Placental function in multifetal pregnancies before and after embryo reduction was investigated by measuring maternal serum concentrations of pregnancy associated placental protein-A (PAPP-A) and pregnancy specific β-1-glycoprotein (SP-1). Three groups of pregnant women were studied following assisted reproduction; groups 1 and 2, were 12 singleton and 12 twin pregnancies respectively, and group 3 comprised 12 women with multifetal pregnancies undergoing embryo reduction. PAPP-A and SP-1 were measured serially at 8-21 weeks gestation. In all pregnancies, maternal serum PAPP-A and SP-1 increased with gestation. In twin pregnancies the mean concentrations of SP-1 were significantly higher than in singletons at all gestations, whereas for PAPP-A, concentrations were similar between these groups. In multifetal pregnancies before embryo reduction, the serum concentrations of both proteins were significantly higher than in twin pregnancies. Following reduction, the concentrations of PAPP-A remained significantly higher than for twins throughout, whereas the concentrations of SP-1 gradually converged towards those of twins; by 19 weeks there was no difference between the means of the two groups. These findings suggest that circulating concentrations of SP-1 reflect total placenta mass, which is proportional to the number of live fetuses, whereas the pattern of PAPP-A changes suggests that this protein is produced by the placenta, decidua and other tissue

Abbas, Anthony

Bersinger, Nicholas

Johnson, Mark

Nicolaides, Kypros H.

Sebire, Neil J.

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Human Reproduction vol.11 no.4 pp.900-902, 1996Maternal serum concentrations of pregnancy associatedplacental protein A and pregnancy specific p-1-glycoprotein in multifetal pregnancies before and afterfetal reductionAnthony Abbas1, Neil J.Sebire1, Mark Johnson2,Nicholas Bersinger3 and Kypros H.Nicolaides114'The Harris Birthright Research Centre for Fetal Medicine,King's College Hospital Medical School, 2Academic Department ofObstetrics and Gynaecology, The Chelsea and WestminsterHospital, London, UK and •'The Department of Obstetrics ar>dGynaecology Endocrinology, University of Berne, Beme,Switzerland^ o whom correspondence should be addressedPlacental function in multifetal pregnancies before andafter embryo reduction was investigated by measuringmaternal serum concentrations of pregnancy associatedplacental protein-A (PAPP-A) and pregnancy specific p"-l-glycoprotein (SP-1). Three groups of pregnant women werestudied following assisted reproduction; groups 1 and 2,were 12 singleton and 12 twin pregnancies respectively, andgroup 3 comprised 12 women with multifetal pregnanciesundergoing embryo reduction. PAPP-A and SP-1 weremeasured serially at 8-21 weeks gestation. In all pregnan-cies, maternal serum PAPP-A and SP-1 increased withgestation. In twin pregnancies the mean concentrations ofSP-1 were significantly higher than in singletons at allgestations, whereas for PAPP-A, concentrations were sim-ilar between these groups. In multifetal pregnancies beforeembryo reduction, the serum concentrations of both pro-teins were significantly higher than hi twin pregnancies.Following reduction, the concentrations of PAPP-Aremained significantly higher than for twins throughout,whereas the concentrations of SP-1 gradually convergedtowards those of twins; by 19 weeks there was no differencebetween the means of the two groups. These findingssuggest that circulating concentrations of SP-1 reflect totalplacental mass, which is proportional to the number of livefetuses, whereas the pattern of PAPP-A changes suggeststhat this protein is produced by the placenta, decidua andother tissues.Key words: embryo reduction/multifetal pregnancy/pregnancyassociated placental protein A/pregnancy-specific pM-glyco-proteinIntroductionPregnancy-specific (J-l-glycoprotein (SP-1) is produced by thesyncytiotrophoblast and is largely secreted into the maternalcirculation, where it is detectable as early as 6 days afterovulation (Gordon et al., 1977). Unlike SP-1, which is purelyplacental in origin, pregnancy associated placental protein A900(PAPP-A) is both placental and decidual in origin and themaximum secretory capacity is determined by both sources(Lin and Halbert, 1976; Schindler et al, 1984; Rosen, 1986).In the maternal circulation PAPP-A increases progressivelyfrom the seventh to the 40th week of pregnancy, whereas SP-1 reaches a plateau at around the 35th week, corresponding tothe gestation when there is a diminishing rate of placentalgrowth (Gordon et al, 1977; Bischof, 1989). Recent studiesalso suggest that the concentrations of these proteins may bealtered in pregnancies affected by fetal trisomies (Bersingeret al, 1994).The aim of the study was to investigate placental functionin multifetal pregnancies before and after embryo reduction,by measuring maternal serum PAPP-A and SP-1.Materials and methodsThree groups of women with pregnancies achieved by assistedreproduction were studied. Groups 1 and 2 included 12 singleton and12 twin pregnancies achieved after in-vitro fertilization (TVF); bloodsamples were obtained on five occasions between 8 and 21 weeksgestation. Group 3 comprised 12 women with multifetal pregnancies(three fetuses, n = 2; four fetuses, n = 5; five fetuses, n = 2; sixfetuses, n = 2; eight fetuses, n = 1). In this group ultrasound-guidedembryo reduction to twins was performed by transabdominal injectionof potassium chloride into the fetal heart. Maternal blood was obtainedfrom all 12 cases immediately before embryo reduction at 8-11 weeksand at subsequent visits at 10-12 weeks, 15-17 and 19-21 weeks.Ultrasound demonstrated complete resorption of the dead fetuses andtheir placentas 8—12 weeks after reduction. All patients gave informedconsent to participate in the study.PAPP-A was measured by double sandwich time-resolved immuno-fluorometric assay (TR-IFMA) as described previously (Bischof,1992) with chelated europium as a label and SP-1 was measured byan enzyme-linked immunosorbent assay (ELISA) method developedin our laboratory and using commercially available reagents. Thesensitivity of the assay was 0.02 IU/1 and the intra- and inter-assayvariations were 8.2 and 11.6% respectively.Serum concentrations of PAPP-A and SP-1 were logarithmicallytransformed to adjust for heterogeneity of variance and achieve aGaussian distribution. The transformed values before and after embryoreduction were plotted against gestational age for each of the groups,singletons, twins and higher multiples, to show the trends withgestation. Grouped linear regression was used to determine whethera significant difference existed between the slopes of the lines, andanalysis of covariance was performed to determine whether therewas significant separation of the lines. In those cases where the lineswere converging, intersection of the 95% confidence intervals wascalculated to determine the point at which the two confidence intervalswere no longer significantly different Multiple regression analysiswas performed to determine the significance of associations betweenthe starting number of fetuses and PAPP-A and SP-1 concentrations.© European Society for Human Reproduction and EmbryologyLog [PAPP-A (mlU/ml)]7 9 11 13 15 17 19 21 23Gestation (weeks)Figure 1. Individual values and regression lines of maternal serumpregnancy associated placental protein A (PAPP-A) with gestationin singleton (•—), twin (•—) and multifetal reduced to twin( • ) pregnancies.Maternal PAPP-A and AP-1 in multifetal pregnanciesLog ISP-1 (mlU/ml)]Gestation (weeks)Figure 2. Individual values and regression lines of maternal serumpregnancy specific protein 1 (SP-1) with gestation in singleton(•—), twin (•—) and multifetal reduced to twin (£3 )pregnancies.ResultsIn singleton, twin and multifetal pregnancies, there weresignificant associations with gestation for maternal serumPAPP-A concentration (Figure 1; r = 0.89, P < 0.0001,r = 0.72, P < 0.0001 and r = 0.86, P < 0.0001 respectively)and serum SP-1 concentration (Figure 2; r = 0.79, P < 0.0001,r = 0.74, P < 0.0001 and r = 0.80, P < 0.0001 respectively).The concentration of SP-1 in twin pregnancies was significantlyhigher than that in singletons at all gestations examined (t =-5.67, P < 0.0001), whereas for PAPP-A there was nosignificant difference between concentrations in singletons andtwins (/ = -1.26, P = 0.10).In the multifetal pregnancies, the serum PAPP-A and SP-1 concentrations before and after embryo reduction weresignificantly higher than in the singletons and twins (PAPP-A: t = -4.84, P < 0.0001; t = -3.65, P = 0.0002; SP-1:t = -14.6, P < 0.0001; / = -9.0, P < 0.0001 respectively).The original number of fetuses was significantly associatedwith the maternal serum concentration of SP-1 (t = 2.16,P = 0.04; Table I) but not PAPP-A (t = 1.2, P = 0.24;Table I). Following embryo reduction, maternal serumPAPP-A concentrations for multifetal pregnancies remainedsignificantly higher than those for singleton or twinpregnancies (Figure 1; t = -4.84, P < 0.0001, and t =-3.65, P < 0.0001 respectively), and the concentrationcontinued to rise in parallel for all three groups. In contrast,serum concentrations of SP-1 progressively convergedtowards those of non-reduced twins such that by 19 weeksthere was no significant difference between the groups(Figure 2).Table L Maternal serum concentrations of SP-1of gestation by starting number of fetusesNumberof fetuses3-421n571212SP-1 concentration[median (range) mg/1]51.127.64.51.9(46.6-6.3)(21.3-58.5)(0.7-11.5)(0.5-9.9)and PAPP-A al 8-11 weeksPAPP-A concentration[median (range) mg/1]2.14 (1.27-7.12)0.56 (0.03-4.95)0.26 (0.06-3.10)0.32 (0.11-1.80)SP-1 = pregnancy specific p^-1-glycoprotein; PAPP-A = pregnancyassociated placental protein-A.DiscussionThe finding that in multifetal pregnancies maternal serum SP-1 concentration increases with the number of fetuses iscompatible with the placental origin of this peptide, as placentalmass is inevitably a major determinant of circulating concentra-tions (Stabile et al, 1988). PAPP-A concentration is alsohigher in multifetal pregnancies than in singleton or twinpregnancies. However, unlike SP-1, PAPP-A does not increasein proportion to the number of fetuses, presumably becausethis protein is produced by the decidua as well as the placentaand the maximum secretory capacity of the endometrium isachieved with twin pregnancy (Lin and Halbert, 1976; Abbaset al., 1995).Multifetal pregnancy reduction to twins was associated witha relative decrease in maternal serum SP-1 concentration tothat of the control twin group (group 2). In this respect, thepattern of change in SP-1 is similar to that of human chorionicgonadotrophin (HCG) and suggests that fetal reduction causesplacental death and therefore decline in production of both901A Abbas et aLplacental products (Johnson et al, 1994a). These findings aredifferent from those of maternal serum relaxin and a-feto-protein (a-FP) (Abbas et al, 1994; Johnson et al, 1994b). Inmultifetal pregnancies relaxin concentration increases with thenumber of fetuses but following reduction to twins, the leveldoes not change; this is presumably because relaxin is aproduct of the corpus luteum whose function is unaffected byfeto-placental death (Johnson et al, 1994b). In the case of a-FP, embryo reduction was associated with an increase inmaternal serum concentration which persisted for at least 10weeks before decreasing to twin values; a-FP is stored in fetaltissues and after fetal death and tissue breakdown it is releasedinto the amniotic fluid from where it is absorbed into thematernal circulation (Abbas et al., 1994).Relative concentrations of maternal serum PAPP-A did notchange significantly following fetal reduction. Unlike SP-1,which has a half-life of ~30 h and disappears from thecirculation soon after delivery, PAPP-A remains detectable inthe maternal circulation for 4-6 weeks post-partum (Bohn,1974; Lin et al, 1976). This long half-life of PAPP-A couldoffer an explanation for the persistence of high concentrationsfollowing fetal reduction. Alternatively, PAPP-A is producednot only by the placenta, but by decidua and additional tissues,with the controlling mechanism set early in the pregnancy.This explanation is probably more likely in respect of thecontinued rise in PAPP-A values in parallel to those of non-reduced twins.In multifetal pregnancies undergoing embryo reduction thereis a procedure-related risk of spontaneous abortion, whichusually occurs within 2 weeks of the intervention and is about1-2%. However, there is a persisting risk of spontaneousabortion or severe preterm delivery which is much higher thanin spontaneously conceived twins. For example the prevalenceof preterm delivery before 32 weeks of gestation is about 1%in singleton pregnancies, 10% in twins, 30% in triplets (USGovernment, 1993) and 15% in multifetal pregnancies reducedto twins (Evans et al, 1994). It is possible that the persistenceof risk of miscarriage for several weeks after the procedure isdue to the release of cytokines and stimulation of prostaglandinsin response to the resorbing placental tissue of the dead fetuses.The slow relative decline in maternal SP-1 concentrationsfollowing embryo reduction presumably reflects the gradualdegeneration of placental tissue and therefore, the persistencefor several weeks of the stimulus for cytokine production.Bohn, H. (1974) Untersuchungen uber das Schwangerschafts-spezifische Bl-Glykoprotein (SP1). Arch. Gynakol, 216, 347-358.Evans, M.I., Goldberg, J.D., Dommergues, M. et al. (1994) Efficacy ofsecond-trimester selective termination for fetal abnormalities: internationalcollaborative experience among the world's largest centers. Am. J. Obstet.GynecoL, 171, 90-94.Gordon, Y.B., Grudanskas, J.G., Jeffrey, D. and Chard, T. (1977)Concentrations of pregnancy-specific pi glycoprotein in maternal blood innormal pregnancy and intrauterine growth retardation. Lancet, I, 331—335.Johnson, M.R., Abbas, A. and Nicolaides, K.H. (1994a) Maternal plasmalevels of hCG, oestradiol and progesterone in multifetal pregnancies beforeand after fetal reduction. / EndocrinoL, 143, 309-312.Johnson, M.R., Abbas, A., Allman, A.CJ., Nicolaides, K.H. and Lightman,S.L. (1994b) The regulation of plasma relaxin levels during pregnancy.J. EndocrinoL, 142, 261-265.Lin, T.M. and Halbert, S.P. (1976) Placental localisation of human pregnancyassociated plasma proteins. Science, 193, 1249-1252.Lin, T.M., Halbert, S.P., Spellacy, W. and Gall, S. (1976) Human pregnancy-associated proteins during the postpartum period. Am. J. Obstet. Gynecol.,124, 382-387.Rosen, S.W. (1986) New placental proteins: chemistry, physiology and clinicaluse. Placenta, 7, 575-594.Schindler, A.M., Bordington, P. and Bischof, P. (1984) Immunohistochemicallocalisation of pregnancy-associated plasma protein A (PAPP-A) in deciduaand trophoblast. Comparison with hCG and fibrin. Placenta, 45, 227-236.Stabile, I., Grudzinskas, J.G. and Chard, T. (1988) Clinical applications ofpregnancy protein estimations with particular reference to pregnancy-associated plasma protein A (PAPP-A). Obstet Gynecol. Surv., 43, 73-82.United States Department of Health Statistics and Research (SR28) (1993)Annual summaries of LHS 27/1 returns. United States Annual Vital StatisticsReports. Volume I. Natality, Department of Health.Received on December 7, 1995; accepted on February 14, 1996ReferencesAbbas, A., Johnson, MR., Bersinger, N. and Nicolaides, K J i (1994) Maternalserum alpha-fetoprotein in multifetal pregnancies before and after fetalreduction. Br. J. Obstet. GynaecoL, 101, 156-158.Abbas, A., Johnson, M.R., Chard, T. and Nicolaides, K J I (1995) Maternalplasma insulin like growth factor binding protein-1 and placental protein14 in multifetal pregnancies before and after fetal reduction. Hum. RepnxL,10, 207-210.Bersinger, N.A., Brizot, MX., Johnson, A. et aL (1994) First trimester maternalserum pregnancy associated placental protein A (PAPP-A) and pregnancy-specific beta-1-glycoprotein (SP-1) in fetal trisomies. Br. J. Obstet.GynaecoL, 101, 156-158.Bischof, P. (1989) Three pregnancy proteins (PP12, PPM and PAPP-A): theirbiological and clinical relevance. Am. J. Perinatal, 6, 110-116.Bischof, P. (1992) Pregnancy-associated plasma protein-A. Semin. Reprod.EndocrinoL, 10, 127-134.902

Maternal serum concentrations of pregnancy associated placental protein A and pregnancy specific β-1-glycoprotein in multifetal pregnancies before and after fetal reduction

Maternal serum concentrations of pregnancy associated placental protein A and pregnancy specific β-1-glycoprotein in multifetal pregnancies before and after fetal reduction

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