Theeffect of fetal gender on the markers of first trimester Down syndrome screening

Objective

The aim of this study was to investigate the effect of fetal gender on first trimester Down syndrome screening markers

Methods

256 pregnancies in that fetal nuchal translucency and maternal serum free β-hCG and PAPP-A were evaluated and delivered in our clinics were included in the study. We investigated if these markers differed on the basis of fetal gender.

Results

Fetal nuchal translucency was measured 0.11 mm more in male fetuses than in female fetuses (P = 0.026). Although
free β-hCG and PAPP-A levels were higher in female fetuses the difference was not statistically significant.

Conclusion

The data of previous literature and the results of the present study suggest that first trimester markers differ on the
basis of fetal gender, however it has no clinical meaning

Keywords

First trimester Down syndrome screening, fetal gender.

Introduction

At present, the most effective trisomy 21 screening method is the estimate of risk combining maternal age, fetal nucal translucence and serum free β- human-corionic-gonadotropin (β-HCG) and pregnancy- associated plasma protein-A (PAPP-A),  which were performed at weeks 11 and 14. In prospective studies, it has been observed that false 
positivity was 5% while determination rate for trisomy 21 was 90%, which, in fact, was superior to the maternal age only (35%), or combination of thematernal age and the second trimester serum biochemical markers (65%).(1,2)
 As already known, adjustments are required particularly in the interpretation of biochemical tests depending on the maternal age, gestational age, maternal weight, multiple pregnancy and presence of diabetes mellitus. In the meantime, a recent study suggested that ethnical origin should be taken into consideration while interpreting the nucal translucence.(3) It has been proposed that gender also should be taken into consideration during the measurement of nucal thickness, and in case  where the fetal gender can be determined, correction would be necessary accordingly.(4 )
Later studies have shown that NT is not the only marker which is affected by the gender, but β-HCG and probably PAPP-A are also related to the fetal gender. If there is really such a divergence in the markers of the first trimester Down syndrome, then it is obvious that the sensitivity and specificity values of these screening tests would also be changing.
The objective of our study was to investigate the impact of fetal gender on the first trimester Down syndrome screening markers in our population. 

Methods

256 patients, who had complete records of first trimester serum screening and fetal NT between 11th and 14th week of pregnancy and in whom gender was confirmed after delivery, were included in this retrospective study. All pregnancies were single and no problem was observed during pregnancy and delivery. Patients identified with chromosomal abnormalities in screening tests and patients in whom gender was identified by only sonography and patients who were lost to follow up were excluded.
According to clinical protocol, invasive diagnostic interventions were applied if any abnormality was identified in screeening tests of pregnant woman at the age of 39 or less. Fetal NT measurements were performed by specialists in our clinic and in measurements, the method recommended by Nicolaides5 was used. In brief, fetal CRL was measured first, by using 5 MHz transabdominal probe with videoloop function (GE Logic 500, Milwaukee, USA). After differentiating the posterior wall of the neck from amnion, markers were located in the inner part. In sagittal cross sections of the fetuses (with a CRL of 45-84 mm) NT measurements were done under magnification in which distance varied 0.1 mm by every movement of the marker. In serum screening, free b-hCG and PAPP-A measurements were performed with Immulite (BioDPC, İstanbul) device by using solid phase, chemiluminescence immunometric sandwich method. MoM values and adjusted risk was calculated by Prisca 4.0 package screening programme (Typolog Software GmBH, Germany).
Data analysis were performed by SPSS 9.0 (SPSS Inc. Chicago, IL). Student t test was used for comparison of MoM values of biochemical markers and for NT measurements in mm. P value of 0.05 and less was considered to be significant.

Results

Of the 256 babies whose gender were identified and first trimester records were complete, 159 were female and 117 were male. Baseline characteristics of these fetuses at the time of testing are summarized in Table 1. Male and female fetuses showed no difference in terms of maternal age, weight at the time of testing and mean gestational week (p>0.05). None of the mothers had type 1 or type 2 diabetes. Mothers of 8 female and 9 male fetuses were smokers at the time of testing (p=0.54). Although the number of male fetuses whose combination risk was found to be 1/270 or less and who demonstrated normal chromosomal structure in the amniosynthesis, was slightly higher, there were no statistically significant difference (Table 1)
In Table 2 fetal NT maternal serum free b-hCG and PAPP-A values are compared according to the gender of the fetuses. Fetal NT measurements of male fetuses were found to be 0.11 mm in average which was higher than female fetuses and the difference was statistically significant (p=0.026). However there was no difference between free ß-hCG and PAPP-A levels in terms of fetal gender (p>0.05). 
 

Discussion

PAPP-A is a dimeric structured glycoprotein consisting of two equal subunits. It is found in circulation depending on the eosinophile major binding protein (eMBP). While PAPP-A is secreted from synsitiotrophablastic and septal X cells, eMBP is only secreted from septal X cells. PAPP-A is presented into obstetric practice in Down syndrome screening by Brambati et al.6 hCG is secreted mainly from placental cytotrophoblasts and especially during the advanced period of pregnancy it is secreted from synsitiotrophablasts. After it reaches to maximum maternal serum level in 9-10 weeks it decreases gradually until 20th week and draws a plateau till delivery. It is 15% and 10% respectively (p<0.0001). However in this trial in which combined risk of 1/300 and lower considered to be risky, there was no significant difference in the male and female fetuses who have a risk potential (6.5% vs. 6.9%, p>0.05). In this trial it is observed that female and male fetuses with trisomy 21 have similar differences. In female fetuses mean fetal NT MoM level is found to be 4% lower (p=0.018), mean free ß-hCG and PAPP-A MoM levels are found to be higher in male fetuses (11% and 13% respectively, p>0.001). In our study although the fetal NT level in mm is found to be 8.1% (0.11) higher, there was no difference between ß-hCG and PAPP-A MoM levels (Table 2).
In a study in which 12189 fetusus are included and which is performed in China, fetal NT values of 10-14 week male and female fetuses compared and while in 10 week fetuses there were no differences, it is observed that female fetuses who are in 11-14 week NT thicknesses are 5% lower than males.9 However authors concluded that it is 0.06-0.1 mm and its’ clinical significance is sceptical. In contrast to these, Yaron et al10 from Israel reported that NT and PAPP-A levels showed no differences, free ß-hCG is higher in female fetuses but this difference decreases after the 12 weeks. Larsen et al11 observed that NT is significantly thinner in female fetuses than male fetuses which is consistent with the literature, but free b-hCG and PAPP-A levels are higher. In our study, although the mean free b-hCG and PAPP-A MoM levels are found to be higher in female fetuses, there were no significant difference probably due to lesser patient number.
As a conclusion, it seems that gender has an effect on Down syndrome markers in the first trimester, however its’ clinical significance is not clear. As in our study and in other studies fetal NT values are approximately 0.1 mm higher. In our opinion this difference rarely provides any contribution to the treatment of the fetus. In addition to Spencer et al, we also showed that the sonographic and biochemical parameters did not increase the rate of invasive interventions significantly. Another obstacle in the adjustment of Down syndrome markers according to gender in the first trimester is the limitation of the possibility of gender identification in only 70-90% of fetuses in these weeks.(12,13)

Conclusion

The results of our study and other data suggest that first trimester markers vary according to gender but this has no clinical significance.

References

1. Bindra R, Heath V, Liao AW, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks: a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol 2002; 20: 219-25.
2. Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, et al. First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003; 349: 1405-13.
3. Chen M, Lam YH, Tang MHY, Lee CP, Sin SY, Tang R, Wong HS, Wong SF. The effect of ethnic origin on nuchal translucency at 10-14 weeks of gestation. Prenat Diagn 2002; 22: 576-8.
4. Drugan A, Weissman A, Avrahami R, Zamir R, Evans MI. Sonographic nuchal markers for Down syndrome are more common but less ominous in gestations with a male fetus. Fetal Diagn Ther 2002; 17: 295-7.
5. Nicolaides KH, Heath V, Cicero S. Increased fetal nuchal translucency at 11-14 weeks. Prenat Diagn 2002; 22: 308-15.
6. Brambati B, Macintosh MCM, Teisner B, Maguiness S, Shrimanker K, Lanzani A, Bonacchi I, Tului L, Chard T, Grudzinskas JG. Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype. Brit J Obstet Gynaecol 1993; 100: 324-6.
7. Eldar-Geva T, Hochberg A, deGroot N, Weinstein D. High maternal serum chorionic gonadotropin level in Downs' syndrome pregnancies is caused by elevation of both subunits messenger ribonucleic acid level in trophoblasts. J Clin Endocrinol Metab 1995; 80: 3528-31.
8. Spencer K, Ong CY, Liao AW, Papademetriou D, Nicolaides KH. The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, beta-hCG and PAPP-A at 10–14 weeks of gestation. Prenat Diagn 2000; 20: 673-5.
9. Lam YH, Tang MHY, Lee CP, Sin SY, Tang R, Wong HS, Wong SF. The effect of fetal gender on nuchal translucency at 10-14 weeks of gestation. Prenat Diagn 2001; 21: 627-9.
10. Yaron Y, Wolman I, Kupferminc MJ, Ochshorn Y, Many A, Orr-Urtreger A. Effect of fetal gender on first trimester markers and on Down syndrome screening. Prenat Diagn 2001; 21: 1027-30.
11. Larsen SO, Wojdemann KR, Shalmi AC, Sundberg K, Christiansen M, Tabor A. Gender impact on first trimester markers in Down syndrome screening. Prenat Diagn 2002; 22: 1207-8.
12. Efrat Z, Akinfenwa OO, Nicolaides KH. First trimester determination of fetal gender by ultrasound. Ultrasound Obstet Gynecol 1999; 13: 305-7.
13. Whitlow BJ, Lazanakis MS, Economides DL. The sonographic identication of fetal gender from 11 to 14 weeks of gestation. Ultrasound Obstet Gynecol 1999; 13: 301-4.

	File/Dsecription
	Table 1 The comparison of the features of female and male fetuses (Mean ± SS or n, %)*
	Table 2 The comparison of the first trimester screening results of female and male fetuses (mean ± SS)*