Maternal serum β-hCG levels in screening for Down syndrome are higher in singleton pregnancies achieved with ovulation induction and intrauterine insemination than in spontaneous singleton pregnancies
2001; Elsevier BV; Volume: 76; Issue: 5 Linguagem: Inglês
10.1016/s0015-0282(01)02831-x
ISSN1556-5653
AutoresRaija Räty, Ulla Ekblad, Leena Anttila, Arja Virtanen, Pertti Koskinen, Päivi Laitinen, Aila Tiitinen,
Tópico(s)Ectopic Pregnancy Diagnosis and Management
ResumoIn pregnancies conceived by assisted reproduction technology (ART), the false-positive rate in maternal midtrimester serum screening for Down syndrome is higher (26.8% to 30%) than in spontaneous pregnancies (5%) (1Heinonen S Ryynänen M Kirkinen P Hippeläinen M Saarikoski S Effect of in vitro fertilization on human chorionic gonadotropin serum consentrations and Down’s Syndrome screening.Fertil Steril. 1996; 66: 398-403Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar). In singleton pregnancies conceived after IVF, levels of total or free β-hCG are higher (1Heinonen S Ryynänen M Kirkinen P Hippeläinen M Saarikoski S Effect of in vitro fertilization on human chorionic gonadotropin serum consentrations and Down’s Syndrome screening.Fertil Steril. 1996; 66: 398-403Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar) and levels of alpha-fetoprotein (α-fetoprotein) are slightly lower (2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar) than in spontaneous pregnancies, changes similar to those in Down syndrome pregnancies.Data on the levels of total or free β-hCG and α-fetoprotein in pregnancies started with ovulation induction and IUI are scarce and confusing (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar, 4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar). Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar) found no differences in serum levels of α-fetoprotein between IUI pregnancies and controls, but levels of hCG were higher in the IUI group than in the control group. In contrast, Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar) reported that mothers with IUI pregnancies have significantly lower α-fetoprotein levels than mothers with spontaneously started pregnancies.We sought to assess the effect of medication used before insemination on levels of free β-hCG and α-fetoprotein in IUI pregnancies.The study sample (19,310 pregnancies) was assembled from the Down syndrome screening program between 1996–1998 in four university hospital catchment areas in Finland. The data on outcomes of pregnancies and newborns were collected from national birth, hospital, abortion, and malformation registries.The maternal midtrimester serum levels of α-fetoprotein and β-hCG were measured at weeks 14–18 of pregnancy. Analyses were made by using the two-site fluoroimmunometric DELFIA hAFP/free hCGβ assay (EG&G Wallac, Turku, Finland).The study group consisted of 48 pregnancies started with IUI that has normal outcome. The study group was further divided into three subgroups according to the hormonal treatment used for ovulation induction before IUI. In group 1 (n=19), ovarian stimulation was done by using sequential clomiphene citrate (cycle days 3 to 7). The total dose of clomiphene citrate varied from 250 mg to 750 mg (50 to 150 mg/d). In group 2 (n=20), sequential clomiphene citrate followed by gonadotropins (hMG or recombinant FSH, 75 to 150 IU/d) was used. The dose of clomiphene citrate was the same as in group 1, and the dose of gonadotropins varied from 150 IU to 450 IU. In group 3 (n=9), gonadotropins alone were used for ovulation induction; the total dose varied from 750 to 1575 IU.Gestational age was calculated according to the known date of the IUI. Fourteen days was added to the day of the insemination to update the gestational age of the pregnancy. A singleton pregnancy was verified by ultrasonography performed 5–6 weeks after IUI.Of the total study sample of 19,310 women, we excluded those with congenital and chromosomal anomalies, multifetal pregnancies, and ART pregnancies. Only women with adequate gestational age dating on ultrasonography were enrolled. The control group consisted of 6548 singleton pregnancies with normal outcome.Levels of free β-hCG and α-fetoprotein were first compared between the whole IUI group and controls by using the Wilcoxon or Kruskal–Wallis test. Levels of the markers in each of the three subgroups were then compared with those in controls by using the Wilcoxon test. Free β-hCG and α-fetoprotein multiple of the median levels were reported, as medians with 5% and 95% percentiles. To reduce the risk for type I error associated with multiple comparisons, a P value <.02 was considered significant at 0.05 level (0.05/3 ≅ 0.02) in pairwise comparisons. To adjust for differences in age between the groups, analysis of covariance to log-transformed multiple of the median values was done. All analyses were done by using SAS for Windows, version 6.12 (SAS Institute, Inc., Cary, NC). Institutional review board approval was obtained.The women in the IUI group were slightly older than those in the control group (31.2 years vs. 29.7 years; P=.038), but the age difference did not explain the differences in the marker levels between the groups. The median with 5% and 95% percentiles for free β-hCG and α-fetoprotein multiple of the median levels in the IUI group were 1.29 (0.52, 2.49) and 1.02 (0.78, 2.16), respectively. For β-hCG multiple of the median levels, the difference between the IUI and control groups was statistically significant (0.29, P=.033) (Table 1). Table 1Free β-hCG and α-fetoprotein multiple of the median values in IUI patients and controls.GroupFree β-hCGα-FetoproteinMultiple of the medianMedian differenceaVersus controls.P valueMultiple of the medianMedian differenceaVersus controls.P valueAll IUI patients (n = 48)1.29 (0.52, 2.49)0.29.031.02 (0.78, 2.16)0.02.17Group 1 (n = 19)bClomiphene citrate only.1.15 (0.56, 2.49)0.15.121.02 (0.83, 1.34)0.02.35Group 2 (n = 20)cClomiphene citrate plus hMG.1.66 (0.52, 6.17)0.66.00091.12 (0.81, 2.36)0.12.09Group 3 (n = 9)dHuman menopausal gonadotropin only.0.70 (0.46, 0.92)−0.30.020.86 (0.57, 2.74)−0.14.50Controls (n = 6548)1.00 (0.37, 3.04)1.00 (0.57, 1.79)Data are medians (5th, 95th percentile).Räty. Down syndrome screening in 101 pregnancies. Fertil Steril 2001.a Versus controls.b Clomiphene citrate only.c Clomiphene citrate plus hMG.d Human menopausal gonadotropin only. Open table in a new tab Table 1 shows the medians and 5% and 95% percentiles for free β-hCG and α-fetoprotein values in the three IUI subgroups. Free β-hCG multiple of the median levels tended to be higher in groups 1 and 2 than in controls, but a statistically significant difference in β-hCG levels was observed only between group 2 and controls (P=.0009) (Table 1). In group 3, the free β-hCG multiple of the median level was lower than in controls, but the difference was only marginally significant (P=.024) (Table 1). α-Fetoprotein levels did not differ statistically between any of the three subgroups and controls. Among the IUI pregnancies, five women screened positive, with a risk ratio for Down syndrome greater than 1:250. The false-positive rate was 10.4%; this value is higher than in unaffected pregnancies among whom the false-positive rate is 5%.Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar) analyzed a sample of 1632 women who had used clomiphene citrate or gonadotropins for ovulation induction. They found that total β-hCG levels were significantly higher (multiple of the medians, 1.09) in the ovulation induction group than in the control group of 34,582 spontaneous pregnancies (multiple of the medians, 1.00). Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar) failed to find significant differences in free β-hCG levels between the IUI and spontaneous pregnancy groups, whereas α-fetoprotein levels were significantly reduced in the former patients (multiple of the medians, 0.76). The authors proposed that the differences in the findings could have resulted from use of different laboratory assays: Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar) measured total hCG, whereas Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar) free β-hCG. Our results of analysis of free β-hCG differ from those of Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar), whereas our results concerning α-fetoprotein seem to parallel those of Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar).According to our data, clomiphene citrate seems to elevate serum free β-hCG level, just as it elevates serum total hCG levels (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar). Gonadotropin treatment before IUI was associated with low free β-hCG levels, a finding that agrees with data obtained previously among 67 IVF pregnancies, in which hMG stimulation for IVF was performed without gonadotropin down-regulation (2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar). Because of the small subgroups, no statistically significant changes were observed in the α-fetoprotein multiple of the median levels. However, the trend toward slightly higher α-fetoprotein levels in women using clomiphene citrate and lower levels among those using pure gonadotropin stimulation was similar to the findings reported by Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar).In normal pregnancy, the concentrations of total and free β-hCG decrease in midtrimester. The mechanisms behind elevated hCG levels in Down syndrome pregnancies are still poorly understood. According to one theory, placental immaturity in Down syndrome pregnancies may explain the higher hCG values. The alterations of hCG levels in ART pregnancies are well documented (1Heinonen S Ryynänen M Kirkinen P Hippeläinen M Saarikoski S Effect of in vitro fertilization on human chorionic gonadotropin serum consentrations and Down’s Syndrome screening.Fertil Steril. 1996; 66: 398-403Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar, 3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar). The reason behind this phenomenon is still unknown. The changes in marker levels may reflect the reasons behind infertility, such as placental failure, which, together with the medication, is expressed as alterations in marker levels.In conclusion, false-positive rate on screening for Down syndrome was more than two times higher in IUI pregnancies (10.4%) than in normal pregnancies (5%). False-positive findings result in unnecessary invasive karyotyping procedures and thus increase the risk for miscarriages in IUI pregnancies. Therefore, the patient with IUI pregnancy undergoing serum screening should be informed of the risks of high false-positive rate. In pregnancies conceived by assisted reproduction technology (ART), the false-positive rate in maternal midtrimester serum screening for Down syndrome is higher (26.8% to 30%) than in spontaneous pregnancies (5%) (1Heinonen S Ryynänen M Kirkinen P Hippeläinen M Saarikoski S Effect of in vitro fertilization on human chorionic gonadotropin serum consentrations and Down’s Syndrome screening.Fertil Steril. 1996; 66: 398-403Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar). In singleton pregnancies conceived after IVF, levels of total or free β-hCG are higher (1Heinonen S Ryynänen M Kirkinen P Hippeläinen M Saarikoski S Effect of in vitro fertilization on human chorionic gonadotropin serum consentrations and Down’s Syndrome screening.Fertil Steril. 1996; 66: 398-403Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar) and levels of alpha-fetoprotein (α-fetoprotein) are slightly lower (2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar) than in spontaneous pregnancies, changes similar to those in Down syndrome pregnancies. Data on the levels of total or free β-hCG and α-fetoprotein in pregnancies started with ovulation induction and IUI are scarce and confusing (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar, 4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar). Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar) found no differences in serum levels of α-fetoprotein between IUI pregnancies and controls, but levels of hCG were higher in the IUI group than in the control group. In contrast, Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar) reported that mothers with IUI pregnancies have significantly lower α-fetoprotein levels than mothers with spontaneously started pregnancies. We sought to assess the effect of medication used before insemination on levels of free β-hCG and α-fetoprotein in IUI pregnancies. The study sample (19,310 pregnancies) was assembled from the Down syndrome screening program between 1996–1998 in four university hospital catchment areas in Finland. The data on outcomes of pregnancies and newborns were collected from national birth, hospital, abortion, and malformation registries. The maternal midtrimester serum levels of α-fetoprotein and β-hCG were measured at weeks 14–18 of pregnancy. Analyses were made by using the two-site fluoroimmunometric DELFIA hAFP/free hCGβ assay (EG&G Wallac, Turku, Finland). The study group consisted of 48 pregnancies started with IUI that has normal outcome. The study group was further divided into three subgroups according to the hormonal treatment used for ovulation induction before IUI. In group 1 (n=19), ovarian stimulation was done by using sequential clomiphene citrate (cycle days 3 to 7). The total dose of clomiphene citrate varied from 250 mg to 750 mg (50 to 150 mg/d). In group 2 (n=20), sequential clomiphene citrate followed by gonadotropins (hMG or recombinant FSH, 75 to 150 IU/d) was used. The dose of clomiphene citrate was the same as in group 1, and the dose of gonadotropins varied from 150 IU to 450 IU. In group 3 (n=9), gonadotropins alone were used for ovulation induction; the total dose varied from 750 to 1575 IU. Gestational age was calculated according to the known date of the IUI. Fourteen days was added to the day of the insemination to update the gestational age of the pregnancy. A singleton pregnancy was verified by ultrasonography performed 5–6 weeks after IUI. Of the total study sample of 19,310 women, we excluded those with congenital and chromosomal anomalies, multifetal pregnancies, and ART pregnancies. Only women with adequate gestational age dating on ultrasonography were enrolled. The control group consisted of 6548 singleton pregnancies with normal outcome. Levels of free β-hCG and α-fetoprotein were first compared between the whole IUI group and controls by using the Wilcoxon or Kruskal–Wallis test. Levels of the markers in each of the three subgroups were then compared with those in controls by using the Wilcoxon test. Free β-hCG and α-fetoprotein multiple of the median levels were reported, as medians with 5% and 95% percentiles. To reduce the risk for type I error associated with multiple comparisons, a P value <.02 was considered significant at 0.05 level (0.05/3 ≅ 0.02) in pairwise comparisons. To adjust for differences in age between the groups, analysis of covariance to log-transformed multiple of the median values was done. All analyses were done by using SAS for Windows, version 6.12 (SAS Institute, Inc., Cary, NC). Institutional review board approval was obtained. The women in the IUI group were slightly older than those in the control group (31.2 years vs. 29.7 years; P=.038), but the age difference did not explain the differences in the marker levels between the groups. The median with 5% and 95% percentiles for free β-hCG and α-fetoprotein multiple of the median levels in the IUI group were 1.29 (0.52, 2.49) and 1.02 (0.78, 2.16), respectively. For β-hCG multiple of the median levels, the difference between the IUI and control groups was statistically significant (0.29, P=.033) (Table 1). Data are medians (5th, 95th percentile). Räty. Down syndrome screening in 101 pregnancies. Fertil Steril 2001. Table 1 shows the medians and 5% and 95% percentiles for free β-hCG and α-fetoprotein values in the three IUI subgroups. Free β-hCG multiple of the median levels tended to be higher in groups 1 and 2 than in controls, but a statistically significant difference in β-hCG levels was observed only between group 2 and controls (P=.0009) (Table 1). In group 3, the free β-hCG multiple of the median level was lower than in controls, but the difference was only marginally significant (P=.024) (Table 1). α-Fetoprotein levels did not differ statistically between any of the three subgroups and controls. Among the IUI pregnancies, five women screened positive, with a risk ratio for Down syndrome greater than 1:250. The false-positive rate was 10.4%; this value is higher than in unaffected pregnancies among whom the false-positive rate is 5%. Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar) analyzed a sample of 1632 women who had used clomiphene citrate or gonadotropins for ovulation induction. They found that total β-hCG levels were significantly higher (multiple of the medians, 1.09) in the ovulation induction group than in the control group of 34,582 spontaneous pregnancies (multiple of the medians, 1.00). Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar) failed to find significant differences in free β-hCG levels between the IUI and spontaneous pregnancy groups, whereas α-fetoprotein levels were significantly reduced in the former patients (multiple of the medians, 0.76). The authors proposed that the differences in the findings could have resulted from use of different laboratory assays: Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar) measured total hCG, whereas Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar) free β-hCG. Our results of analysis of free β-hCG differ from those of Hsu et al. (4Hsu T.-Y Ou C.-Y Hsu J.-J Kung F.-T Chang S.-Y Soong Y.-K Maternal serum screening for Down syndrome in pregnancies conceived by intra-uterine insemination.Prenat Diagn. 1999; 19: 1012-1014Crossref PubMed Scopus (15) Google Scholar), whereas our results concerning α-fetoprotein seem to parallel those of Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar). According to our data, clomiphene citrate seems to elevate serum free β-hCG level, just as it elevates serum total hCG levels (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar). Gonadotropin treatment before IUI was associated with low free β-hCG levels, a finding that agrees with data obtained previously among 67 IVF pregnancies, in which hMG stimulation for IVF was performed without gonadotropin down-regulation (2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar). Because of the small subgroups, no statistically significant changes were observed in the α-fetoprotein multiple of the median levels. However, the trend toward slightly higher α-fetoprotein levels in women using clomiphene citrate and lower levels among those using pure gonadotropin stimulation was similar to the findings reported by Barkai et al. (3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar). In normal pregnancy, the concentrations of total and free β-hCG decrease in midtrimester. The mechanisms behind elevated hCG levels in Down syndrome pregnancies are still poorly understood. According to one theory, placental immaturity in Down syndrome pregnancies may explain the higher hCG values. The alterations of hCG levels in ART pregnancies are well documented (1Heinonen S Ryynänen M Kirkinen P Hippeläinen M Saarikoski S Effect of in vitro fertilization on human chorionic gonadotropin serum consentrations and Down’s Syndrome screening.Fertil Steril. 1996; 66: 398-403Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 2Ribbert L.S Kornman L.H De Wolf B.T Simons A.H Jansen C.A Beekhuis J.R et al.Maternal serum screening for fetal Down syndrome in IVF pregnancies.Prenat Diagn. 1996; 16: 35-38Crossref PubMed Scopus (74) Google Scholar, 3Barkai G Goldman B Ries L Chaki R Dor J Cuckle H Down’s Syndrome screening marker levels following assisted reproduction.Prenat Diagn. 1996; 16: 1111-1114Crossref PubMed Scopus (74) Google Scholar). The reason behind this phenomenon is still unknown. The changes in marker levels may reflect the reasons behind infertility, such as placental failure, which, together with the medication, is expressed as alterations in marker levels. In conclusion, false-positive rate on screening for Down syndrome was more than two times higher in IUI pregnancies (10.4%) than in normal pregnancies (5%). False-positive findings result in unnecessary invasive karyotyping procedures and thus increase the risk for miscarriages in IUI pregnancies. Therefore, the patient with IUI pregnancy undergoing serum screening should be informed of the risks of high false-positive rate. The authors thank Pertti Mörsky, Ph.D., Central Laboratory, Tampere University Hospital, for help with data collection and Jari Forsström, M.D., MIRCIT, Turku University, for assistance with data collection and study design.
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