http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2014; 27(14): 1418–1421 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.866644
ORIGINAL ARTICLE
Biochemical screening for aneuploidy in patients with donor oocyte pregnancies compared with autologous pregnancies Simi Gupta1, Nathan S. Fox1,2,3, Andrei Rebarber1,2,3, Daniel H. Saltzman1,2,3, Chad K. Klauser1,2,3, and Ashley S. Roman1,2,3 1
Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, New York, NY, USA, 2Carnegie Imaging for Women, PLLC, New York, NY, USA, and 3Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA
Abstract
Keywords
Objective: The objective was to determine if the rate of abnormal biochemical markers is different in pregnancies conceived by donor oocyte versus those conceived by autologous oocytes. Methods: This is a retrospective cohort study of patients who underwent risk assessment for aneuploidy. Pregnancies conceived by egg donation were matched with control groups who conceived using their own eggs. The primary outcomes were incidence of low PAPP-A or free bHCG in the first trimester or elevated MSAFP, free bHCG or Inhibin A, or low uE3 in the second trimester. Results: 260 singleton gestations were identified who conceived via oocyte donor. There was a significantly higher rate of unexplained elevated MSAFP in pregnancies conceived by egg donation (8% versus 2%, p ¼ 0.028) compared to a control group matched by maternal age. There was also a significantly higher rate of unexplained elevated MSAFP in pregnancies conceived by egg donation (7% versus 2%, p ¼ 0.01) compared to a control group matched by age of the egg donor. Conclusion: Pregnancies conceived by egg donation are more likely to have an unexplained elevation in MSAFP compared to pregnancies not conceived by egg donation regardless of age. Egg donation itself is not associated with other biochemical abnormalities.
Aneuploidy screening, donor egg, MSAFP
Introduction In the United States, impaired fecundity affects approximately 10.9% of women between the ages of 15–44 years [1]. Many women choose or require oocyte donation to achieve fertility, and in 2010 there were 15 504 embryo transfers that used donor oocytes [2]. Pregnancies achieved using donor oocytes appear to be at increased risk of certain obstetric complications such as pregnancy induced hypertension, preterm birth and protracted labor [3,4]. It is recommended that the age of the egg donor be used in calculating a patient’s risk assessment for aneuploidy because it is more accurate in calculating the patient’s risk than using the patient’s age [5]. Aside from aneuploidy screening, the biochemical markers used for the prediction of aneuploidy have been found to be associated with other adverse obstetrical outcomes such as
Address for correspondence: Simi Gupta, Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, Maternal Fetal Medicine Associates, PLLC, 70 East 90th Street, New York, NY 10128, USA. Tel: +713-548-6998. Fax: 212-722-7185. E-mail: [email protected]
History Received 5 June 2013 Revised 31 October 2013 Accepted 13 November 2013 Published online 11 December 2013
preterm birth, intrauterine fetal growth restriction (IUGR), preeclampsia and stillbirth [6]. It is believed that abnormal biochemistry on this screening may represent aberrant placental function, and thus identifies a population of women who might benefit from closer fetal surveillance. While pregnancies conceived via donor eggs appear to be at increased risk of outcomes associated with placental insufficiency, there is little data on whether pregnancies conceived via donor oocytes are at increased risk of having abnormal biochemical markers. The objective of this study was to determine if the rate of abnormal biochemical markers or the screen positive rate for aneuploidy is different in pregnancies conceived by oocyte donation versus pregnancies not conceived by egg donation.
Methods We conducted a retrospective cohort study of women carrying singleton gestations who underwent first and/or second trimester risk assessment for aneuploidy at a single fetal diagnostic center between June 1, 2005 and July 31, 2011. Institutional review board approval was obtained. The study group consisted of patients who underwent first trimester risk assessment for aneuploidy and who conceived
Donor oocyte screening
DOI: 10.3109/14767058.2013.866644
via oocyte donation. Patients were categorized as having conceived by donor oocyte if this was noted on the biochemical screening assay. Patients were excluded from analysis if they were carrying a multiple gestation, or if the fetus had a known abnormal karyotype, open neural tube defect or ventral wall defect. Two control groups were obtained from the remaining cohort of patients using the same exclusion criteria. The first control group (subsequently referred to as control group A) consisted of women carrying singleton gestations with pregnancies conceived spontaneously or via assisted reproduction using autologous oocytes matched by the age of the egg donor in the study group. The second control group (subsequently referred to as control group B) consisted of women carrying singleton gestations with pregnancies conceived spontaneously or via assisted reproduction using autologous eggs matched by the age of the patient at the estimated time of delivery. A subset of the initial study group had to be used for this comparison because of an inability to match patients at the upper end of maternal age who conceived using autologous eggs. Controls were matched to the study group at a ratio of 1:1. All included patients had biochemical screening sent as part of the aneuploidy risk assessment; biochemical assays were performed through Perkin Elmer Labs/NTD (Melville, NY). Biochemical screening for aneuploidy included pregnancy-associated plasma protein-A (PAPP-A) and free beta HCG sent between nine 0/7 and thirteen 6/7 weeks’ gestation and maternal serum alpha-fetoprotein (MSAFP), Inhibin-A, free beta HCG and estriol (uE3) sent between 15 0/7 and 21 6/7 weeks’ gestation. The outcomes of interest were incidence of PAPP-A (5th percentile) and free beta HCG (1st percentile) in the first trimester, and abnormal MSAFP (2.0 MOM), free beta HCG (2.0 MOM), Inhibin A (42.0 MOM) or uE3 (50.5 MOM) in the second trimester. An unexplained elevated biochemical result was defined as any of these abnormal biochemical findings in the presence of a fetus without aneuploidy or, in the case of elevated MSAFP, open neural tube defect or ventral wall defect. The groups were compared
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using Student t-test or Pearson’s Chi-square as appropriate with p50.05 as significance.
Results Between June 1, 2005 and July 31, 2011, 15,167 women underwent first and/or second trimester aneuploidy screening at our institution and 363 of these patients conceived via oocyte donation. Of these 363 patients, 260 were carrying a singleton gestation and underwent aneuploidy screening. All 260 underwent first trimester screening; of these women, two were diagnosed with a fetus with aneuploidy and were excluded from further analysis leaving 258 patients. 197 subsequently completed second trimester screening with the second half of the modified sequential screen and five underwent second trimester screening with MSAFP alone. Demographic characteristics of the patients, including maternal age, age of the oocytes, maternal weight, gestational age at first trimester screening and gestational age at second trimester screening were compared between the study groups and control groups A and B. As expected, there was a significant difference in the age of the patient between the study group and control group A (40.4 versus 30.3 years, p50.001), however no other significant differences were noted between the groups. In Table 1, the oocyte donor group (study group) was compared to control group A. There was no difference in the incidence of screen-positive results between the study group and control group A. In Table 2, the study group is compared to control group B. There is a significantly increased incidence of a screen-positive result for Down syndrome in the first and second trimesters. These findings are expected because of the difference in ages used in the risk calculation for aneuploidy. In Table 3, the incidence of abnormal biochemical markers in the study group and control group A is shown. The incidence of abnormal MSAFP 2.0 MOM was significantly increased in the donor oocyte group (7% versus 2%, p ¼ 0.01). There were no significant differences between the study group and control group A for any of the other biochemical markers.
Table 1. Incidence of screen positive results for egg donor group and control group matched by age of egg donor (control group A).
Screen test result Increased Increased Increased Increased
first trimester Down syndrome risk first trimester T18/T13 risk second trimester Down syndrome risk second trimester T18 risk
Conceived via oocyte donation (N ¼ 258) 7 3 2 0
(2.7%) (1.2%) (1%) (n ¼ 197) (0%) (n ¼ 197)
Control group A (N ¼ 258) 6 0 8 1
(2.3%) (0%) (4%) (n ¼ 197) (0.5%) (n ¼ 197)
p 0.779 0.082 0.158 0.606
T18 ¼ trisomy 18; T13 ¼ trisomy 13.
Table 2. Incidence of screen positive results for egg donor group and control group matched by age of egg donor (control group B). Screen test result Increased Increased Increased Increased
first trimester Down syndrome risk first trimester T18/T13 risk second trimester Down syndrome risk second trimester T18 risk
T18, trisomy 18; T13, trisomy 13.
Conceived via oocyte donation (N ¼ 249) 7 3 2 0
(2.8%) (1.2%) (1%) (n ¼ 189) (0%) (n ¼ 189)
Control group B (N ¼ 249) 37 2 12 1
(14.9%) (1.3%) (8%) (n ¼ 150) (0.7%) (n ¼ 150)
p 50.001 0.653 0.004 0.908
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J Matern Fetal Neonatal Med, 2014; 27(14): 1418–1421
Table 3. Incidence of abnormal biochemical markers for egg donor group and control group matched by age of egg donor (control group A). Biochemical marker PAPP-A ( 5%) First trimester free beta hCG ( 1%) MSAFP (2.0 MOM) Second trimester hCG (2.0 MOM) uE3 (50.5MOM) Inhibin A (42.0 MOM)
Pregnancies conceived via oocyte donation 15 (6%) 2 (1%) 15 (7%) 32 (16%) 2 (1%) 20 (10%)
(n ¼ 258) (n ¼ 258) (n ¼ 202) (n ¼ 197) (n ¼ 197) (n ¼ 197)
Control group A 13 (5%) 2 (1%) 4 (2%) 21 (11%) 1 (1%) 14 (7%)
(n ¼ 258) (n ¼ 258) (n ¼ 202) (n ¼ 198) (n ¼ 195) (n ¼ 195)
p 0.698 1.0 0.010 0.1 0.568 0.296
PAPP-A, pregnancy-associated plasma protein-A; hCG, human chorionic gonadotropin; MSAFP, maternal serum alphafetoprotein; uE3, estriol.
Table 4. Incidence of abnormal biochemical markers for egg donor group and control group matched by age of the patient (control group B). Biochemical marker PAPP-A (5%) First trimester free beta-hCG (1%) MSAFP (2.0 MOM) Second trimester hCG (2.0 MOM) uE3 (50.5MOM) Inhibin A (42.0 MOM)
Pregnancies conceived via oocyte donation 14 (6%) 2 (1%) 15 (8%) 32 (17%) 2 (1%) 20 (11%)
(n ¼ 249) (n ¼ 249) (n ¼ 194) (n ¼ 189) (n ¼ 189) (n ¼ 189)
Control group B 15 (6%) 2 (1%) 4 (2%) 17 (11%) 1 (1%) 11 (7%)
(n ¼ 249) (n ¼ 249) (n ¼ 162) (n ¼ 152) (n ¼ 150) (n ¼ 150)
p 0.848 1.0 0.028 0.133 0.702 0.303
PAPP-A, pregnancy-associated plasma protein-A; hCG, human chorionic gonadotropin; MSAFP, maternal serum alphafetoprotein; uE3, estriol.
In Table 4, the incidence of abnormal biochemical markers in the study group and control group B is shown. Again, the incidence of abnormal MSAFP 2.0 MOM was significantly increased in the donor oocyte group (8% versus 2%, p ¼ 0.028). There were no significant differences between the study group and control group B for any of the other biochemical markers in this comparison as well.
Discussion This study is a large retrospective cohort study evaluating the rate of abnormal biochemical markers used for aneuploidy screening in patients who conceive via donor oocytes. Our study shows that women who conceive with donor oocytes are significantly more likely to have an unexplained elevated MSAFP result than women who conceive via autologous oocytes. This finding remained statistically significant when patients were matched both by the age of the egg donor and the age of the patient at the time of delivery. Since patients were excluded in the case of known abnormal karyotype or open neural tube defect and ventral wall defect, this represents unexplained elevations in MSAFP results for these fetal anomalies. In addition, this study shows that women who conceive via egg donation are significantly less likely to have a false positive result for increased risk of Down syndrome when compared to women who are matched by maternal age at the time of delivery, but no difference when compared to women who are matched by the age of the egg donor. This reflects the recommendation to use the age of the egg donor to calculate aneuploidy risk for patients who conceive via egg donation. Our results are similar to several other studies that compared donor oocytes to a control group and found significantly higher levels of MSAFP MoM in pregnancies conceived using donor eggs [5,7–10]. However, unlike prior
studies, our study found no difference in Inhibin A levels [7], uE3 prior to adjustment for gravidity [9], beta HCG in the first trimester [11] or beta HCG in the second trimester [5]. One major difference between these other studies and ours is that we evaluated each biochemical marker as a categorical variable instead of comparing them as continuous variables. We chose to study the data in this manner as these categorical cutoffs are used clinically and therefore are more meaningful as an outcome in a study such as ours [6]. The second major difference between our study and previously published data is that our control groups were matched by age of the egg donor as well as the age of the patient. Since there is usually a significant difference in maternal and donor ages in studies that evaluate oocyte donation, controlling for age is important in order to separate differences due to maternal age from differences due to the oocyte. Our findings are consistent with prior studies that showed no significant differences in screen positive results for aneuploidy when matched by age of egg donor [7,8,10,11]. However, our study contributes new data demonstrating an increased risk for unexplained elevations in MSAFP in pregnancies conceived using donor eggs independent of maternal age or age of the egg donor. Elevated MSAFP in the absence of fetal structural malformation has been shown to be an early marker of placental insufficiency. MSAFP is produced by the fetal yolk sac, liver and gastrointestinal tract. It is then excreted by the fetal kidneys into the fetal urine and transported into the maternal serum through the placenta. The exact role of AFP is unknown but is thought to be related to immunoregulation, carrier/transport functions and growth regulation [12]. Elevations in MSAFP have been associated with a number of adverse outcomes, particularly outcomes mediated by abnormal placental function such as preeclampsia, fetal loss and intrauterine growth restriction [6]. It has been theorized
Donor oocyte screening
DOI: 10.3109/14767058.2013.866644
that abnormal placental implantation or subsequent disruption of the fetal–maternal–placental barrier via placental vascular damage or ischemia may be related to some of these adverse outcomes [6]. Aberrant immunoregulation or vascular disruption of the maternal–placental interface in pregnancies conceived using donor oocytes may explain why MSAFP is increased in our study population. Our findings mirror the conclusion of other studies in which pregnancies conceived via donor oocytes were found to be at increased risk of preeclampsia and IUGR, outcomes linked to abnormal placentation. However, the association of elevated MSAFP with outcomes associated with abnormal placentation in this population has yet to be determined. Our study has several strengths. One of the main strengths is the large sample size of our population. With 258 patients, this number exceeds the number studied in all prior published studies combined [5,7–10]. We also matched our control group by both age of the patient and age of the oocyte donor. This ensures that differences seen between the donor and autologous oocyte groups are not confounded by age. Finally, we compared groups by rate of abnormal results instead of by differences in mean MoM. The cut-offs we used to define abnormal are those that are commonly used as clinically significant. Therefore, our study reflects clinically significant differences and similarities. Our study also had some limitations, the main ones being that we could not confirm through medical record review donor oocyte status for all of the patients in our study group and could not differentiate between patients who used assisted reproduction treatments versus natural conception in our control groups of patients with autologous oocytes. This is because many patients were referred to our center only for genetic screening and not full prenatal care. Also, we excluded patients carrying multiple gestations at the time of the first and second trimester screening, but we were unable to take into consideration patients who may have had multiple embryos transferred followed by either failure of implantation or early loss of one or more embryos. In summary, our study demonstrates that patients who conceive via donor oocytes have higher rates of unexplained elevations in MSAFP in the second trimester, but similar rates of the other first and second trimester biochemical markers used for aneuploidy screening. When matched with a control
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group by the age of the oocyte donor, our study showed no differences between the two groups of patients in rates of false positives for aneuploidy screening. However, the differences in rate of abnormal MSAFP may be important for physicians who are using the biochemical markers as predictors of adverse outcomes.
Declaration of interest The authors report no declarations of interest
References 1. Infertility. Centers for Disease Control and Prevention. 2006–2010. Available from: http://www.cdc.gov/nchs/fastats/fertile.htm [last accessed 3 Jun 2013]. 2. Clinic Summary Report. Society for Assisted Reproductive Technology. 2010. Available from: https://www.sartcorsonline. com/rptCSR_PublicMultYear.aspx?ClinicPKID¼0 [last accessed 3 Jun 2013]. 3. Henne MB, Zhang M, Paroski S, et al. Comparison of obstetric outcomes in recipients of donor oocytes vs. women of advanced maternal age with autologous oocytes. J Reprod Med 2007;52: 585–90. 4. Wiggins DA, Main E. Outcomes of pregnancies achieved by donor egg in vitro fertilization – a comparison with standard in vitro fertilization pregnancies. Am J Obstet Gyncol 2005;192:2002–6. 5. Donnenfeld AE, Icke KV, Pargas C, Dowman C. Biochemical screening for aneuploidy in ovum donor pregnancies. Am J Obstet Gynecol 2002;187:1222–5. 6. Dugoff L. Society for Maternal-Fetal Medicine. First- and secondtrimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol 2010;115:1052–61. 7. Lambert-Messerlian G, Dugoff L, Vidaver J, et al. First- and second-trimester Down syndrome screening markers in pregnancies achieved through assisted reproductive technologies (ART): a FASTER trial study. Prenat Diagn 2006;26:672–8. 8. Maymon R, Shulman A. Comparison of triple serum screening and pregnancy outcome in oocyte donation versus IVF pregnancies. Hum Reprod 2011;16:691–5. 9. Barkai G, Goldman B, Ries L, et al. Down’s syndrome screening marker levels following assisted reproduction. Prenat Diagn 1996; 16:1111–14. 10. Shulman A, Maymon R. Mid-gestation Down syndrome screening test and pregnancy outcome among unstimulated assisted-conception pregnancies. Prenat Diagn 2003;23:625–8. 11. Bellver J, Lara C, Soares SR, et al. First trimester biochemical screening for Down’s syndrome in singleton pregnancies conceived by assisted reproduction. Hum Reprod 2005;20:2623–7. 12. Mizejewski GJ. Physiology of alpha-fetoprotein as a biomarker for perinatal distress: relevance to adverse pregnancy outcome. Exp Biol Med (Maywood) 2007;232:993–1004.
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ORIGINAL ARTICLE
Biochemical screening for aneuploidy in patients with donor oocyte pregnancies compared with autologous pregnancies Simi Gupta1, Nathan S. Fox1,2,3, Andrei Rebarber1,2,3, Daniel H. Saltzman1,2,3, Chad K. Klauser1,2,3, and Ashley S. Roman1,2,3 1
Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, New York, NY, USA, 2Carnegie Imaging for Women, PLLC, New York, NY, USA, and 3Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA
Abstract
Keywords
Objective: The objective was to determine if the rate of abnormal biochemical markers is different in pregnancies conceived by donor oocyte versus those conceived by autologous oocytes. Methods: This is a retrospective cohort study of patients who underwent risk assessment for aneuploidy. Pregnancies conceived by egg donation were matched with control groups who conceived using their own eggs. The primary outcomes were incidence of low PAPP-A or free bHCG in the first trimester or elevated MSAFP, free bHCG or Inhibin A, or low uE3 in the second trimester. Results: 260 singleton gestations were identified who conceived via oocyte donor. There was a significantly higher rate of unexplained elevated MSAFP in pregnancies conceived by egg donation (8% versus 2%, p ¼ 0.028) compared to a control group matched by maternal age. There was also a significantly higher rate of unexplained elevated MSAFP in pregnancies conceived by egg donation (7% versus 2%, p ¼ 0.01) compared to a control group matched by age of the egg donor. Conclusion: Pregnancies conceived by egg donation are more likely to have an unexplained elevation in MSAFP compared to pregnancies not conceived by egg donation regardless of age. Egg donation itself is not associated with other biochemical abnormalities.
Aneuploidy screening, donor egg, MSAFP
Introduction In the United States, impaired fecundity affects approximately 10.9% of women between the ages of 15–44 years [1]. Many women choose or require oocyte donation to achieve fertility, and in 2010 there were 15 504 embryo transfers that used donor oocytes [2]. Pregnancies achieved using donor oocytes appear to be at increased risk of certain obstetric complications such as pregnancy induced hypertension, preterm birth and protracted labor [3,4]. It is recommended that the age of the egg donor be used in calculating a patient’s risk assessment for aneuploidy because it is more accurate in calculating the patient’s risk than using the patient’s age [5]. Aside from aneuploidy screening, the biochemical markers used for the prediction of aneuploidy have been found to be associated with other adverse obstetrical outcomes such as
Address for correspondence: Simi Gupta, Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, Maternal Fetal Medicine Associates, PLLC, 70 East 90th Street, New York, NY 10128, USA. Tel: +713-548-6998. Fax: 212-722-7185. E-mail: [email protected]
History Received 5 June 2013 Revised 31 October 2013 Accepted 13 November 2013 Published online 11 December 2013
preterm birth, intrauterine fetal growth restriction (IUGR), preeclampsia and stillbirth [6]. It is believed that abnormal biochemistry on this screening may represent aberrant placental function, and thus identifies a population of women who might benefit from closer fetal surveillance. While pregnancies conceived via donor eggs appear to be at increased risk of outcomes associated with placental insufficiency, there is little data on whether pregnancies conceived via donor oocytes are at increased risk of having abnormal biochemical markers. The objective of this study was to determine if the rate of abnormal biochemical markers or the screen positive rate for aneuploidy is different in pregnancies conceived by oocyte donation versus pregnancies not conceived by egg donation.
Methods We conducted a retrospective cohort study of women carrying singleton gestations who underwent first and/or second trimester risk assessment for aneuploidy at a single fetal diagnostic center between June 1, 2005 and July 31, 2011. Institutional review board approval was obtained. The study group consisted of patients who underwent first trimester risk assessment for aneuploidy and who conceived
Donor oocyte screening
DOI: 10.3109/14767058.2013.866644
via oocyte donation. Patients were categorized as having conceived by donor oocyte if this was noted on the biochemical screening assay. Patients were excluded from analysis if they were carrying a multiple gestation, or if the fetus had a known abnormal karyotype, open neural tube defect or ventral wall defect. Two control groups were obtained from the remaining cohort of patients using the same exclusion criteria. The first control group (subsequently referred to as control group A) consisted of women carrying singleton gestations with pregnancies conceived spontaneously or via assisted reproduction using autologous oocytes matched by the age of the egg donor in the study group. The second control group (subsequently referred to as control group B) consisted of women carrying singleton gestations with pregnancies conceived spontaneously or via assisted reproduction using autologous eggs matched by the age of the patient at the estimated time of delivery. A subset of the initial study group had to be used for this comparison because of an inability to match patients at the upper end of maternal age who conceived using autologous eggs. Controls were matched to the study group at a ratio of 1:1. All included patients had biochemical screening sent as part of the aneuploidy risk assessment; biochemical assays were performed through Perkin Elmer Labs/NTD (Melville, NY). Biochemical screening for aneuploidy included pregnancy-associated plasma protein-A (PAPP-A) and free beta HCG sent between nine 0/7 and thirteen 6/7 weeks’ gestation and maternal serum alpha-fetoprotein (MSAFP), Inhibin-A, free beta HCG and estriol (uE3) sent between 15 0/7 and 21 6/7 weeks’ gestation. The outcomes of interest were incidence of PAPP-A (5th percentile) and free beta HCG (1st percentile) in the first trimester, and abnormal MSAFP (2.0 MOM), free beta HCG (2.0 MOM), Inhibin A (42.0 MOM) or uE3 (50.5 MOM) in the second trimester. An unexplained elevated biochemical result was defined as any of these abnormal biochemical findings in the presence of a fetus without aneuploidy or, in the case of elevated MSAFP, open neural tube defect or ventral wall defect. The groups were compared
1419
using Student t-test or Pearson’s Chi-square as appropriate with p50.05 as significance.
Results Between June 1, 2005 and July 31, 2011, 15,167 women underwent first and/or second trimester aneuploidy screening at our institution and 363 of these patients conceived via oocyte donation. Of these 363 patients, 260 were carrying a singleton gestation and underwent aneuploidy screening. All 260 underwent first trimester screening; of these women, two were diagnosed with a fetus with aneuploidy and were excluded from further analysis leaving 258 patients. 197 subsequently completed second trimester screening with the second half of the modified sequential screen and five underwent second trimester screening with MSAFP alone. Demographic characteristics of the patients, including maternal age, age of the oocytes, maternal weight, gestational age at first trimester screening and gestational age at second trimester screening were compared between the study groups and control groups A and B. As expected, there was a significant difference in the age of the patient between the study group and control group A (40.4 versus 30.3 years, p50.001), however no other significant differences were noted between the groups. In Table 1, the oocyte donor group (study group) was compared to control group A. There was no difference in the incidence of screen-positive results between the study group and control group A. In Table 2, the study group is compared to control group B. There is a significantly increased incidence of a screen-positive result for Down syndrome in the first and second trimesters. These findings are expected because of the difference in ages used in the risk calculation for aneuploidy. In Table 3, the incidence of abnormal biochemical markers in the study group and control group A is shown. The incidence of abnormal MSAFP 2.0 MOM was significantly increased in the donor oocyte group (7% versus 2%, p ¼ 0.01). There were no significant differences between the study group and control group A for any of the other biochemical markers.
Table 1. Incidence of screen positive results for egg donor group and control group matched by age of egg donor (control group A).
Screen test result Increased Increased Increased Increased
first trimester Down syndrome risk first trimester T18/T13 risk second trimester Down syndrome risk second trimester T18 risk
Conceived via oocyte donation (N ¼ 258) 7 3 2 0
(2.7%) (1.2%) (1%) (n ¼ 197) (0%) (n ¼ 197)
Control group A (N ¼ 258) 6 0 8 1
(2.3%) (0%) (4%) (n ¼ 197) (0.5%) (n ¼ 197)
p 0.779 0.082 0.158 0.606
T18 ¼ trisomy 18; T13 ¼ trisomy 13.
Table 2. Incidence of screen positive results for egg donor group and control group matched by age of egg donor (control group B). Screen test result Increased Increased Increased Increased
first trimester Down syndrome risk first trimester T18/T13 risk second trimester Down syndrome risk second trimester T18 risk
T18, trisomy 18; T13, trisomy 13.
Conceived via oocyte donation (N ¼ 249) 7 3 2 0
(2.8%) (1.2%) (1%) (n ¼ 189) (0%) (n ¼ 189)
Control group B (N ¼ 249) 37 2 12 1
(14.9%) (1.3%) (8%) (n ¼ 150) (0.7%) (n ¼ 150)
p 50.001 0.653 0.004 0.908
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J Matern Fetal Neonatal Med, 2014; 27(14): 1418–1421
Table 3. Incidence of abnormal biochemical markers for egg donor group and control group matched by age of egg donor (control group A). Biochemical marker PAPP-A ( 5%) First trimester free beta hCG ( 1%) MSAFP (2.0 MOM) Second trimester hCG (2.0 MOM) uE3 (50.5MOM) Inhibin A (42.0 MOM)
Pregnancies conceived via oocyte donation 15 (6%) 2 (1%) 15 (7%) 32 (16%) 2 (1%) 20 (10%)
(n ¼ 258) (n ¼ 258) (n ¼ 202) (n ¼ 197) (n ¼ 197) (n ¼ 197)
Control group A 13 (5%) 2 (1%) 4 (2%) 21 (11%) 1 (1%) 14 (7%)
(n ¼ 258) (n ¼ 258) (n ¼ 202) (n ¼ 198) (n ¼ 195) (n ¼ 195)
p 0.698 1.0 0.010 0.1 0.568 0.296
PAPP-A, pregnancy-associated plasma protein-A; hCG, human chorionic gonadotropin; MSAFP, maternal serum alphafetoprotein; uE3, estriol.
Table 4. Incidence of abnormal biochemical markers for egg donor group and control group matched by age of the patient (control group B). Biochemical marker PAPP-A (5%) First trimester free beta-hCG (1%) MSAFP (2.0 MOM) Second trimester hCG (2.0 MOM) uE3 (50.5MOM) Inhibin A (42.0 MOM)
Pregnancies conceived via oocyte donation 14 (6%) 2 (1%) 15 (8%) 32 (17%) 2 (1%) 20 (11%)
(n ¼ 249) (n ¼ 249) (n ¼ 194) (n ¼ 189) (n ¼ 189) (n ¼ 189)
Control group B 15 (6%) 2 (1%) 4 (2%) 17 (11%) 1 (1%) 11 (7%)
(n ¼ 249) (n ¼ 249) (n ¼ 162) (n ¼ 152) (n ¼ 150) (n ¼ 150)
p 0.848 1.0 0.028 0.133 0.702 0.303
PAPP-A, pregnancy-associated plasma protein-A; hCG, human chorionic gonadotropin; MSAFP, maternal serum alphafetoprotein; uE3, estriol.
In Table 4, the incidence of abnormal biochemical markers in the study group and control group B is shown. Again, the incidence of abnormal MSAFP 2.0 MOM was significantly increased in the donor oocyte group (8% versus 2%, p ¼ 0.028). There were no significant differences between the study group and control group B for any of the other biochemical markers in this comparison as well.
Discussion This study is a large retrospective cohort study evaluating the rate of abnormal biochemical markers used for aneuploidy screening in patients who conceive via donor oocytes. Our study shows that women who conceive with donor oocytes are significantly more likely to have an unexplained elevated MSAFP result than women who conceive via autologous oocytes. This finding remained statistically significant when patients were matched both by the age of the egg donor and the age of the patient at the time of delivery. Since patients were excluded in the case of known abnormal karyotype or open neural tube defect and ventral wall defect, this represents unexplained elevations in MSAFP results for these fetal anomalies. In addition, this study shows that women who conceive via egg donation are significantly less likely to have a false positive result for increased risk of Down syndrome when compared to women who are matched by maternal age at the time of delivery, but no difference when compared to women who are matched by the age of the egg donor. This reflects the recommendation to use the age of the egg donor to calculate aneuploidy risk for patients who conceive via egg donation. Our results are similar to several other studies that compared donor oocytes to a control group and found significantly higher levels of MSAFP MoM in pregnancies conceived using donor eggs [5,7–10]. However, unlike prior
studies, our study found no difference in Inhibin A levels [7], uE3 prior to adjustment for gravidity [9], beta HCG in the first trimester [11] or beta HCG in the second trimester [5]. One major difference between these other studies and ours is that we evaluated each biochemical marker as a categorical variable instead of comparing them as continuous variables. We chose to study the data in this manner as these categorical cutoffs are used clinically and therefore are more meaningful as an outcome in a study such as ours [6]. The second major difference between our study and previously published data is that our control groups were matched by age of the egg donor as well as the age of the patient. Since there is usually a significant difference in maternal and donor ages in studies that evaluate oocyte donation, controlling for age is important in order to separate differences due to maternal age from differences due to the oocyte. Our findings are consistent with prior studies that showed no significant differences in screen positive results for aneuploidy when matched by age of egg donor [7,8,10,11]. However, our study contributes new data demonstrating an increased risk for unexplained elevations in MSAFP in pregnancies conceived using donor eggs independent of maternal age or age of the egg donor. Elevated MSAFP in the absence of fetal structural malformation has been shown to be an early marker of placental insufficiency. MSAFP is produced by the fetal yolk sac, liver and gastrointestinal tract. It is then excreted by the fetal kidneys into the fetal urine and transported into the maternal serum through the placenta. The exact role of AFP is unknown but is thought to be related to immunoregulation, carrier/transport functions and growth regulation [12]. Elevations in MSAFP have been associated with a number of adverse outcomes, particularly outcomes mediated by abnormal placental function such as preeclampsia, fetal loss and intrauterine growth restriction [6]. It has been theorized
Donor oocyte screening
DOI: 10.3109/14767058.2013.866644
that abnormal placental implantation or subsequent disruption of the fetal–maternal–placental barrier via placental vascular damage or ischemia may be related to some of these adverse outcomes [6]. Aberrant immunoregulation or vascular disruption of the maternal–placental interface in pregnancies conceived using donor oocytes may explain why MSAFP is increased in our study population. Our findings mirror the conclusion of other studies in which pregnancies conceived via donor oocytes were found to be at increased risk of preeclampsia and IUGR, outcomes linked to abnormal placentation. However, the association of elevated MSAFP with outcomes associated with abnormal placentation in this population has yet to be determined. Our study has several strengths. One of the main strengths is the large sample size of our population. With 258 patients, this number exceeds the number studied in all prior published studies combined [5,7–10]. We also matched our control group by both age of the patient and age of the oocyte donor. This ensures that differences seen between the donor and autologous oocyte groups are not confounded by age. Finally, we compared groups by rate of abnormal results instead of by differences in mean MoM. The cut-offs we used to define abnormal are those that are commonly used as clinically significant. Therefore, our study reflects clinically significant differences and similarities. Our study also had some limitations, the main ones being that we could not confirm through medical record review donor oocyte status for all of the patients in our study group and could not differentiate between patients who used assisted reproduction treatments versus natural conception in our control groups of patients with autologous oocytes. This is because many patients were referred to our center only for genetic screening and not full prenatal care. Also, we excluded patients carrying multiple gestations at the time of the first and second trimester screening, but we were unable to take into consideration patients who may have had multiple embryos transferred followed by either failure of implantation or early loss of one or more embryos. In summary, our study demonstrates that patients who conceive via donor oocytes have higher rates of unexplained elevations in MSAFP in the second trimester, but similar rates of the other first and second trimester biochemical markers used for aneuploidy screening. When matched with a control
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group by the age of the oocyte donor, our study showed no differences between the two groups of patients in rates of false positives for aneuploidy screening. However, the differences in rate of abnormal MSAFP may be important for physicians who are using the biochemical markers as predictors of adverse outcomes.
Declaration of interest The authors report no declarations of interest
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