The current global prevalence rate of infertility ranges from 3.5% to 16.7%. Approximately 2% of all infants born annually in the United States are conceived using Assisted Reproductive Technology (ART) (1,2). In vitro fertilization (IVF) is the most common type of ART, which further involves ovarian stimulation, oocytes/ sperm retrieval, cultures, and embryo transfer (fresh and frozen). Insemination can occur with or without intracytoplasmic sperm injection (ICSI). ICSI is associated with an increased risk of sex chromosomal abnormalities among offspring of men with severe male factor infertility. Currently, prenatal screening requires information on the combination of maternal age, maternal weight, morbidities (such as diabetes and smoking), race, gestational age (GA), and number of fetuses to apply the correction factor. In 2019, the College of American Pathologists Laboratory Accreditation Program introduced a requirement to solicit patients on in vitro fertilization status on both prenatal screening requisition forms (CHM.31550) and reports (CHM.32300). At the time of prenatal screening, information about the method of conception is requested, since different IVF treatment methods seem to alter the screening biomarkers in different ways by altering the median MoM’s, causing a higher false-positive rate.

Routine prenatal screening requires information on GA using ultrasound, last menstrual period (LMP), physical exam, nuchal translucency (NT). In IVF/ICSI, gestational method is calculated using egg retrieval, and/or egg transfer date. If either is not available, LMP is used. On the other hand, the maternal age at the estimated due date can be calculated from the egg donor birth date and/or egg retrieval date. If the egg retrieval date is set and is earlier than the calculated LMP date, it is assumed that the egg was frozen.

Studies have concluded that in first trimester of IVF/ICSI pregnancies, there is a decrease in the multiple of the medians (MoM’s) of pregnancy-associated plasma protein A (PAPP-A) and alpha fetal protein (AFP), while beta-human chorionic gonadotropin (b-hCG) increased when compared to spontaneous pregnancies. In frozen embryo transfer, there is a decrease in PAPP-A, increase in AFP and NT, whereas hCG MoM’s varied in direction. After fresh embryo transfer, the first trimester marker PAPP-A decreases and found no difference in the NT. In the second trimester, there is an increase in hCG and decrease in AFP and unconjugated estriol (uE3), leading to false positive rate and therefore, triple test is not recommended in IVF/ICSI. Lambert-Messerlian et al. have found that the MoM’s of PAPP-A, AFP, total hCG, and inhibin-A were increased and free b-hCG, µE3, and NT were decreased in donor oocytes. Due to the heterogeneity of the prenatal results, the clinicians have shown concerns if prenatal testing is the most appropriate approach in IVF pregnancies [3-5].

Clinical labs can add a correction factor by standardizing marker values against the median values for GA to IVF/ICSI pregnancies either based on literature or collect population specific data to establish an appropriate correction factor to limit risk of false positive outcome. In addition, labs need to be aware of the risk associated with missing or incorrect information on data surrounding fresh/ frozen embryo transfers or donor oocytes, that will affect the accuracy of screening results.


  1., Art success rates. Centers for Disease Control and Prevention. 2020. Accessed on 05/09/2022
  2. Radojcic BA, B.-T.A., Starcevic N, Kapovic M, Vlastelic I, Randic L, Chromosome studies in patients with defective reproductive success. Am J Reprod Immunolvol, 2000. 44 (pg. 279-283).
  3. Andrea Lanes, T.H., Ann E. Sprague, Arthur Leader, Beth Potter, Mark Walker, Maternal serum screening markers and nuchal translucency measurements in in vitro fertilization pregnancies: a systematic review. Fertility and sterility, 2016. November, Vol. 106 NO. 6 .
  4. Anne Cathrine Gjerris, A.T., Anne Loft, Michael Christiansen, and Anja Pinborg, First trimester prenatal screening among women pregnant after IVF/ICSI. Human Reproduction Update, 2012. Vol.18, No.4 pp. 350–359.
  5. G. Lambert-Messerlian, L.D., J. Vidaver,J. A. Canick,F. D. Malone,R. H. Ball,C. H. Comstock,D. A. Nyberg,G. Saade,K. Eddleman,S. Klugman,S. D. Craigo,I. E. Timor-Tritsch,S. R. Carr,H. M. Wolfe,M. E. D'Alton, First- and second-trimester Down syndrome screening markers in pregnancies achieved through assisted reproductive technologies (ART): a FASTER trial study. June 2006.