Tamsen et aL, 8Ρχ in IUGR 19

J. Perinat. Med.11(1983)19

Pregnancy-specific i-glycoprotein (SPi) in serum from women withpregnancies complicated by intrauterine growth retardation

L. Tamsen*, S. G. O. Johansson**, O. Axelsson*

* Department of Obstetrics and Gynecology, University Hospital, Uppsala, Sweden** Department of Clinical Immunology, Karolinska Hospital, Stockholm, Sweden

At present there is no universally accepted defini-tion of intrauterine growth retardation (IUGR). Inthis report IUGR infants are defined as those witha birth weight below — 2 SD of the normal meanfor the gestational age [7]. These infants have ahigh perinatal mortality [21] and morbidity [11].For detection of IUGR both the "gravidogram"[29] and ultrasound examination [23] have beenfound to be effective methods.For monitoring of already diagnosed or suspectedcases of IUGR the concentrations of severalproducts of the fetus and/or the placenta havebeen measured in maternal blood or urine. Amongthe most frequently evaluated for this purposehave been estriol [17] and human placental lacto-gen(HPL)[16].During the last 10 years many additional bio-chemical markers have been identified. One ofthem is pregnancy-specific jSj-glycoprotein (SPj)[2], which is a placental product [12]. Duringlate pregnancy the serum concentration of SP1correlates with infant birth weight and placentalweight both in uncomplicated and in complicatedpregnancies [24, 26, 28].Previous reports have indicated that SPt seemspromising as a predictor of IUGR [8,25, 28]. Theaim of the present study was to examine thepossibility of detecting and monitoring IUGRfrom SPj concentrations in maternal serum,measured by nephelometry, during pregnancyweeks 29 to 40. The SPi values obtained werecompared with a reference range of serum SPj

Curriculum vitae

LAILA TAMSEN, born in1942, M.D. 1971, Spe-cialist in Obstetrics andGynecology 1977. At pre-sent registered physician,Department of Obstetricsand Gynecology, Univer-sity Hospital, Uppsala,Sweden.

levels in uncomplicated single pregnancies from across-sectional study [24] and with serial valuesfrom individual women with uncomplicated singlepregnancies.

1 Material and methods

Thirty-seven women in pregnancy weeks 29 to 40,all of whom subsequently gave birth to singleIUGR infants, volunteered for this study. A totalof 67 blood samples were obtained for SP1 ana-lyses. The women were 19 to 42 years old (mean27 years). Twenty-three women were primiparousand 14 were multiparous. Detailed clinical data onthese women are given in Tab. I. Preeclampsia wasdiagnosed and classified according to the criteriaof the U. S. Comittee on Maternal Welfare issuedin 1952 [18]. The WHITE classification was usedfor diabetes mellitus [19].

0300-5577/83/0011-0019$02.00© by Walter de Gruyter & Co. · Berlin · New York

20 Tamsen et al., SPi in IUGR

Tab. I. Clinical grouping of 37 women with pregnanciescomplicated by intrauterine growth retardation (infantbirth weight below - 2 SD of the normal mean forthe gestational age) [7].

Group APGAR score at 1 minute<6 >7

Total

No maternalcomplication 1

Pre-eclampsialevis 3**

Pre-eclampsiagravis 5

Diabetesmellitusgroup D 1**group F

Miscellaneous1) 1

Total 11

11

6*

2

1

6**

26

12

9

7

11

7

37

1) essential hypertension, pre-partum hemorrhage, pre-mature rupture of the membranes, ulcerative colitis,cervical insufficiency, congenital malformation

+ two stillborns* one pre-partum hemorrhage

** one lethal congenital malformation

Cesarean sections were performed on 19 womenfrom pregnancy weeks 29 to 41 because of mater-nal and/or fetal complications. In all, 10 infantswere born before the 35th week of pregnancy.Induced or spontaneous vaginal labor occurred inpregnancy weeks 36 to 42 except in three cases,where stillborn infants were delivered in weeks 30to 36 of pregnancy, one with a lethal congenitalmalformation. Another infant died later fromlethal congenital malformation.From 21 women with uncomplicated single preg-nancies giving birth to healthy infants of normalbirth weight [7] in pregnancy weeks 38 to 42, 210blood samples were collected weekly or biweekly.Serum or plasma was stored at — 20°C untilassayed.Nephelometry was performed as described else-where [24]. The interassay variation was 5 % andthe detection limit 0.5 mg/1. No differences werefound between plasma and serum concentrationsof SPi [24]. Whether the analyses were performedon plasma or serum, the term "serum concentra-tion" will be used in the following.

The reference range of serum SPj concentrationsfor uncomplicated single pregnancies used forcomparison with the SP^ values obtained is thesame as previously described [24].

2 ResultsThe SPj values in 67 blood samples from 37women with single pregnancies complicated byIUGR are illustrated in Fig. 1. Most of the values

, mg/l

100-

10-1)

30 35Pregnancy weeks

Fig. 1. Pregnancy-specific ^-glycoprotein (SPj) levelsmeasured by nephelometry in serum from 37 women(67 samples) with single pregnancies complicated byintrauterine growth retardation (infant birth weightbelow — 2 SD of the normal mean for the gestationalage) [7J.The shaded area represents a 95 % reference range for SPjlevels in uncomplicated single pregnancies obtained froma cross-sectional study of 323 women [24], and the solidline is the geometric mean.The following symbols are used: APGAR score at 1minute > 7 (·), idem < 6 (o), an infant with acrania andother malformations (Δ), an infant with ZELLWEGER'ssyndrome (A), an infant stillborn in pregnancy week 30(+) and one stillborn in pregnancy week 35 (++).The woman with an extremely low SPj value [1] had anormal value of human placental lactogen.

J. Perinat. Med. 11 (1983)

Tamsen et al., S?i in IUGR 21

were below the geometric mean of the referencegroup and serial samples showed a tendency to adecrease in SPj levels, which was more markedwhen the APGAR score at l min was low.A serum SPj value of 80mg/l (approximatelycorresponding to the geometric mean — 1 SD)was chosen as the most appropriate discriminatorylevel between uncomplicated pregnancies andpregnancies complicated by IUGR in gestationalweeks 32 to 34. The distributions of the initialSPj values among women with IUGR infantsand those with uncomplicated pregnancies inrelation to the 80 mg/1 level were compared andthe results are given in Table II. Of 15 women with

IUGR infants, 10 (67%) had a serum S?l valuebelow 80 mg/1, while the corresponding figure foruncomplicated pregnancies was 10 out of 76women (13%).The SPi values in serial samples from 21 womenwith uncomplicated pregnancies are presented inFig. 2. From pregnancy weeks 30 to 36 therewas a steady increase in the SPj concentrationand after week 36 there was a tendency to aplateau. Using the function for linear regressionlog y = ax + b, where y = SPj value and χ = preg-nancy week, two average linear developmentswere determined (Fig. 3). The mean increase inthe SPj concentration from pregnancy weeks

o//oSPj, mg/l

100-

30 35Pregnancy weeks

Fig. 2. Pregnancy-specific j-glycoprotein (SPj) levelsmeasured by nephelometry in serum from 21 women withuncomplicated single pregnancies (total 210 samples). Theinfants were born in pregnancy weeks 38 to 42 and werehealthy and of normal weight (mean ± 2 SD for thegestational age) [7].The shaded area represents a 95 % reference range for SPjlevels in uncomplicated single pregnancies obtained froma cross-sectional study of 317 women [24].*) This woman had normal serum values of alpha-feto-protein, estriol and human placental lactogen.

170-1

Pregnancy weeksFig. 3. The mean increase ± 1 SD (solid line and shadedarea) in the serum concentration of pregnancy-specific01-glycoprotein (SPj), measured by nephelometry, inserial samples from 21 women with uncomplicated singlepregnancies in pregnancy weeks 30 to 36, in percent ofthe initial value. The mean increase of the 8Ρχ concen-tration is continued for pregnancy weeks 36 to 40.The developments of the SPj levels in serum from sixwomen with pregnancies complicated by intrauterinegrowth retardation (infant birth weight below - 2 SDof the normal mean for the gestational age) [7] are alsoshown. Serial samples from each woman are connectedwith a solid line; open circles represent an APGAR scoreor < 6 at l min and closed circles an APGAR score of> 7 at l min.

J.Perinat.Med. 11 (1983)

22 Tamsen et al., S?i in IUGR

30 to 36 was 49%. During weeks 36 to 40 themean increase was 13 %.The S?i values in serum from six women withIUGR infants from whom at least three serialsamples were drawn over a period of at least twoweeks showed a decreasing tendency (Fig. 3.)·The decline was most marked in the womanwhose infant had a low APGAR score at l minafter birth.

3 Discussion

As the etiology of IUGR is multifactorial [15], nosingle abnormal clinical or biochemical finding issufficient in itself for diagnosis and intervention.Reliable diagnosis of this condition and/or moni-toring of already diagnosed IUGR must dependupon a combination of clinical and laboratoryapproaches [9] as well as on an accurate estima-tion of gestational age. If there is any doubt aboutthe length of a pregnancy* an early ultrasoundexamination will give correct dating [3]. Withreliable dating, the simple "gravidogram" canbe used as a routine examination and 75% ofinfants of low birth weight for their gestational agecan be detected [29]. An ultrasound examinationmeasuring the biparietal diameter and the bodycircumference [23] can confirm suspected growthretardation.However, even if the fetus and the placentatogether form one entity, the causes of IUGR canbe mainly fetal (e.g. congenital malformation) orpurely placental [15]. It might therefore be ofvalue to combine at least two biochemical markersthat mainly depend on the status of either thefetus or the placenta.Of the placental proteins, HPL is the hithertomost frequently evaluated in different complica-tions during late pregnancy [14]. Like SPj, ithas a low day-to-day variation, but the concentra-tion of HPL in maternal serum is about 20—30times lower than that of SPj [27] and for ana-lyses of HPL a sensitive method such as a radio-immunoassay or an enzyme immunoassay has tobe used. SPl9 however, is easily measured bysimple immunoprecipitation methods or nephelo-metry [24].

In earlier studies in which SPi was compared withHPL, the predictive value of SPj for IUGR wasfound to be equally good as [22] or even betterthan that of HPL [28].In the present investigation it was found that aserum 8Ρχ level below 80 mg/1 in a single bloodsample drawn in pregnancy weeks 32 to 34 had apredictive value of 50% for IUGR and that a levelabove or at 80 mg/1 had a value of 93 % for pre-dicting a normal infant birth weight (Tab. II). Inthis study IUGR infants were defined as thosewith a birth weight below — 2 SD of the normalmean for the gestational age [7]. Even if otherreports define IUGR as a birth weight below the10th percentile of normal infant birth weight forthe gestational age, it would seem of interest tocompare our results with those of other studies.CHAPMAN etal. [5] used a serum SP1 value of100 mg/1 as a cut-off level in pregnancy weeks 31to 34 and found a predictive value of 24 % for

Tab. II. Sensitivity and predictive value of a single valueof pregnancy^specific ^-glycoprotein (SP^ in serum,with 80 mg/1 as the discriminatory level between uncom-plicated pregnancies and pregnancies complicated withIUGR (infant birth weight below - 2 SD of the normalmean for the gestational age [7]). The S?! levels in thefirst blood samples drawn in pregnancy weeks 32 to 34from 15 women were compared with the 8Ρχ levels froma cross-sectional study of uncomplicated single preg-nancies [24] for the same period,η = number of womenTP = true positive and FP = false positive, i.e. SPj level

= > 80 mg/1.TN = true negative and FN = false negative, i.e. 8Ρχ level

< 80 mg/1.

IUGR(n)

8Ρχ level< 80 mg/1 10

SPj level> 80 mg/1 5

Total 15

TNaensmvny TN + FP

TNPredictive value τ^χτ τ?χτ ~" 50%

Uncomplicatedpregnancy (n)

10

66

76

TP' TP + FN

TPTP + FP

86.8%

92.9%

J. Ferinat.Med.il (1983)

Tamsen et al., 8Ρχ in 1UGR 23

IUGR. GORDON etal. [8] reported that duringpregnancy weeks 31 to 40 more than 70% ofwomen with IUGR infants had SPj concentrationsbelow the 10th percentile of the reference range.TOWLER et al. [28] found the predictive value of8Ρχ levels below a 95 % reference range for detec-tion of IUGR to be 60% during the last trimester.Thus, despite differences in the definition ofIUGR and in the selection of reference ranges, thepredictive values of the serum SPi level for IUGRare in the same range.During uncomplicated single pregnancies, therewas an average increase of 49% in the SPj con-centration from pregnancy weeks 30 to 36 asassessed from serial samples from individualwomen (Fig. 3). It was also found that eachindividual woman maintained a certain concentra-tion level throughout late pregnancy, i.e. they allshowed the same relative increase but at individuallevels. In serial samples from women with IUGRinfants there was no such increase and even adecrease occurred (Fig. 3), a finding indicatingthat serial measurements of SPj can be used formonitoring cases of suspected IUGR. An absenceof an increase in the SPj concentration, or theoccurrence of a decrease, will strengthen thesuspicion of IUGR. Besides, very low values or anearly decrease seem to correlate with a low APGARscore.One woman with an IUGR infant had an extrem-ely low serum SPX value (Fig. 1). A similar case has

only been reported once [10], suggesting a rareand specific defect in the SPj synthesis, as boththese women had normal HPL values. It is ofinterest to note that a similar rare deficiency hasbeen reported for HPL in cases with a normalpregnancy and delivery. In these cases the SPjvalues were normal [1,6,20]. An immunosuppres-sive effect of SPj has been found in studies in vitro[4, 13], which could indicate that SP1 has afunction as an immunological protector of thepregnancy against the mother, but the findings ofvery low 8Ρχ values in rare cases might cast somedoubt on this suggestion.In pregnancies complicated by congenital malfor-mations combined with IUGR (Fig. 1) no specialpattern of SPi values was found as compared withthe reference group of uncomplicated pregnancies.This finding is interesting. A normal serum SPjvalue in a woman with an IUGR infant could pointtowards a fetal cause of the growth retardation,e.g. congenital malformation.It is concluded that SPl measurements are valuableadjuncts to the "gravidogram" and ultrasonarexamination for the detection and monitoring ofIUGR. As the day-to-day variation of SPX is low,as is the methodological variation of nephelo-metry, a determination of SP1 in a single sample isin most cases sufficient to detect pregnancies atrisk of IUGR in the beginning of the last trimester.Serial determinations will increase the predictivevalue even further.

Summary

Serum concentrations of pregnancy-specific /3j-glyco-protein (SPi) were measured by nephelometry in 37women with single pregnancies complicated by intra-uterine growth retardation (IUGR). Sixty-seven bloodsamples were examined for their contents of SPj inpregnancy weeks 29 to 40. The SPj values were comparedwith those obtained in a cross-sectional study of 323women and a serial study of 21 women (210 samples)with uncomplicated single pregnancies.It was found that a serum SPj value below 80 mg/1 in asingle blood sample drawn in pregnancy weeks 32 to 34

had a predictive value of 50% for IUGR and a valueabove or at 80 mg/1 had a value of 93 % for predicting anormal infant birth weight.Serial samples from individual women with uncom-plicated single pregnancies showed an average increase inthe SPj concentration of 49 % from pregnancy weeks 30to 36. In serial samples from six women with IUGRinfants there was no such increase, or a decrease occurred.It is concluded that SPj measurements in maternal serumare valuable for the detection and monitoring of preg-nancies complicated by IUGR.

Keywords: Fetal growth retardation, human pregnancy, nephelometry, placental function tests, pregnancy proteins,

J.Perinat.Med. 11 (1983)

24 Tamsen et al., SPj in IUGR

Zusammenfassung

Schwangerschaftsspezifisches jSj-Glukoprotein (SPi) immütterlichen Serum bei Schwangerschaften mit intra-uteriner MangelentwicklungBei 37 Frauen mit Einzelschwangerschaften, kompliziertdurch intrauterine Mangelentwicklung, wurden nephelo-metrisch die Serumkonzentrationen des schwanger-schaftsspezifischen 0rGlukoproteins (8 ) bestimmt. In67 Blutproben wurde der SPx-Gehalt in der 29- bis 40.Schwangerschaftswoche bestimmt. Als Vergleich zudiesen SPj-Werten dienten die Ergebnisse einer Reihen-untersuchung an 323 Frauen und die Serienuntersuchun-gen an 21 Frauen (mit 210 Einzelproben), bei denen Ein-zelschwangerschaften komplikationslos verlaufen waren.Wir fanden, daß eine SPj-Konzentration < 80 mg/1 -bestimmt in der 32. bis 34. Schwangerschaftswoche —

einen prognostischen Wert von 50%, eine SPx-Konzen-tration > 80 mg/1 einen proighostischen Wert von 93 %für ein normales Geburtsgewicht des Kindes hat.Serienuntersuchungen einzelner Frauen mit komplika-tionslosen Einzelschwangerschaften zeigten zwischen der30. bis 36. Schwangerschaftswoche eine durchschnittlicheZunahme der SPi-Konzentration ufn 49%. Serienunter-suchungen an 6 Frauen mit intrauterin mangelentwickel-ten Kindern ließen diese Zunahme nicht erkennen, hiertrat im Gegenteil eine Abnahme ein. Wir schließen ausunseren Ergebnissen, daß ISP j -Bestimmungen in regel-mäßigen Abständen ein wertvoller Parameter für dieErkennung und Verlaufskontrolle von Schwangerschaftenmit intrauterin mangelentwickeltem Kind sind.

Schlüsselwörter: Fetale Wachstumsretardierung, Nephelometrie, Plazentafunktionstest, schwangerschaftsspezifischeProteine, SP .

Resume

Glycoprotein ßi (SPj) specifique de la grossesse dans leserum de femmes dont la grossesse est compliquee d'ünretard de croissance intra-uterinDes concentrations de glycoproteine (SPj), specifique dela grossesse, ont ete mesurees par nephelometrie chez 37femmes presentant des grossesses uniques compliquees deretard de croissance intra-uterin (RCIU), 67 prelevementsde sang ont ete analyses pour determiner le taux de SPjde la 29eme ä la 40eme semaine de grossesse. Les tauxde SPj releves ont ete compares "ä ceux obtenus parFetude d'un groupe de 323 femmes ~et l'etude serielle de21 femmes (210 prelevements) presentant des grossessesuniques normales.II a ete mis en evidence qu'un taux de serum SPj inferieura 80 mg/1 dans un seul prelevement sanguin effectue de la

32eme ä la 34eme semaine de grossesse avait une valeurdiagnostique de 50 % pöür un RCIU et qu'un taux egal ousuperieur ä 80 mg/1 permettait de diagnostiquer ä 93 % unpoids de naissance normal.Des prelevements periodiques effectues individuellementsur des femmes presentant une grossesse simple sanscomplications ont montre une augmentation moyenne dela concentration de SPj de 49% de la 30eme a la 36emesemaine de grossesse. Lors d'une serie de prelevementseffectues sur des femmes presentant un RCIU, U n'a eteconstate ni augmentation, ni dimination.En conclusion, les mesures de SPj effectuees sur le serummaternel jouent un role important dans la detection et lasurveillance des grossesses compliquees de RCIU.

Mots-cles: Grossesse, nephelometrie, proteines de la grossesse, retard de croissance foetal, SPj, tests de functionplacentaire.

Acknowledgements: This study was supported financially by the Medical Faculty of the University of Uppsala, theSwedish Medical Research Council (grant no. 16X-105) and Foreningen Margarethahemmet,Knivsta, Sweden.

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Received July 20, 1982. Accepted September 17, 1982.Dr. L. TamsenDept. of Obstetrics and GynecologyUniversity HospitalS-750 14 UppsalaSweden

J. Perinat.Med.il (1983)