Second-trimester Down syndrome maternal serum screening in twin pregnancies: impact of chorionicity

OBJECTIVE: To evaluate the diagnostic value of second-trimester maternal serum screening for Down syndrome in twin pregnancies. METHOD: On the basis of a prospective study of second-trimester maternal serum screening, we studied the distribution of alpha-fetoprotein (AFP) and free ss hCG in 3043 twin pregnancies with known outcome. There were 1561 dichorionic and 244 monochorionic pregnancies. The placental type was not available in 1238 cases. We compared 5 screening policies with the same risk, 1/250, cut-off: maternal age, maternal age corrected for the risk of having at least one affected twin in dichorionic pregnancies, maternal serum marker screening using observed AFP and free ss-hCG values divided by a factor of 2, by using the median values actually observed in the global twin population, or by the median values specific to mono- or dichorionic twins. RESULTS: When expressed in singleton-derived MoMs, the median was 2.10 for AFP and 2.11 for free ss-hCG. The median AFP did not differ between monochorionic and dichorionic pregnancies. The distribution of free ss-hCG was significantly shifted towards greater values in monochorionic (2.16 MoM) compared to dichorionic (2.07) pregnancies (p < 0.0001). Screened-positive and detection rates were, respectively, 6.6% and 27.3% using maternal age alone, 24.6% and 54.5% using maternal age corrected for the risk of having at least one affected twin in dichorionic pregnancies, 7.75% and 54.5% using observed AFP and free beta-hCG values divided by a factor of 2, 8.05% and 54.5% using the median values actually observed in the global twin population, and 7.75% and 54.5% using the median values specific to mono- or dichorionic twins. CONCLUSION: Trisomy 21 second-trimester maternal serum screening is feasible in twins, and is better than a policy based on maternal age alone.     

Prenatal screening for Down syndrome and neural tube defects in twin pregnancies

Prenatal screening and diagnosis in a twin pregnancy is not straightforward. Once a twin pregnancy has been identified, women and their partners need time to consider the implications and decide whether they wish the pregnancy to be screened for Down syndrome or neural tube defects. We discuss here how multiple marker screening for Down syndrome and alpha-fetoprotein screening for neural tube defects can be carried out, given that this is the parents' chosen option and that the health professionals involved are capable of performing a diagnosis and selective feticide, should this arise.     

Down syndrome screening in multiple pregnancies

First or second trimester screening in twin pregnancies is feasible and still efficacious by using either a combination of ultrasound and maternal serum biochemistry in the first trimester or maternal serum biochemistry in the second trimester. Special care, however, should be emphasized in what concerns biochemical screening, since it is much less sensitive in multiples. These "pseudo-risks" have been challenged for their scientific and clinical validity, however. Until more data are available from larger studies on the distribution of markers in concordant or discordant twins, nuchal translucency estimated for each fetus should be the predominant factor by which women who present with increased risk should be counseled regarding invasive testing. In dizygotic pregnancies, pregnancy-specific risk should be calculated by summing the individual risk estimates for each fetus. In monozygotic twins, the risk should be calculated based on the geometric mean of both nuchal translucency measurements, not forgetting that the false-positive rate of nuchal translucency screening is expectantly higher than in singletons.     

Medically assisted reproduction and second-trimester maternal serum marker screening for Down syndrome

OBJECTIVES: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on total hCG, free ss-hCG, AFP and unconjugated estriol (uE3) used as markers for second-trimester Down syndrome maternal serum screening. METHODS: Second-trimester maternal sera from 1515 singleton pregnancies (970 by IVF, 545 by ICSI) were compared with control sera (21 014 cases). Free ss-hCG, total hCG, AFP and uE3 were compared between the control group and the medically assisted reproduction groups. The percentages of at-risk patients (>/=1/250) were also compared. RESULTS: No differences in values of the maternal serum markers were observed between the medically assisted and control groups. When maternal age was taken into account, the screen-positive rate for Down syndrome screening did not differ between the two groups. CONCLUSION: Patients undergoing assisted reproduction techniques can be counseled for maternal serum Down syndrome screening with the same efficacy as patients with naturally conceived pregnancies.     

First trimester screening for Down syndrome and assisted reproduction: no basis for concern

In pregnancies obtained after assisted reproduction the false-positive rate of second trimester Down syndrome (DS) screening is increased by 1.5-3-fold. This may cause an increase in the number of amniocenteses and the fetal loss rate. The present study for the first time examined whether assisted reproductive technologies affect the results of first trimester screening. The markers PAPP-A, free beta-hCG and the nuchal translucency (NT) thickness were examined at 12-14 weeks' gestation. Screening markers in 47 in vitro fertilisation (IVF), 63 ovulation induction (OI) and 3026 spontaneously conceived singleton pregnancies were compared. The MoM (multiples of the median) value in the IVF pregnancies was 1.02 (95% CI: 0.85-1.22) for PAPP-A, 1.14 (95% CI: 0.95-1.37) for beta-hCG and 0.97 (95% CI: 0.89-1.05) for NT; the MoM value in the OI pregnancies was 0.89 (95% CI: 0.76-1.05) for PAPP-A, 1.08 (95% CI: 0.93-1.25) for beta-hCG and 1.02 (95% CI: 0.95-1.11) for NT. The first trimester marker values in assisted reproductive pregnancies and spontaneously conceived pregnancies were not significantly different. Estimated false-positive rates for a risk cut-off of 1:400 varied from 4.7% in IVF pregnancies to 5.1% in OI pregnancies. Therefore the false-positive rate in Down syndrome screening should be independent of the method of conception.     

Non-invasive prenatal screening of fetal Down syndrome by maternal plasma DNA sequencing in twin pregnancies

Non-invasive prenatal screening for fetal Down syndrome (NIFTY) by maternal plasma sequencing was performed in 12 subjects with twin pregnancies, including 11 with normal fetuses and 1 with discordant fetal Trisomy 21. For every sample, it was processed, sequenced and reported as soon as it was collected as other clinical samples for singleton pregnancies. The NIFTY test was negative in the 11 pregnancies carried normal fetuses, and was positive (high risk) in the case with discordant fetal Trisomy 21. The sensitivity and specificity were both 100%. This small case series suggested the NIFTY as a screening test for fetal Trisomy 21 is feasible in twin pregnancies.     

Combining nuchal translucency and serum markers in prenatal screening for Down syndrome in twin pregnancies

A method is described to combine the ultrasound marker nuchal translucency (NT) with serum markers so that they can be used together in prenatal screening for Down syndrome in twin pregnancies. For monochorionic twin pregnancies (taken as monozygous), the two fetus-specific NT measurements are averaged before risk is calculated and before the contribution of the serum markers is incorporated. For dichorionic twin pregnancies (taken as dizygous), the risk for each fetus based on the individual NT measurements is calculated, the two fetus-specific risks are added together, and then the contribution of the serum markers is incorporated. In this way, all the screening markers can be used in combination to produce a pregnancy-specific "pseudo-risk", rather than a fetus-specific pseudo-risk. We refer to pseudo-risk because in the absence of sufficient data on the screening markers in affected twin pregnancies, a true risk estimate cannot be calculated. Tentative estimates are given of screening performance in twins using NT, the combined test (NT with first-trimester serum markers), and the integrated test (NT with first- and second-trimester serum markers), all interpreted with maternal age.     

Down's syndrome screening in twin pregnancies by nuchal translucency measurement. Current concept

During the last 2 decades various non-invasive Down syndrome (DS) screening methods were introduced in clinical practice. However, specific problems were encountered when these methods were applied for twin pregnancies. The current review aims to explore the problematic issue of antenatal DS screening in twins. The implication and the adjusted management in the attempt to achieve the best evaluation for this type of gestation is discussed. Overall more women with twin pregnancies (mainly those who conceived via assisted reproduction) are found false positive for DS. This is because the standard screening algorithms include maternal age. In addition, mid-trimester maternal serum screening is associated with a higher false positive rate; secondary to changes in the feto-placental endocrinologic metabolism in assisted conception pregnancies. Therefore, in twins mid-trimester maternal serum screening is of limited clinical value. In those pregnancies, DS screening by means of nuchal translucency measurements at 10-14 weeks is associated with a lower false positive rate than mid-trimester serum screening. In addition, this screening method enables to specifically identify those fetuses at risk of DS and other anomalies, and thus contributes to a better outcome.     

Stepwise sequential screening for trisomy 21 in assisted reproduction pregnancies

We offered a modified stepwise sequential integrated screening for Down syndrome to 72 singleton and 16 twin pregnancies obtained with assisted reproductive techniques, observing no cases of trisomy 21 and obtaining a false positive rate of 10% in singleton and 7% in twin pregnancies. In our population, this approach for regulating access to invasive karyotyping can avoid a substantial number of unnecessary procedures, comparing favourably with current practice even in spontaneous pregnancies.     

Early loss rates of entire pregnancies after assisted reproduction are lower in twin than in singleton pregnancies

Case-control studies on plurality dependent spontaneous embryonic loss rates after assisted reproduction found that twin pregnancies have a two to five times lower miscarriage rate of the entire pregnancy compared with singletons.     

Down syndrome screening in multiple pregnancies by nuchal translucency measurement

Various non-invasive screening methods for Down syndrome have been introduced in clinical practice during the last two decades. Specific problems were encountered when these methods were applied for multiple pregnancies (twins and high-order multiples). The aim of the current review is to explore these issues and propose an adjusted methodological approach for this highly selected population. Overall, more women with twin pregnancies (mainly those who conceived via assisted reproduction) are found to be false-positive for Down syndrome. This is because the standard screening algorithms include maternal age. In addition, mid-trimester maternal serum screening is associated with a higher false-positive rate, secondary to changes in the fetoplacental endocrinologic metabolism in assisted reproduction pregnancies. Therefore, in multiple pregnancies, mid-trimester maternal serum screening is of limited clinical value. In those pregnancies, screening for Down syndrome by means of nuchal translucency measurements at 10-14 weeks is associated with a lower false-positive rate than mid-trimester serum screening. Nuchal translucency measurement is among the best available and most efficient screening methods for multiple pregnancies. This method for screening enables us to specifically identify those fetuses at high risk of Down syndrome and other anomalies and thus contribute for a better outcome. In addition, it should be systematically performed before any fetal reduction in high-order multiples is planned.     

Primiparity, assisted reproduction, and preterm birth in twin pregnancies: a population based study

Objective To determine the prevalence of pregnancy complications among primiparous patients with twin gestation in our population and to investigate the association between the increased rates of assisted reproduction (ART) in twin gestation and preterm birth (PTD). Material and methods A retrospective population based cohort study was designed, including all twin deliveries after 24 weeks gestation (n = 2,601). The study group included 666 primiparous women and the comparison group 1,935 multiparous women. Maternal characteristics and perinatal outcome were evaluated. Women with fetal malformations were excluded. A multiple logistic regressions analysis for independent risk factors was performed including factors that were significantly different between the study groups in the univariate analysis. Patient’s data were obtained from computerized database and analyzed using SPSS statistical package. Results Primiparous women had a significantly higher rate of preeclampsia, chronic hypertension, ART, prelabor rupture of membranes (PROM) preterm deliveries (PTD), labor dystocia, cesarean section (CS) and vacuum extraction of the first twin than the multiparous group. Primiparous patients had a significantly lower gestational age at delivery and neonatal birth weight of the first and second twin. In multiple logistic regressions analysis primiparity and ART were independent risk factors for PTD, (OR 1.45, 95% CI 1.18–1.78; OR 1.36, 95% CI 1.09–1.71, respectively). Conclusions (1) Primiparous patients with twin gestation represent a unique population with high rate of infertility and underlying diseases such as chronic hypertension in comparison to the multiparous women with twin gestation; (2) primiparity is an independent risk factor for prematurity in twin gestations; and (3) although primiparous women had an increased maternal complications, neonatal mortality rates were not significantly different from multiparous women.     

Biochemical screening for Down syndrome in pregnancies following renal transplantation

OBJECTIVE: To assess the performance of the double marker test [free beta-human chorionic gonadotrophin (beta-hCG) and alpha-fetoprotein (AFP)] as a screening test for Down syndrome in pregnant patients who had a prior renal transplant. DESIGN: A retrospective study. SETTING: The Fetal Medicine Unit, Royal Free Hospital, London, UK. METHODS: Detailed records of 14 post-renal transplant pregnancies were obtained from the Renal Unit of our hospital where the patients were followed up. The serum concentrations of urea, creatinine, free beta-hCG and AFP at the time of the double marker test were recorded, with a cut-off point of 1:250 for the double marker test. A control group of 14 normal pregnancies matched for age, parity and gestational age was used. The Mann-Whitney U-test and t-tests of unequal variance were applied to compare parameters of the study and the control groups. RESULTS: Two patients in each group were high risk for Down syndrome and amniocentesis revealed normal karyotype. No babies with Down syndrome were delivered in either group. Regression analysis showed significant correlation between free beta-hCG and urea concentrations (p<0.001) and free beta-hCG and creatinine concentrations (p<0.001), but not for AFP. CONCLUSIONS: The present study demonstrates that residual renal function alterations persisting after renal transplantation can affect the levels of free beta-hCG and AFP, thus resulting in false-positive screening for Down syndrome. First trimester nuchal translucency (NT) measurement in combination with second trimester ultrasonographic markers can be used in these patients, or alternatively the free beta-hCG levels should be corrected according to the serum creatinine levels.     

自然妊娠和辅助生育技术妊娠双胎的母婴围产期预后

目的比较自然妊娠和辅助生育技术（assisted reproduction technology,ART）妊娠双胎的母婴围产期预后。方法选择北京协和医院定期随诊并分娩的双胎211例,其中自然妊娠142例,ART妊娠69例,回顾性分析两组孕妇一般情况、围产期并发症、分娩情况及新生儿并发症。结果 ART组孕妇年龄[（34.23±4.13）岁]大于自然妊娠组孕妇[（32.02±4.45）岁],P〈0.05。两组孕妇围产期并发症的发生率差异无统计学意义（P〉0.05）;②ART组新生儿平均孕龄小于自然妊娠组,（251.87±15.16）d比（256.04±12.26）d,且新生儿感染发生率低,5（3.7%）比26（9.4%）,P〈0.05。结论与自然妊娠双胎相比,ART双胎妊娠不增加孕妇围产期并发症的风险,而且新生儿健康状态与自然妊娠双胎相当。     

Prevention of multiple pregnancies in assisted reproduction

The incidence of multiple births has increased parallel with the success of assisted reproduction treatments (ART) mainly because of the multiple embryo transfer. As a response to the increased multiple birth rate, the number of embryos transferred was reduced in 1992–1994 from three or more to two in many European countries. After that, a dramatic drop in the number of triplet and higher-order pregnancies was seen, but the twin rate still remained high. According to the European registers by ESHRE, in 2001 still 34.4% of children conceived with ART originated from multiple pregnancies, of which 94% were twin pregnancies. Obstetric and perinatal complications affect twins more often than singletons, contributing to increased health risk of the mother of twins and the children born as twins. In addition to the medical complications, twin families are at a greater risk for psychosocial burden. From the health-economic point of view, cost impact for twins is threefold to that of singletons. Recently, the standards of success of infertility treatment have been widely debated in journals of reproductive medicine. The general conclusion from this debate is that both the delivery rate per treatment and the final outcome of the pregnancy should be considered when the success of ART is reported. The high iatrogenic twin rate resulting from ART still offers the infertility treatment providers a challenge to strive for minimizing the number of ART-related twins. The most efficient way to reduce twin rate in ART is single embryo transfer (SET). However, the worry about impairment of delivery rate if only one embryo is transferred has hampered the acceptance of SET. The four randomised controlled trials and some retrospective cohort studies published until now have confirmed the effectiveness of elective single embryo transfer (eSET) in reducing the twin rate below 10%. In addition, highly acceptable delivery rate is achieved with eSET. The final results of eSET are most obviously further improved by transfer of frozen-thawed embryos. The experience of eSET until now encourages mowing towards an individualised embryo transfer policy, where eSET is performed in good prognosis patients at high risk for a twin pregnancy when two embryos would be transferred. The aim of this article is to review studies about eSET as a method to prevent ART-related twin pregnancies and the ways used in nationwide implementation of eSET in Finland, Belgium and Sweden.