Objective
The objective of the study was to evaluate the efficacy of maternal serum markers in detecting Down syndrome after 18 weeks of gestation in women who book late for maternity care in a large national retrospective study.
Study Design
During the period 2007-2012, 27,648 women, regardless of maternal age (17.4% were 35 years old and over), were included in a late Down syndrome screening program (18 +0 to 35 +6 weeks) using the maternal serum markers alpha-fetoprotein and human chorionic gonadotrophin-beta. Samples were assayed in a single laboratory. A dataset of median markers previously established in our laboratory was used for risk calculation. The control group consisted of 27,648 women (14 +0 to 17 +6 weeks) randomly selected from the routine database.
Results
When the later screening group was compared with the standard second-trimester control group, the median multiples of medians (1.01 vs 0.98 for alpha-fetoprotein, 1.03 vs 0.98 for human chorionic gonadotrophin-beta), median risks (1 of 2414 vs 1 of 2720), false-positive rates (11.1% vs 11.6%), and trisomy 21 detection rates (83.3% vs 85.7%) did not differ significantly.
Conclusion
Late Down syndrome maternal serum screening is feasible with a good sensitivity/specificity compromise throughout gestation and is of clinical value in late-booking women.
Down syndrome (DS) screening based on maternal serum markers was initially described at 14 +0 to 18 weeks of gestation. The efficacy of this screening has been largely demonstrated, and in recent years this screening has been focused on the first trimester. In France, Down syndrome screening is organized on a national scale and is offered to every pregnant woman.
Maternal serum screening concerns 85% of the 820,000 women pregnant in any given year. The specific regulation for this screening stipulates the sampling period: from 14 +0 to 17 +6 weeks for second-trimester screening and, since 2009, from 11 +0 to 13 +6 weeks for first-trimester screening. However, pregnant women who have access to prenatal care only later in pregnancy may still wish to undergo this screening.
In France, about 6.6% of pregnant women have their first prenatal visit during the second trimester and 1.2% during the third trimester and therefore do not undergo prenatal screening for DS. Most of these are in socially deprived situations.
Programs have been implemented locally to promote early access to prenatal care, but despite these efforts, the number of late-booking women remains high. Using a dataset previously established in our laboratory and adapted to new software, we studied the efficacy of DS screening in a large series of 27,648 late-booking women (after 18 weeks of gestation) to provide solid results for the information given to such women.
Materials and Methods
This retrospective study was conducted in our laboratory using the database of women included in second-trimester DS maternal serum marker screening during the period 2007-2012. Twin pregnancies were excluded. Two groups of women were defined: (1) the late screening group (LS group) of the 27,648 women included in a late screening program (18 +0 to 35 +6 weeks of gestation) and (2) a control group of 27,648 women (14 +0 to 17 +6 weeks) randomly selected from the routine database. No matching was done to allow comparison of maternal age and other confounding factors in the 2 groups. In the vast majority of controls, pregnancy dating was based on first-trimester ultrasound crown-rump length measurement, but when pregnancy was discovered later, dating was based on the last menstrual period or biparietal diameter measurement.
Parameters taken into account in the risk calculation were recorded in the database: maternal age, maternal weight, and smoking status. Markers were human chorionic gonadotrophin-beta (hCGβ) and alpha-fetoprotein (AFP) (Dualkit; AutoDelfia, PerkinElmer, Turku, Finland). Results were expressed in multiple of median (MoM) corrected for maternal weight and smoking status.
We adapted our published reference values for AFP and hCGβ between 18 +0 and 35 +6 weeks (Multicalc Wallac software) for LifeCycle software (PerkinElmer, Turku, Finland). The reference medians were checked every trimester. DS risk calculation (LifeCycle) was based on a combination of maternal age and maternal serum markers, with a decision cutoff at 1:250. Pregnancy outcomes were recorded, especially fetal karyotyping for at-risk women or karyotyping at birth if DS was clinically suspected.
In accordance with French law, informed consent for biochemical testing was obtained from each woman prior to blood sampling as part of routine antenatal care. If amniocentesis was performed, a second written consent was needed for fetal karyotyping.
The Mann-Whitney test was used for MoM comparisons and Student t test for quantitative variables. The χ 2 test was used for comparison of percentages. P < .05 was considered as significant.
Results
Table 1 presents a description of the database. Median gestational age at sampling was 20.4 weeks in the LS group and 15.4 weeks in the control group, a 5 week difference. Median maternal age was 28 years (range, 13–52 years) in the LS group, significantly younger than in the control group ( P < .0001). The percentage of women smoking during pregnancy was significantly higher in the LS group (17.1% vs 12.4% in the control group, P < .0001). The maternal weight was higher in the LS group corresponding to the normal increase in the weight of pregnant women over the 5 week difference.
| Demographic | Control group (14 +0 to 17 +6 wks) (n = 27,648) | LS group (18 +0 to 35 +6 wks) (n = 27,648) |
|---|---|---|
| Median gestational age, wks | ||
| 14 to 17 +6 (n = 27,648) | 15 +4 | |
| 18 to 21 +6 (n = 18,753) | 19 +4 | |
| 22 to 25 +6 (n = 6576) | 23 +2 | |
| 26 to 35 +6 (n = 2319) | 28 +2 | |
| Maternal age, y (median and ranges) | 30 (14–51) | 28 (13–52) a |
| ≥38 years, % | 8.9 | 7.3 b |
| Smokers, % | 12.4 | 17.1 a |
| Maternal weight, kg (median and ranges) | 66 (30–180) | 72 (32–163) a |
| AFP MoM (median) | 0.98 | 1.01 |
| hCGβ MoM (median) | 0.98 | 1.03 |
| Risk (1/×) (median) | 2720 | 2414 |
| False-positive rate, % | 11.6 | 11.1 |
| Age <38 years | 8.6 | 8.4 |
| Age ≥38 years | 43.4 | 43.7 |
| Trisomy 21 | ||
| Screened-positive, n | 36 | 30 |
| Screened-negative, n | 6 | 6 |
| Detection rate, % | 85.7 | 83.3 |
| Frequency (1/×) | 658 | 762 |
| AFP ≥2.5 MoM, % | 1.33 | 2.0 |
| Neural tube defect | 7 | 10 |
| Ventral wall defect | 1 | 5 |
| Congenital nephrotic syndrome | 1 | 1 |
| PPV (1/×) | 41 | 35 |
Table 1 also presents the results of the maternal serum marker screening. Median MoMs, median risks, false-positive rates, and trisomy 21 detection rates did not differ between the 2 groups. Detection rates were 80.7% (21 of 26) in an 18 to 21 +6 week subgroup (n = 18,741) and 90% (9 of 10) in a 22-35 week subgroup (n = 8907), and false-positive rates were 9.8% and 11.3%, respectively in the subgroups.
When the AFP greater than 2.5 MoM is considered, neural tube defects, ventral wall defects, and nephrotic syndrome can be detected at the same level between the 2 groups.
Trisomy 21-affected pregnancies are presented in Table 2 . No significant difference was found between the LS group and the control group.
| Variable | Control group (14 +0 to 17 +6 weeks) | LS group (18 +0 to 35 +6 weeks) | ||
|---|---|---|---|---|
| Trisomy 21 | Screened positive | Screened negative | Screened positive | Screened negative |
| n | 36 | 6 | 30 | 6 |
| Maternal age, y | 39 (27-46) | 33 (23-42) | 38 (31-43) | 33 (28-40) |
| GA at sampling, wks | 15.1 (14-17.4) | 15.3 (14.3-17.4) | 20.2 (18.1-30.3) | 19.4 (18-23.6) |
| AFP MoM | 0.64 (0.38-1.78) | 0.73 (0.62-1.50) | 0.73 (0.34-2.45) | 0.97 (0.79-1.31) |
| hCGβ MoM | 2.71 (1.1-9.67) | 1.1 (0.77-1.35) | 2.93 (1.21-8.43) | 1.07 (0.61-2.18) |
Results
Table 1 presents a description of the database. Median gestational age at sampling was 20.4 weeks in the LS group and 15.4 weeks in the control group, a 5 week difference. Median maternal age was 28 years (range, 13–52 years) in the LS group, significantly younger than in the control group ( P < .0001). The percentage of women smoking during pregnancy was significantly higher in the LS group (17.1% vs 12.4% in the control group, P < .0001). The maternal weight was higher in the LS group corresponding to the normal increase in the weight of pregnant women over the 5 week difference.
| Demographic | Control group (14 +0 to 17 +6 wks) (n = 27,648) | LS group (18 +0 to 35 +6 wks) (n = 27,648) |
|---|---|---|
| Median gestational age, wks | ||
| 14 to 17 +6 (n = 27,648) | 15 +4 | |
| 18 to 21 +6 (n = 18,753) | 19 +4 | |
| 22 to 25 +6 (n = 6576) | 23 +2 | |
| 26 to 35 +6 (n = 2319) | 28 +2 | |
| Maternal age, y (median and ranges) | 30 (14–51) | 28 (13–52) a |
| ≥38 years, % | 8.9 | 7.3 b |
| Smokers, % | 12.4 | 17.1 a |
| Maternal weight, kg (median and ranges) | 66 (30–180) | 72 (32–163) a |
| AFP MoM (median) | 0.98 | 1.01 |
| hCGβ MoM (median) | 0.98 | 1.03 |
| Risk (1/×) (median) | 2720 | 2414 |
| False-positive rate, % | 11.6 | 11.1 |
| Age <38 years | 8.6 | 8.4 |
| Age ≥38 years | 43.4 | 43.7 |
| Trisomy 21 | ||
| Screened-positive, n | 36 | 30 |
| Screened-negative, n | 6 | 6 |
| Detection rate, % | 85.7 | 83.3 |
| Frequency (1/×) | 658 | 762 |
| AFP ≥2.5 MoM, % | 1.33 | 2.0 |
| Neural tube defect | 7 | 10 |
| Ventral wall defect | 1 | 5 |
| Congenital nephrotic syndrome | 1 | 1 |
| PPV (1/×) | 41 | 35 |
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