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Apollo Medicine 2012 SeptemberVolume 9, Number 3; pp. 171e175 Original Article

Obstetric outcomes associated with second trimester unexplainedabnormal maternal blood markers: A comparative study betweenoutcomes of normal and abnormal blood values

Pooja Lodha, A. Sharma, C. Singh, T. Tayal, A. Kaul*

Apollo*CorreReceivCopyrihttp://d

ABSTRACT

Objectives: 1) To compare the adverse obstetrical outcomes in the patient population with normal blood MoMs.2) To determine the probability of occurrence of an adverse obstetric event in relation with abnormal maternal bloodanalytes.

Study setting: Retrospective caseecontrol study from August 2006 to December 2011 at the Apollo Centre for FetalMedicine, Indraprastha Apollo Hospital, New Delhi.

Methods: The study cohort comprised of 2813 women between 16 and 20 weeks of gestation. Women withaneuploidy fetuses were excluded. The study population was categorized into Group A (with abnormal blood MoMs)and Group B (with normal blood MoMs). This was done for all the four blood markers; Maternal Serum Alpha-FetoProtein (MSAFP), Human Chorionic Gonadotropin (hCG), Unconjugated Estriol (uE3) and Inhibin. The cut off used tocategorize the women in Group A were MSAFP � 2 MoMs, Free hCG � 2 MoMs, uE3 � 0.5 MoMs and Inhibin � 2MoMs. The outcomes studied were live births, preterm birth, fetal growth restriction and hypertensive disorders ofpregnancy.

Results: The live birth rate was significantly higher in Group B for all the four blood markers as compared to Group A.Preterm birth, fetal growth restriction and hypertensive disorders of pregnancy were significantly higher (p < 0.001) inGroup A than Group B.

Conclusion: Apart from being used as an aneuploidy screen, the second trimester maternal blood analytes can alsopredict adverse obstetrical outcomes.

Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved.

Keywords: Maternal serum alpha-feto protein, Human chorionic gonadotropin, Unconjugated estriol, Inhibin,Adverse obstetric outcomes

INTRODUCTION

A major goal of antenatal care is to intervene in high-riskpregnancies. Preterm birth, fetal growth restriction andpre-eclampsia remain significant causes of perinatal deathand childhood disability.1

Although there has been an expressive increase of thesurvival rate among low birth weight newborns receivingintensive care, but these babies often face severe short-

Centre for Fetal Medicine, Indraprastha Apollo Hospitals, New Delhi,sponding author. email: anita_kaul@apollohospitals.comed: 8.6.2012; Accepted: 2.7.2012; Available online: 7.7.2012ght � 2012, Indraprastha Medical Corporation Ltd. All rights reservedx.doi.org/10.1016/j.apme.2012.07.003

and long-term health consequences.2 Low birth weightapart from the short-term outcomes also has a long-termimpact on health outcomes in adult life. The short-termmorbidities include hyaline membrane disease, hyperbiliru-binemia, increased susceptibility to infections and intra-ventricular hemorrhage. Babies affected by fetal growthrestriction on reaching adulthood are at greater risk ofdeveloping cardiovascular disease, hypertension, and non-insulin dependent diabetes.3

India.

.

Fig. 1 Mechanisms which trigger the placenta to releaseabnormal levels of hormones.

172 Apollo Medicine 2012 September; Vol. 9, No. 3 Lodha et al.

Multiple-marker screening for Down syndrome is anestablished part of routine prenatal care in most countries.Most centers in the US use at least 3 s trimester maternalserum markers, while the European centers use firsttrimester serum markers together with concurrent ultra-sound nuchal translucency measurement, and some haveadopted sequential policies using both first and secondtrimester markers.

In India, however there is no National AneuploidyScreening Policy as yet. Second trimester serum screeningseems confined mainly to the urban centers. Although thegold standard is combined first trimester screening, butthis still is offered to Fetal Medicine Foundation (FMF)standards only in a few centers. Majority of women in Indiaseek antenatal health care for the first time in secondtrimester. This is the population of women who are thensubjected to second trimester maternal biochemistry andthe genetic sonogram as a part of aneuploidy screening.Reliable antenatal identification of PET and SGA is crucialto judicious allocation of monitoring resources and use ofpreventative treatment with the prospect of improvingmaternal and perinatal outcome.4

This study is an attempt to focus on the applicability ofhormone measurements in the risk assessment, early diag-nosis, and management of pregnancies with adverseobstetric outcomes.

AIMS AND OBJECTIVES

d To review the obstetrical outcomes associated withunexplained abnormal second trimester maternal bloodanalytes.

d To compare adverse obstetrical outcomes in the popula-tion with normal and abnormal blood MoMs.

d To determine the probability of occurrence of an adverseobstetric outcome in relation with abnormal maternalblood analyte.

d To find the feasibility of the second trimester bloodmarkers in being used as a screening test for adverseobstetrical outcomes.

RATIONALE

A plethora of hormonal changes contribute to the physiolog-ical maternal adaptations during human gestation. Abnormalplacental hormones are the clinically accessible signs ofplacental injury. The excessive or deficient release of someplacental hormones in association with gestational diseasesmay reflect an abnormal differentiation of the placenta, animpaired fetal metabolism, or an adaptive response of thefeto-placental unit to adverse conditions (Fig. 1).

We postulate that identification of certain pregnanciesfor adverse obstetric outcomes could be carried out withthe long-term goal of improving maternal/perinataloutcome.

MATERIALS AND METHODS

Type of study e Retrospective case control study.Study period e August 2006 to December 2011.Study setting e Apollo Centre for Fetal Medicine, Indrap-rastha Apollo Hospital, New Delhi.Inclusion criteria e Women between 16 and 20 weeksgestation with singleton pregnancy, who gave bloodsamples for triple marker/quadruple marker and whoseoutcomes were available, were included in the study.Exclusion criteria e Women diagnosed to have aneu-ploidy fetuses, and ongoing pregnancies were excludedfrom the study.

Association between abnormal second trimester maternalblood markers and aneuploidy has long been studied andproven. Therefore, to reduce bias of adverse pregnancyoutcomes, aneuploidies have been excluded so that the asso-ciation between outcomes like preterm delivery, hyperten-sive disorders of pregnancy and fetal growth restriction canbe studied independent of aneuploidies.

To evaluate the associations between single secondtrimester serum markers and adverse pregnancy outcomes,MoMs of serum markers in women with adverse pregnancyoutcomes were compared with those of women without anadverse outcome. The outcomes studied were live birthrates, preterm delivery, hypertensive disorders of

Fig. 2 Odds ratio for live births.

A comparative study between outcomes of normal and abnormal blood values Original Article 173

pregnancy and fetal growth restriction (Birthweight < 10th centile was taken as a surrogate markerfor fetal growth restriction).

Abnormal levels of serum markers were defined as eMSAFP ‡ 2 MoMs, hCG ‡ 2 MoMs, uE3 £ 0.5MoMs, Inhibin ‡ 2 MoMs.

Pregnancies were then grouped according to whetherthey had abnormal levels of serum markers (high or low eGROUP A) or not (control e GROUP B). The risk ofhaving an adverse outcome was compared between thetwo groups to generate an odds ratio (OR), which wasthen tested for statistical significance by the chi-squaretest (univariate analysis). Logistic regression analysis wassubsequently performed to identify markers that were inde-pendently associated with any of the identified adverseoutcomes. The probability of occurrence of the adverseobstetric outcomes was studied with respect to each bloodanalyte and compared.

Fig. 3 Comparison of FGR in two groups.

RESULTS

From the total population of 2813 women, 874 womencould be included in the study after excluding ongoingpregnancies, pregnancies without outcomes, multifetalgestation and pregnancies with aneuploidies. Out of these,704 were triple tests and 170 were quadruple tests. Thestudy population who had undergone a triple test wasmore than that who had undergone a quadruple test asquadruple test was only recently introduced in India(2009).

Demographic characteristics: Maternal age and BMIare significantly higher in Group A (32 years, 29.8 kg/m2)than Group B (29 years, 26.2 kg/m2) (p < 0.05). Meangestational age at delivery is significantly lower in GroupA (34.5 weeks) than in Group B (38.3 weeks) (p < 0.05).

Live birth rate: The live birth rates are significantlyhigher in Group B, than in Group A for all the four bloodmarkers (p < 0.05). Women with normal MSAFP MoMshad 1.21 times more chances of having a live birth ascompared to women with abnormal MSAFP MoMs(Fig. 2).

Fetal growth restriction: The incidence of FGR wassignificantly higher in Group A than in Group B (p < 0.001).The odds ratio was highest for hCG (4.522) (Fig. 3).

Preterm birth: The incidence of preterm birth was signif-icantly higher in Group A than in Group B (p < 0.001). Theodds ratio was highest for MSAFP (2.933) (Fig. 4).

Hypertensive disorders of pregnancy: The incidenceof hypertensive disorders of pregnancy was significantlyhigher in Group A than in Group B (p < 0.001). Theodds ratio was highest for hCG (2.933) (Fig. 5).

Probability of occurrence of adverse obstetric event:The probability of occurrence for Fetal Growth Restrictionand Hypertensive Disorders of Pregnancy was highest inwomen with abnormal hCG MoMs. The probability ofoccurrence for preterm birth was highest with abnormalMSAFP MoMs (Fig. 6).

DISCUSSION

Second trimester maternal serum markers have long beenused in prenatal screening for the most common aneu-ploidies. But their exploitation in predicting adverseobstetric outcomes remains to be accepted universally.

Elevated AFP and elevated hCG have each been associ-ated with low birth weight, intrauterine growth restriction(IUGR), PTB, pre-eclampsia and fetal loss.6e8

A retrospective review by Tianhua Huang et al in 2010showed that decreased second trimester unconjugatedestriol (uE3), increased second trimester serum alpha-feto-protein (AFP), or increased second trimester total humanchorionic gonadotrophin (hCG) were at greater risk ofdeveloping adverse pregnancy outcomes. Alain Gagnon

Fig. 4 Comparison of preterm birth in two groups.

174 Apollo Medicine 2012 September; Vol. 9, No. 3 Lodha et al.

in 2008 had found similar results. Our study is in accor-dance with these studies.

In our study, the highest OR for fetal growth restrictionand preterm birth was with Inhibin. But due to the signifi-cant difference in sample size of the other three markersversus that for Inhibin, the probability of occurrence wascalculated according to the other three markers. AlthoughKim SY et al in 2006 have shown a strong associationbetween high Inhibin in second trimester and pre-eclampsia, we did not find this association.

Morris in 2008 found that a combination of tests is moreaccurate in predicting adverse outcomes rather than

Fig. 5 Comparison of hypertensive disorders of pregnancy intwo groups.

individual markers.9,10 A review of combination of markerswith adverse obstetric events has been studied in 2010 byTianhua et al6 and Dini hui et al. In our study, we studiedindividual markers and their associations, as this hasenabled the delineation as to which marker contributesmost to which adverse obstetric outcome.

Although the association between all unexplainedabnormal second trimester maternal blood markers andadverse obstetric outcomes reached statistical significance,randomized control studies with larger study populationare needed to establish these markers as a screening toolfor adverse obstetric outcomes. Also, studies on multiple

Fig. 6 Probability of occurrence of adverse obstetric event.

A comparative study between outcomes of normal and abnormal blood values Original Article 175

markers from both trimesters have shown that a combinationof low first trimester PAPP-A and higher second trimesterAFP predicts an increased risk for SGA, low birth weightand PTB.6 This would be the most accurate method forscreening adverse obstetric outcomes on the basis ofmaternal blood markers.

Infact, a recent study based on subjects in the FASTERTrial explored the use of serum markers in both trimestersto identify pregnancies at increased risk of fetal loss,including fetal demise occurring before 24 weeks of gesta-tion and stillbirth at 24 weeks or later.5

To conclude, second trimester maternal serum markersare independent risk factors for the course and outcomeof pregnancy. Our study underlines the need of intensifyingsurveillance and anticipating complications in such cases.

CONFLICTS OF INTEREST

All authors have none to declare.

ACKNOWLEDGMENT

We acknowledge the Department of Obstetrics and Gynae-cology, Indraprastha Apollo Hospitals, for the shared care.

REFERENCES

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2. Konstantyner T, Leite HP, Taddei, et al. Effects of a very lowbirth weight newborn on family: literature review. Nutr Hosp.2007;22(2):138e145.

3. Barker DJ. The developmental origins of chromic adultdisease. Acta Paediatr Suppl. 2004;93(446):26e33.

4. Askie L, Duley L, Henderson-Smart D, Stewart L. Antipla-telet agents for preventing pre-eclampsia: a meta-analysisof individual patient data. Lancet. 2007;369(9575):1791e1798.

5. Lambert-Messerlian Geralyn, Wald Nicholas J,D’Alton Mary E. First- and Second-Trimester Evaluationof Risk (FASTER) Research Consortium. N Engl J Med.2005;353:2001e2011.

6. Huang Tianhua, Hoffman Barry, Meschino Wendy. Predic-tion of adverse pregnancy outcomes by combinations of firstand second trimester biochemistry markers used in theroutine prenatal screening of Down syndrome. Prenat Diagn.May 2010;30(5):471e477. http://dx.doi.org/10.1002/pd.2505.

7. Gagnon Alain, Douglas Wilson R, Audibert François, et al.Obstetrical Complications Associated with AbnormalMaternal Serum Markers Analytes. Society of Obstetriciansand Gynaecologists of Canada, Genetics Committee; 2008.Clinical Update.

8. Ayse Yasemin Karageyim Karsidag, Esra Esim Buyukbayrak,Bulent Kars et al. The relationship between unexplainedelevated serum markers in triple test, uterine artery dopplermeasurements and adverse pregnancy outcome, Vol. 60, No.3, March 2010 Obstetric and Gynecology Department, Dr.Lutfi Kirdar Kartal Education and Research Hospital, Istanbul,Turkey.

9. Morris RK, Cnossen JS, Langejans M, et al. Serum screeningwith Down’s syndrome markers to predict preeclampsia andsmall for gestational age: systematic review and meta-analysis.BMC Pregnancy Childbirth. 2008;8:33.

10. Androutsopoulos G, Gkogkos P, Papadopoulos V, et al.Mid-trimester maternal serum markers in predicting adversepregnancy outcome. Clin Exp Obstet Gynecol. 2009;36:237e240.

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