First trimester prenatal screening in multiple pregnancies. Part II: serum proteins PAPP-A and β-hCG as markers of adverse pregnancy outcomes

Aim: to evaluate the ability of serum biochemical markers in pregnant woman - PAPP-A (pregnancy-associated plasma protein-A) and β-hCG (the в-subunit of human chorionic gonadotropin) studied in the first trimester (11⁺⁰-13⁺⁶) during combined prenatal screening to predict adverse perinatal outcomes of multiple pregnancy that occurred spontaneously and as a result of in vitro fertilization (IVF).

Materials and methods. The main group consisted from 65 women with pregnancy occurred as a result of IVF; comparison group included 56 women with spontaneous pregnancy. All pregnancies were multiple and their outcomes were known. Serum PAPP-A and β-hCG levels were measured in the first trimester. The results were expressed in absolute values and in MoM (multiples of median). Subgroups were compared with mono- and dichorionic pregnancies, complicated and uncomplicated pregnancies, distributed according to MoM index: within the reference values (0.5-2.0), below or above the reference values.

Results. PAPP-A MoM values in the spontaneous pregnancy group were 1.12 [0.8; 1.57], in the IVF group - 1.35 [1.11; 1.72] (p = 0.01). In subgroup of low PAPP-A MoM antenatal fetal death occurred in 50 %, in subgroup of normal PAPP-A MoM - in 14.58 %, in subgroup of high PAPP-A MoM - in 5.88 % (p = 0.011). In addition, a positive correlation was found between serum PAPP-A level and time of fetal death (r_s = 0.564; p = 0.036). Low PAPP-A MoM values were associated with 50 % fetal mortality, 75 % of them were attributable to pregnancy as a result of IVF.

Conclusion. Identification of adverse outcomes in multiple pregnancies is still a difficult task, but evaluation of serum biochemical markers during the first trimester screening can help in early diagnosis of necessity and extent of timely prophylaxis.

1. Alhamdan D., Bora S., Condous G. Diagnosing twins in early pregnancy. Best Pract Res Clin Obstet Gynecol. 2009;23(4):453—6. DOI: 10.1016/j.bpobgyn.2009.02.003.

2. Santolaya J., Faro R. Twins-twice more trouble? Clin Obstet Gynecol. 2012;55(1):296—306. DOI: 10.1097/GRF.0b013e3182446f51.

3. Chauhan S.P., Scardo J.A., Hayes E. et al. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol. 2010;203(4):305—15. DOI: 10.1016/j.ajog.2010.04.031.

4. Qin J.B., Wang H., Sheng X. et al. Assisted reproductive technology and risk of adverse obstetric outcomes in dichorionic twin pregnancies: a systematic review and meta-analysis. Fertil Steril. 2016;105(5):1180-92. DOI: 10.1016/j.fertnstert.2015.12.131.

5. Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free p-hCG and PAPP-A, combined with fetal nuchal translucency thickness. Prenat Diagn. 2000;20(2):91-5. DOI: 10.1002/(sici)1097-0223(200002)20:2<91::aid-pd759>3.0.co;2-x.

6. Gjerris A.C., Tabor A., Loft A. et al. First trimester prenatal screening among women pregnant after IVF/ICSI. Hum Reprod Update. 2012;18(4):350-9. DOI: 10.1093/humupd/dms010.

7. Linskens I.H., Spreeuwenberg M.D., Blankenstein M.A., van Vugt J.M. Early first-trimester free beta-hCG and PAPP-A serum distributions in monochorionic and dichorionic twins. Prenat Diagn. 2009;29(1):74-8. DOI: 10.1002/pd.2184.

8. Khalil A., Rodgers M., Baschat A. et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol. 2016;47(2):247-63. 10.1002/uog.15821.

9. Gjerris A., Loft A., Pinborg A. et al. The effect of a ‘vanishing twin’on biochemical and ultrasound first trimester screening markers for Down’s syndrome in pregnancies conceived by assisted reproductive technology. Hum Reprod. 2008;24(1):55-62. DOI: 10.1093/humrep/den362.

10. Chasen S.T., Martinucci S., Perni S.C., Kalish R.B. First-trimester biochemistry and outcomes in twin pregnancy. J Reprod Med. 2009;54(5):312-4.

11. Amor D.J., Xu J., Halliday J.L. et al. Pregnancies conceived using assisted reproductive technologies (ART) have low levels of pregnancy-associated plasma protein-A (PAPP-A) leading to a high rate of false-positive results in first trimester screening for Down syndrome. Hum Reprod. 2009;24(6):1330-8. DOI: 10.1093/humrep/dep046.

12. Giorgetti C., Vanden Meerschaut F., De Roo C. et al. Multivariate analysis identifies the estradiol level at ovulation triggering as an independent predictor of the first trimester pregnancy-associated plasma protein-A level in IVF/ICSI pregnancies. Hum Reprod. 2013;28(10):2636—42. DOI: 10.1093/humrep/det295.

13. Tul N., Novak-Antolic Ż. Serum PAPP-A levels at 10-14 weeks of gestation are altered in women after assisted conception. Prenat Diagn. 2006;26(13):1206-11. DOI: 10.1002/pd.1589.

14. Dunne C., Cho K., Shan A. et al. Peak serum estradiol level during controlled ovarian stimulation is not associated with lower levels of pregnancy-associated plasma protein-A or small for gestational age infants: a cohort study. J Obstet Gynaecol Can. 2017;39(10):870-9. DOI: 10.1016/j.jogc.2017.01.031.

15. Chasen S.T., Perni S.C., Predanic M. et al. Does a “vanishing twin” affect first-trimester biochemistry in Down syndrome risk assessment? Am J Obstet Gynecol. 2006;195(1):236-9. DOI: 10.1016/j.ajog.2006.01.044.

16. Saygan-Karamursel B., Tekęam O., Aksu T. et al. Perinatal outcomes of spontaneous twins compared with twins conceived through intracytoplasmic sperm injection. JPerinat Med. 2006;34(2):132-8. DOI: 10.1515/JPM.2006.024.

17. Asztalos E.V., Hannah M.E., Hutton E.K. et al. Twin Birth Study: 2-year neurodevelopmental follow-up of the randomized trial of planned cesarean or planned vaginal delivery for twin pregnancy. Am J Obstet Gynecol. 2016;214(3):371.e1-371.e19. DOI: 10.1016/j.ajog.2015.12.051.

18. Corsello G., Piro E. The world of twins: an update. J Matern Fetal Neonatal Med. 2010;23(Suppl 3):59-62. DOI: 10.3109/14767058.2010.508218.

19. Suhag A., Berghella V. Intrauterine growth restriction (IUGR): etiology and diagnosis. Curr Obstet Gynecol Rep. 2013;2(2):102-11. DOI: 10.1007/s13669-013-0041-z.

20. Bebbington M., Tiblad E., Huesler-Charles M. et al. Outcomes in a cohort of patients with Stage 1 twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2010;36(1):48-51. DOI: 10.1002/uog.7612.