 pregnancies. Nowadays,pearance of assisted reproductive techniques (ART),ce of twin pregnancies has increased two-fold, triplets approximately twelve-fold and quadruplet pregnan-imately eighty-fold compared to expected values by thela [16]. Furthermore, it has been suggested by some

that gestational folic acid supplementation may also increase the risk for multiple pregnancy at least in caseonception. However, subsequent papers failed to con-9,27].

ding author at: Semmelweis University, 1st Department of Gynecol-trics, 1088 Budapest, Baross utca 27, Hungary. Tel.: +36 1 266 04 73;

61 74.ress: joogabor@hotmail.com (J.G. Jo).

Based on what factors result in the development of mul-tiple pregnancy, different kinds of placentation may occur[1,12,20,23,24]. In dizygotic fetuses, as well as in monozygoticfetuses when separation of amniotic sacks occurs within a fewhours after fertilization of the egg, dichorionic diamniotic placen-tation develops. If the spatial separation occurs after separationof trophoblasts from embryoblasts, monoplacental diamnioticpregnancy will develop. Monochorionic monoamniotic pregnancydevelops when the embryoblasts split immediately before orimmediately after implantation.

The following maternal complications may be associated withmultiple pregnancy: preeclampsia, anemia, cervical incompetence,abruptio placentae, and placenta previa. In terms of fetal complica-tions with multiple pregnancy, increased perinatal morbidity andmortality and increased risk for miscarriage and premature deliveryhave been observed [5,18,20,23,24].

In this study, we attempted to evaluate and summarize theresults of perinatal autopsies performed after spontaneous abor-tions that occurred in multiple pregnancies between gestationalweeks 1224. In cases of mid-term miscarriages in multiplepregnancy, perinatal autopsy may provide useful informationrelevant to the risk of future miscarriages. This may be espe-cially valuable if fetal congenital malformation is diagnosed atthe autopsy, providing a valuable tool in risk assessment forrecurrence.

see front matter 2012 Elsevier GmbH. All rights reserved.rg/10.1016/j.prp.2012.05.011neous abortion in multiple pregnancy:

bor Jo , kos Csaba, Zsanett Szigeti, Jnos Rig Jriversity, General Medical Faculty, 1st Department of Gynecology and Obstetrics, Hung

e i n f o

ctober 2011vised form 2 January 2012y 2012

bortionancyc placentationpsyl disordersfection

a b s t r a c t

Multiple pregnancy with its wide arrpregnancy.

We performed perinatal autopsy incies during the study period.

Twenty-seven of the 44 twin preg17 were conceived through assisted in miscarriage was conceived througof miscarriage in 22.4% of the cases.pregnancies terminating with miscacongenital malformation was found reproductive techniques, and 5 were in 36% of the cases.m/locate /prp

us on fetal pathology

medical consequences poses an important condition during

ses of spontaneous abortion resulting from multiple pregnan-

es ending in miscarriage were conceived naturally, whereasductive techniques. Each of the 5 triplet pregnancies endingisted reproductive techniques. There was a positive historyochorial placentation occurred more commonly in multiple

than in multiple pregnancies without miscarriage. A fetalases. Three of these cases were conceived through assistedived naturally. Miscarriage was due to intrauterine infection

J.G. Jo et al. / Pathology Research and Practice 208 (2012) 458 461 459

Materials and methods

In this study, we report data from perinatal biopsies per-formed at The First Department of Gynecology and Obstetrics,Faculty of Hungary afnancies du31st, 2010.pregnanciepregnanciedonor oocygestational formed in operformed protocols fother well-[2,9,21,22,2of placentatas relevant of chorioamduring the (the evaluadepartmen

We havecerning premissed abonancy pogenetic mal

If amongfound for tof the medous pregnarise to miscnonspecictical in thespecic forwere incluthen used fwe used aincluded: Hcus adenomsyndrome.

Results

A total oratory durinperinatal au16 years, thbirth, wher(7.3% per livfrom multipout of the 4were from (61.4%) werthrough asswere concenumber of f

A positiv(22.4%) mucases (63.64 (36.4%) whistory was

The meayears vs. th

Table 1Fetal gender distribution in twin pregnancies ending in spontaneous abortion.

Gender distribution N %

Male/male 23 52.3e/female 18 40.9emale 3 6.8

iple pregnancy conceived spontaneously at 29 3.2 years5).

indises (/17

al gesponmbehighendeutionon (4ous

typeilablochoferens waen thed fo

pregogy w

waic fe46 yeedianermshere c fetaot bl weonal5). F

twinplaiot inain

ntie wasne ofanalntiewhiles. In entied af tripd rep

place

tation N %

chorionicmonoamniotic placentation 1 2.9chorionicdiamniotic placentation 10 29.4rionicdiamniotic placentation 23 67.7General Medicine, Semmelweis University, Budapest,ter mid-term spontaneous abortions in multiple preg-ring the study period of January 1, 1995December

We performed 49 perinatal autopsies from 44 twins and 5 triplet pregnancies. Among the 17 multiples conceived by ART, no case with the application ofte occurred. In each case, miscarriage occurred betweenweeks 1224. All ultrasound examinations were per-ur departmental ultrasound laboratory. Autopsies werein our departmental pathology laboratory based onrom our own department, as well as on those fromrecognized pathology laboratories around the world5]. During the autopsy, we were able to judge the typeion, the eventual presence of chorioamnionitis, as wellcharacteristics of fetal pathology. The diagnostic criterianionitis were positive vaginal discharge sample taken

pregnancy and histologically veried chorioamnionitistion of vaginal discharge samples was performed in thetal Chemistry Lab).

collected detailed information about the history con-vious obstetrical complications (spontaneous abortion,rtion, premature birth, intrauterine death, ectopic preg-sitive obstetric history), and previous pregnancies withformations (positive genetic history).

the clinical diagnoses a likely obstetric etiology washe miscarriage, this was identied based on reviewical records. If a malformation was present in previ-ncies which was different from the condition givingarriage in the current pregnancy, we regarded it as a

genetic risk. If, however, the malformation was iden- present and previous pregnancies, risk was regarded

that condition. All relevant pieces of informationded in a computerized database. This database wasor all subsequent analyses. For statistical signicance,

p value of 0.0the 44may exones (nthe rembe idemationonly obirth cbe idecases, of casewas ididenticases oassiste

Table 2Types of

Placen

MonoMonoDichocation for applying ART technique was pelvic factor in47.1%), male factor in 5/17 cases (29.4%), ovulatory fac-cases (17.6%), and unexplained infertility in 1/17 cases

nder distribution in the multiple pregnancies result-taneous abortion is displayed in Table 1. In our series,r of cases where fetal gender was identical was signi-er (p < 0.05) than the number of cases with heterogenousr. In triplet pregnancies, male/male/male fetal gender

and female/female/female distribution were equally0%; 2 cases each). There was a single case with het-fetal gender (20%).

of placentation could be identied in 34 cases basede information. These are described in Table 2. The ratiorionic vs. dichorionic multiple pregnancies was 11:23.ce in occurrence between mono- and dichorionic preg-

s not signicant (p > 0.05).e small number of triplet pregnancies, maternal age wasr the whole multiple pregnancy group, i.e., twin andnancies taken together. In cases where no specic fetalas identied on perinatal biopsy, the median mater-

s 30 3.64 years (range: 1645 years). In cases wheretal pathology was seen, the maternal median age wasars (range: 1744 years). The difference between these

values was not statistically signicant (p > 0.05). of gestational age at the time of spontaneous abor-was no statistical difference between cases where al pathology was found vs. cases where fetal pathology

e identied. The respective values were 19.5 2.77 ges-eks in the positive fetal pathology group vs. 20 2.35

weeks in the group with no fetal pathology identiedetal congenital malformation was identied in 8 out of

pregnancy cases (18.2%); major malformations (whichn the abortion) were veried in 6/44 (13.6%) and minorcompatible with postnatal life) in 2/44 (4.6%) cases. Ining 36 cases (81.8%), no specic fetal pathology couldd. As is demonstrated in Table 3, a congenital malfor-

present in both fetuses in 1 case, whereas in 7 cases, the fetuses was affected (fetus A: the fetus closer to). In the cases where a congenital malformation couldd, the pregnancy was naturally conceived in 63.5% of

assisted reproduction techniques were used in 36.5%the triplet pregnancy cases, a congenital malformationed in a single case. This congenital malformation wass spina bida lumbosacralis. In this case, as in all otherlet pregnancies, the pregnancy was conceived throughroductive techniques.

ntation in multiple pregnancies ending in spontaneous abortion.

460 J.G. Jo et al. / Pathology Research and Practice 208 (2012) 458 461

Table 3Fetal pathology found on perinatal autopsy after spontaneous abortion in multiplepregnancy.

Affected fetus Observed pathology

1 B Auricular aplasia, oligodactyly, pes equinovarus2 B Hydrocephalus internus3 A Accessory renal pelvis (double pelvis)4 B CAM type II5 B Renal agenesis, right-sided6 A Single umbilical artery7 B Single umbilical artery8 A and B Lumbosacral spina bida cystica

Table 4 describes the most likely etiologies leading to miscar-riage in our study. This data tends to conrm previous reportsrevealing inAmong theoccurred datively com(TTTS) in 13

Discussion

Our ndobstetric cocommon inthere was somewhat difference i

It is remaurally vs. covs. 36%) wavs. pregnanductive tecabortion in sion [7], promay even cconceived t

There w64% of muductive tectechnique wproduce liv

The medhigher thanpregnancy. to become expected.

The risk higher in cathe given pphenomenois the sameis more likehigher in m

Table 4Most likely cpregnancy.

Clinical diag

ChorioamnioTwintwin tIncompetenPreeclampsiFetal malforEtiology unc

However, our ndings suggest that the inuence of fetal gendergoes beyond the question of chorinicity or amnionicity. We foundthat in the setting where fetal gender was malemale, there wasa 13% higher risk for miscarriage compared to cases where fetalgender was

In the 34based on avnicantly m68% vs. 32%tiple pregnbetween 15that monocdevelopme

There isneou

Our nce iarria

es inilarlyl ageogy w

is nted

earli14]. n.win plopmgh thpresmpaton aion riageces;ed [egarture ormd by ationorbi

ur sent

ed 3s prence

casean bin thectioent ampt

thatt thitrauterine infections as the most common etiology. 16 cases of diagnosed intrauterine infection, 4 (25%)ue to premature rupture of membrane. Another rel-mon diagnosis was twintwin transfusion syndrome.6% of the cases.

ings support the widely recognized phenomenon thatmplications, including spontaneous abortion, are more

multiple vs. single pregnancy. In our study population,an eight-fold higher incidence of miscarriage; this ishigher than the previously reported two- to four-foldn occurrence [10,13,20,23,24].rkable that the ratio of twin pregnancies conceived nat-nceived through assisted reproductive techniques (64%s identical irrespective of whether miscarriage occurredcy was carried to term. This suggests that assisted repro-hnique does not affect the likelihood of spontaneousthis context. Fitzsimmons et al. came to a similar conclu-posing that naturally conceived multiple pregnanciesarry a higher risk for miscarriage compared to thosehrough assisted reproductive techniques.as a positive history for spontaneous abortion in nearlyltiple pregnancies conceived through assisted repro-hniques. In some of these cases, assisted reproductiveas employed precisely because of previous failure to

e birth due to underlying pathology.ian age of patients undergoing ART was signicantly

that of women having spontaneously conceived twinAs ART is usually applied after years of several attemptspregnant spontaneously, this result was as was to be

for miscarriage in multiple pregnancies is signicantlyses where fetal gender is identical in all fetuses withinregnancy [26]; this is supported by our ndings. Thisn can be explained by the fact that when fetal gender, monochorial, and monoamniotic multiple pregnancyly. It is well recognized that the risk for miscarriage isonochorionic forms of multiple pregnancy [1,15,20].

spontanancy.differeof miscvs. cas

Simtationapathology. Itassociaweekstied [not see

In ta devealthoudata retion coLivingsformatmiscarincidenidenti

In rthe naof malfinduceobservfetal m[7].

In oprominresentconrmprominin this

As cfound ine inftreatman atteto noteing thalinical diagnosis resulting in spontaneous abortion in multiple

nosis N %

nitis 16 36.40ransfusion syndrome (TTTS) 6 13.60t cervix 3 6.80a 1 2.30mation 8 18.20lear 10 22.70

studies to eIn concl

cies are asscompared reproductivfor spontanfetuses havis a signicple pregna femalefemale. cases in which chorionicity could be accurately judgedailable information, dichorionic placentation was sig-ore common than monochorionic (23 vs. 11 cases or). Considering that the ratio of monochorionic mul-ancies to all multiple pregnancies is expected to be

and 25% [11,12], this tends to support previous beliefshorionicity in multiple pregnancy is a risk factor for thent of miscarriage in this setting [4,10,17].

no difference in maternal age between cases wheres abortion occurred through singular or multiple preg-study shows that in multiple pregnancy there was non maternal age between cases where, in the backgroundge, a fetal congenital malformation could be identied

which fetal pathology was not seen., there was no signicant difference with regard to ges-

at the time of miscarriage in the cases where a fetalas identied vs. cases where there was no such pathol-oteworthy that in singular pregnancies, miscarriagewith congenital malformation generally takes place 3er, compared to cases where a malformation is not iden-In multiple pregnancies, this time difference is usually

regnancies ending in spontaneous abortion, we foundental disorder in at least 1 fetus in 18% of the casese rate of major fetal malformations was 13.2%. Theseent a higher incidence of fetal congenital malforma-red to miscarriage in singular pregnancies (10%) [14].nd Poland found a similar incidence of congenital mal-

in at least one fetus in twin pregnancies ending in (21%) [20]. Arteaga et al. observed substantially higher

in more than 46% cases were congenital malformations3].d to the relationship of congenital malformations andof conception, we found no difference in the incidenceations on the basis of whether conception was natural orassisted reproductive techniques. This contradicts priors made by Fitzsimmons et al., demonstrating a higherdity in spontaneously conceived multiple pregnancies

tudy, disorders of the central nervous system wereamong the type of fetal pathology identied. This rep-

out of the 9 cases of congenital malformation. Thisevious nding by Arteaga et al., who observed a similar

of central nervous system (or craniospinal) disorders scenario [3].e seen in Table 4, the most common clinical diagnosise background of spontaneous abortion was intrauter-n (chorioamnionitis). This underlines the importance ofnd especially the prevention of intrauterine infection into decrease the incidence of miscarriage. It is important

TTTS occurred in more than 30% of the cases, suggest-s phenomenon deserves further attention, and futurevaluate the nature of this relationship are warranted.usion, our study demonstrated that multiple pregnan-ociated with a higher rate of obstetric complicationsto singular pregnancies. Conception through assistede techniques does not necessarily predict a higher riskeous abortion in multiple pregnancies. In cases wheree identical gender within a given pregnancy, thereantly higher incidence of miscarriage. Among multi-ncies ending in spontaneous abortion, there was no

J.G. Jo et al. / Pathology Research and Practice 208 (2012) 458 461 461

difference in the incidence of fetal congenital malformationsbetween pregnancies conceived through assisted reproductivetechniques vs. naturally conceived pregnancies.

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Spontaneous abortion in multiple pregnancy: Focus on fetal pathologyIntroductionMaterials and methodsResultsDiscussionReferences