Hum. Reprod. Advance Access originally published online on April 1, 2008
Human Reproduction 2008 23(7):1545-1552; doi:10.1093/humrep/den103
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Prenatal testing among women pregnant after assisted reproductive techniques in Denmark 1995–2000: a national cohort study
1 Department of Fetal Medicine 4002, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark 2 The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark 3 Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark
4 Correspondence address. Tel: +45-22-30-29-36; Fax: +45-35-45-47-49; E-mail: ac{at}gjerris.dk
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Abstract |
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BACKGROUND: Women pregnant after assisted reproductive techniques (ART) are generally older than women with spontaneously conceived pregnancies, and are consequently more likely to carry a child affected by a chromosomal disorder. Furthermore, a significantly increased rate of chromosomal abnormalities after intracytoplasmatic sperm injection (ICSI) has been reported. The aim of this study was to describe the use and results of prenatal invasive diagnostic testing in a national Danish cohort of in vitro fertilization (IVF)/ICSI pregnancies. Additionally, we examined to what extent second trimester serum screening was used.
METHODS: We used a register-based cohort study including all ongoing clinical pregnancies achieved by IVF/ICSI in 1995–2000 in Denmark. Data on fertility treatment, pregnancy and pregnancy outcome together with data on cytogenic testing and the use of triple test were retrieved from national statutory registers. Data on the invasive testing rate among the general Danish population were retrieved from the same national registers.
RESULTS: In this 6 year period, 8531 ART pregnancies were recorded representing an unselected national ART population (6122 IVF, 2087 ICSI and 322 ‘IVFICSI’). The number of prenatal invasive procedures was relatively low, 16.3%, and the uptake of second trimester serum screening was very low, 7.4%. The invasive testing rate, corrected for advanced maternal age distribution, was lower in the study population than in the general population. The rate of karyotype aberrations detected by prenatal testing was 2.7% (43/1586), whereas the overall rate of pre- and post-natally detected aberrations was 0.6% (62/9625). Chromosome aberrations were more common in the ICSI-treated group compared with the IVF-treated group [1.3% (30/2297) versus 0.5% (32/6957), P < 0.0001]. This was also the case if only prenatally diagnosed chromosome aberrations were compared [4.3% (24/556) versus 1.9% (19/975), respectively, P < 0.01].
CONCLUSIONS: ART pregnancies represent a group of high-risk pregnancies with regard to chromosomal aberrations, but nevertheless their uptake of prenatal testing was low. ICSI pregnancies compared with IVF pregnancies had a higher rate of chromosomal abnormalities, even though the average maternal age was lower.
Key words: prenatal screening/assisted reproduction/chorionic villus sampling/amniocentesis/chromosome abnormalities
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Introduction |
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Women pregnant after assisted reproductive techniques (ART) are generally older than women with spontaneously conceived pregnancies; the proportion of women aged 35 years or more is higher (Geipel et al., 1999
; Pinborg et al., 2004a,b) and the incidence of multiple gestation is increased (Weisz and Rodeck, 2006). In consequence, women pregnant after ART are more likely to carry a child affected by a chromosomal disorder (primarily Down's syndrome) compared with spontaneously pregnant women (Snijders et al., 1995; Meyers et al., 1997). Thus, women pregnant after ART constitute a high-risk population that could benefit from prenatal invasive testing. However, fertility treatment is often a long and psychologically wearing process (Schmidt, 2006) and it is generally believed that women who have conceived after ART wish to avoid invasive testing due to the risk of abortion (Meschede et al., 1998; Schover et al., 1998; Loft et al., 1999) and prefer prenatal screening before making a decision about invasive testing or not (Geipel et al., 1999, 2004). Prenatal screening aimed at identifying pregnancies at high risk of fetal aneuploidy can be done by risk calculation based on maternal age, ultrasonic and/or biochemical markers.
The introduction of intracytoplasmatic sperm injection (ICSI), which is a more invasive technique than conventional in vitro fertilization (IVF), brought up questions about the safety of the procedure as regards chromosomal aberrations in ICSI outcomes. Two studies have found a significantly increased rate of chromosomal abnormalities in ICSI children compared with a reference group of naturally conceived children or the general population (Aboulghar et al., 2001; Bonduelle et al., 2002), whereas in several uncontrolled studies the prevalence of chromosomal abnormalities was 1.4–12.7% (Govaerts et al., 1998; Wennerholm et al., 2000; Samli et al., 2003; Jozwiak et al., 2004). In the first years after the introduction of ICSI in 1992, all Danish women pregnant after this method were therefore recommended to have a prenatal invasive diagnostic test performed (Loft et al., 1999).
In 2004, first trimester screening with double test and nuchal translucency scan was introduced as a routine offer for all pregnant women in Denmark. Prior to this, no prenatal screening tests were offered consistently, although a second trimester serum screening test (the triple test) was available but only used sporadically and with great regional variation. Invasive diagnostic tests were offered to all women of ‘advanced maternal age’ (
35 years). Today almost 7% (www.fertilitetsselskab.dk) of the yearly birth cohort is conceived by some type of ART in Denmark, and IVF with or without ICSI accounts for 3–4%.
The aim of this study was to describe the use and results of prenatal invasive diagnostic testing in a national Danish cohort of IVF/ICSI pregnancies in the years 1995–2000. Additionally, we examined to what extent prenatal second trimester serum screening was used.
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Materials and Methods |
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This population-based cohort study included all Danish clinical pregnancies (positive fetal cardiac activity at early ultrasound in weeks 7–8) achieved by IVF/ICSI treatment with an embryo transfer date in the period from 1 January 1995 to 31 December 2000. Only pregnancies resulting from fresh embryo transfer were included. Maternal age was defined as the woman's age at treatment start (follicle stimulation).
Since January 1994, all Danish fertility clinics, both public and private, have been obliged to report all ART treatment cycles to the Danish IVF Register in the National Board of Health (Pinborg et al., 2004a,b). The data are reported using the personal identification number (CPR number) allocated by the Centralized Civil Registry. By record linkage, the IVF Registry retrieves information on pregnancy outcome, including CPR number of each individual infant.
For this study, data on fertility treatment, pregnancy and pregnancy outcome were retrieved from the IVF Registry. Data on the use of second trimester serum screening, and data on the use and results of cytogenetic analysis, were retrieved from the Prenatal Registry at Statens Serum Institut (SSI) and the Danish Cytogenetic Central Registry (DCCR) or Odense University Hospital (OUH), as described in the following sections. The data file was conducted in May 2005, allowing for follow-up of the children for at least 5 years.
In the study period, all second trimester triple tests performed in Denmark were analysed at the Prenatal Registry at SSI, and information was achieved by linkage of maternal CPR numbers to this registry. We only included second trimester screen tests where date of embryo transfer from the Danish IVF Registry and date of screen test analysis from SSI matched within 6–20 weeks (gestational age from 8 to 22 weeks). If more than one test was performed, only the latter was recorded. Data from 1995 and 4 months in 1999 could not be retrieved due to a technical impediment. An estimated number for 1999 was calculated based on the actual number in the other 8 months of the year.
All chromosome analyses performed in Denmark both pre- and post-natally are centrally registered in DCCR except for examinations carried out at OUH which represents a small part of the total number, in this study 5.9%.
Both the mothers and the infants CPR numbers were linked to DCCR and to OUH. As for the triple test we made a date-match in order to include only prenatal karyotypes, where date of embryo transfer from the Danish IVF Registry and date of karyotyping from DCCR and OUH matched within 6–30 weeks (gestational age from 8 to 32 weeks). If more than one invasive test was performed in the same pregnancy, we manually evaluated which to be the match. ‘Invasive test’ covers both amniocentesis (AC) and chorionic villus sampling. In the study period, 
60% of all invasive tests were AC in the general Danish population.
Data on ‘the general Danish population’ were provided by the Danish Birth Registry and DCCR and thus, do not contain data from Odense County.
Pregnancy outcome could be singletons, twins, triplets or abortions. The infants could be either live born or stillborn and the abortions could be either spontaneous or elective. Pregnancy outcome was registered as an abortion or as one or more live born/stillborn in the IVF Registry, thus an original twin pregnancy with a spontaneous or elective reduction resulting in only one live born singleton was only registered with the latter outcome.
Statistical analysis
The results were analysed using SAS 9.2 with Enterprise Guide version 2.1. Statistical significance was defined as P < 0.05. The one-way analysis of variance (ANOVA) was used to compare numerical data, the 
2 test was used to compare categorical data.
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Results |
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Overall
Altogether 8531 pregnancies were identified. Owing to the large number of twin pregnancies, and to a lesser extent triplets, this resulted in 10 506 outcomes (Tables I and II), of which 881 were registered as abortions, leaving 9625 pregnancy outcomes.
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There were 523 second trimester triple test matches detected. Owing to the missing data from 4 months in 1999, a calculation was made and gave an estimated total number of 561.
Invasive testing was done in 1394 pregnancies and 1586 fetuses were karyotyped.
Maternal age
The overall mean maternal age was 32.4 ± 3.9 years. Women with pregnancies that resulted in an abortion were significantly older when compared with all other outcome groups and mothers with singletons were older than mothers with multiple pregnancies. Likewise, the mean age was different depending on treatment method, thus women who conceived after IVF were slightly, although significantly, older than those who conceived after ICSI (32.7 ± 3.7 versus 31.8 ± 4.0 years, P < 0.001). The proportion of women of advanced maternal age (35 years at treatment start) was overall 31.2% and as expected the number of women aged 35 years was higher in singleton pregnancies (Table I). Mean maternal age and the proportion of women of advanced maternal age did not change during the study period (Table II).
Treatment method
The majority of women in this cohort conceived after IVF (Table I), although there was a significant shift towards more ICSI pregnancies during the time period (P < 0.001) (Table II). In 322 (3.8%) pregnancies, the treatment was recorded as IVFICSI; this was not defined but could be either unknown or, more likely, cases where both methods were used in the same cycle.
Pregnancy outcome
Overall, the twin rate in this study was 21.8% (range 20.7–22.7% per year) and did not change during the study period. There were 57 cases of triplet pregnancies (0.7%). Higher order multiple pregnancies did not occur in this cohort.
After proven positive fetal cardiac activity at early ultrasound, the rate of abortion due to either spontaneous or elective abortion was 11.2% (Table I) and the spontaneous fetal loss rate was 10.3% (881/8531) (Table I). There was no difference in the abortion rate in ICSI pregnancies compared with IVF pregnancies, 10.8% (225/2087) versus 10.2% (628/6122), respectively.
Use of prenatal testing
Second trimester screening
There were 561 women who had a second trimester screening test performed. Overall, the test rate was 7.4% (range 5.8–9.7% per year) and this decreased significantly during the study period (Fig. 1). The mean maternal age was significantly higher among women having a triple test compared with those who did not (34.0 ± 3.4 versus 32.3 ± 3.9 years, P < 0.001).
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Prenatal invasive diagnostic testing
The overall invasive testing rate was 16.3% and this did not change significantly over time (Table II).
There were significantly more women with singleton pregnancies who had an invasive test performed compared with twin pregnancies, 1151 (20.3%) versus 188 (10.1%) (P < 0.001). It was primarily in pregnancies conceived after ICSI that invasive testing was used, 484 (23.2%) versus 863 (14.1%) (P < 0.001) in IVF pregnancies (in 47 cases the treatment was IVFICSI). The mean age was higher in the invasive test group, 35.6 ± 3.4 versus 31.8 ± 3.7 years in the remaining part of the study population (P < 0.001) and as expected the proportion of women aged 35 years was higher, 70.5% versus 23.5% (P < 0.001).
Figure 1 shows the yearly invasive testing rate during the study period compared with national data from the DCCR. The dotted line is the national invasive testing rate, the full line is an estimated rate based on the distribution of advanced maternal age in the study population and the invasive testing rate in the general population at age 35 and<35 years, respectively. It thus represents the invasive testing rate in the general population if the women had had the same advanced maternal age distribution as our study population.
The invasive testing rate among women older than 34 years was 36.9%, significantly lower than in the general Danish population (53.5%, P < 0.001) (Table II). Among women <35 years of age, the overall invasive testing rate was 7.0%, and in women pregnant after ICSI, the rate was 16.0%. Of those women who had invasive testing performed, 82.6% were singleton pregnancies and 34.7% had conceived after ICSI. Their mean age was 35.6 (3.4) years and 70.5% were 35 years or older; 10.0% had a triple test performed prior to the invasive test.
Results of the cytogenic testing
Table III shows the prevalence and type of abnormal karyotypes found both pre- and post-natally according to treatment and pregnancy outcome.
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There were 62 abnormal karyotypes detected, 43 prenatally and 19 post-natally. The prevalence of karyotype aberrations in the 1586 fetuses tested was 2.7% (43/1586) and in the total study population, it was 0.6% (62/9625 outcomes).
The prenatal detection rate (DR) of chromosome abnormalities did not differ in singleton pregnancies 71.1% (32/45) compared with twin pregnancies 64.7% (11/17); however, the DR of Down's syndrome was higher in singleton pregnancies 76.5% (13/17) compared with twin pregnancies 33.3% (3/9) (P < 0.05). There were no differences in DR in pregnancies conceived after ICSI compared with those conceived after IVF.
Chromosome aberrations were detected significantly more often in the ICSI-treated group compared with the IVF-treated group [1.3% (30/2297) versus 0.5% (32/6957), P < 0.0001]. This was also the case if prenatally diagnosed chromosome aberrations were compared [4.3% (24/556) versus 1.9% (19/975), respectively, P < 0.01]. All the karyotypes performed among the IVFICSI pregnancies were normal. The difference between the rates of chromosome abnormalities in IVF versus ICSI pregnancies remains significant, regardless of whether all the IVFICSI pregnancies are included in either group.
The overall rate of chromosome aberrations in singletons was higher compared with twins: 0.8% (45/5660) versus 0.5% (17/3720), respectively (P < 0.05). The prevalence of Downs's syndrome was overall 0.3% (26/8531) and there was no difference between the rate in singletons 0.3% (17/5660) and twins 0.2% (9/3720).
There were 75 post-natal karyotypings performed and 19 abnormal karyotypes were found: 1 sex chromosome abnormality, 12 autosomal aneuploidies and 6 autosomal structural chromosome abnormalities, of which 5 were de novo.
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Discussion |
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This follow-up study included all pregnancies achieved by IVF and ICSI during the period 1995–2000 in Denmark, thus this cohort of 8531 ART pregnancies represents an unselected national ART population with data on both pre- and post-natal karyotypes. This is in contrast to other studies, which only present data on either prenatal (Van et al., 1997
; Bonduelle et al., 2002; Jozwiak et al., 2004) or post-natal analysis (Aboulghar et al., 2001). In this 6 year period, the mean rate of prenatal invasive testing was relatively low, 16.3%. This rate did not change during the study period and was higher than in the general population (Fig. 1). When the invasive testing rate is corrected for advanced maternal age distribution, the rate is, however, lower in our study population than in the general population (Fig. 1). This finding should, however, be interpreted with caution as our study group has a high rate of twin pregnancies (21.8%), and women with twin pregnancies may be less willing to have an invasive test due to the perceived increased abortion rate in multiple pregnancies following invasive procedures. During the study period, women aged 35 years were offered an invasive diagnostic test, whereas women who had conceived after ICSI were recommended to have one. In our study population, 49.2% were either 35 years or had conceived after ICSI. It thus seems that the assisted mode of conception is associated with reluctance to use invasive testing in women aged 35 years or more, as well as in women pregnant after ICSI. Indeed, the invasive testing rate among women pregnant after ICSI was very low, 16% among women <35 years. These findings are in agreement with most previous studies (Meschede et al., 1998; Schover et al., 1998; Loft et al., 1999), although one study found no difference in the acceptance rate of invasive testing among women with ART pregnancies compared with the general population (Elimian et al., 2003). The risk of spontaneous abortion is most likely responsible for the lower invasive testing rate among women pregnant after ART, but the attitudes towards terminating a pregnancy given the findings of a fetal abnormality may also play a role (Schover et al., 1998).
A surprising finding was the limited use of the triple test. In our study period, second trimester serum screening was available but apparently not used much, as only 7.4% had a triple test performed. One reason could be the geographically heterogeneous use of the test due to different screening policies in the 15 Danish counties. Another reason could be the concerns about the validity of the test when used among ART pregnancies (Barkai et al., 1996; Wald et al., 1999). The results of the triple test were not available, which is a limitation of this study; there is, however, no reason to believe that the results would have differed from those found in other studies (Barkai et al., 1996; Frishman et al., 1997; Wald et al., 1999; Bar-Hava et al., 2001; Maymon and Jauniaux, 2002).
In this unselected national cohort, the prevalence of karyotype aberrations was significantly higher in ICSI compared with IVF pregnancies. This difference is not explainable by age as the IVF-treated women were older than the women who conceived after ICSI. Table III indicates that a higher rate of autosomal structural aberrations, mainly inherited from the father or de novo, is responsible for the difference.
Several studies have assessed the rate of karyotype abnormalities detected by prenatal diagnosis in pregnancies conceived by ICSI (Table IV). Nearly all the studies find a higher rate of chromosomal abnormalities (1.4–4.3%) than in spontaneous pregnancies where invasive testing is performed because of advanced maternal age (Ferguson et al., 1990; Hackett et al., 1991). The higher rate is mainly caused by a higher proportion of sex chromosome aneuploidy and autosomal structural aberrations, inherited or de novo. The frequency of aberrant karyotypes is increased in couples opting for fertility treatment, especially in males with suboptimal semen quality (Kayed et al., 2006; Riccaboni et al., 2007). Furthermore, these men, despite a normal somatic karyotype, have a high occurrence of sperm chromosome aneuploidy, perhaps suggesting that not only the spermatogenesis is affected but also the mechanisms involved in chromosome segregation (Burrello et al., 2005; Nagvenkar et al., 2005). This underlines the requirement of genetic evaluation of infertile couples, especially the male partner, before undergoing ICSI.
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In ICSI pregnancies, Bonduelle et al. (2002)
found an overall risk of chromosomal abnormalities of 3.0%, mainly due to a higher rate of sex chromosome abnormalities, but also to a higher rate of structural anomalies. Jozwiak et al. (2004) also described a series of more than a thousand ICSI fetuses, but it should be noted that ICSI was used in all their patients regardless of underlying infertility factor. Both papers report a lower rate of prenatal chromosomal abnormalities than our findings. An explanation could be the higher invasive testing rate (40–50%) in these studies and therefore a more ‘low risk’ population. In contrast to other studies (Table IV), we found a low rate of sex chromosome abnormalities in ICSI outcomes. Our population may be a group with less severe male infertility, as it consisted of unselected infertile couples from all over the country, and from both private and public clinics.
The incidence of chromosomal abnormalities is, theoretically, higher in a prenatally investigated population compared with a post-natally tested population, because prenatal invasive procedures most often are performed in women at increased risk, but more importantly because of the high spontaneous fetal loss rate among aneuploid fetuses (Snijders et al., 1995). In contrast Aboulghar et al. reported a rate of 3.5% abnormal karyotypes (1.4% sex chromosome abnormalities) in 430 ICSI babies from 320 consecutive deliveries assessed post-natally. No information about prenatal screening or invasive diagnosis prior to delivery was available from this study (Aboulghar et al., 2001).
Among the general newborn population, an overall rate of abnormal karyotypes of 0.85–0.92% has been reported (0.19–0.23% sex chromosomal aberrations) (Nielsen and Wohlert, 1991; Jacobs et al., 1992). In our ART population, the overall rate was 0.6%, and in the ICSI group 1.3% which is higher than in the general population, although not as high as in the study of Aboulghar et al. (2001). It thus seems that ICSI treatment entails an increased risk of chromosome abnormality. Our findings should, however, be interpreted with caution due to the relatively small numbers.
An invasive prenatal test with fetal karyotyping would detect these chromosome abnormalities. However, as is clearly apparent from the present study that women pregnant after ART wish to avoid invasive testing. These women would benefit from a prenatal screening test with high performance (low FPR rate and high DR), also when used among ART pregnancies.
First trimester screening with both ultrasonic (nuchal translucency scan) and biochemical markers has become extensively used during the last decade in many countries. Studies have so far shown varying results of this screening test when used in ART pregnancies. The nuchal translucency thickness does not seem to differ significantly between spontaneous pregnancies and pregnancies conceived after ART (Liao et al., 2001; Wøjdemann et al., 2001; Orlandi et al., 2002). Regarding the biomarkers, several studies have reported that they are significantly affected by ART resulting in a higher false positive rate (FPR) of first trimester screening (FPR between 4.6% and 10.3% compared with 3.3% and 7.1% in spontaneously conceived pregnancies) (Liao et al., 2001; Orlandi et al., 2002; Ghisoni et al., 2003) as well as of second trimester screening (FPR between 18.5–30.4% versus 5.0–16.6%) (Barkai et al., 1996; Frishman et al., 1997; Wald et al., 1999; Bar-Hava et al., 2001; Maymon and Jauniaux, 2002).
In conclusion, ART pregnancies represent a group of high-risk pregnancies with regard to chromosomal aberrations, but nevertheless their uptake of prenatal testing was low. One reason for low invasive testing rate might be the high rate of twin pregnancies. ICSI pregnancies compared with IVF pregnancies had a higher rate of chromosomal abnormalities, even though the average maternal age was lower. Paternal characteristics might explain this difference and underlines the importance of genetic evaluation of men before ICSI is performed. The reluctance to use prenatal diagnostic techniques suggests that further development of prenatal screening towards the use of tests with a lower FPR could be of particular value in ART pregnancies.
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Funding |
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This study was supported by grants from the Danish Health Foundation (2006B034 2005B055, 2004B149) and The Danish Medical Research Council.
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Submitted on October 21, 2007; resubmitted on February 26, 2008; accepted on March 4, 2008.
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