Abstract
Introduction
In this register‐based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age‐related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms.
Material and methods
We followed a nationwide cohort of 542 375 singleton‐pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register.
Results
We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age‐related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies.
Conclusion
This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter.
Keywords: aneuploidy, genetic risk factors, maternal age, numeric chromosomal anomalies, pregnancy risk, sex chromosome aberrations, triploidy, trisomy
With this study, we found an association between advanced maternal age and the risk of trisomy 21, 18, 13 and other sex chromosome aberrations. In addition to this, we observed that cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. In other words, we confirm the findings of previous studies, but we are one of the first to provide meaningful estimates on maternal age‐related risk of more specific types of aneuploidies due to our large dataset and high level of power.
Abbreviations
- FISH
fluorescence in situ hybridization
- MLPA
multiplex ligation‐dependent probe amplification
- QF‐PCR
quatitative fluorescence PCR
Key message.
We confirm the associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations whereas we find no age‐related associations with triploidy or monosomy X.
1. INTRODUCTION
The average age of women at childbirth in Europe and North America has steadily increased over the past five decades. 1 As a woman ages, her oocyte supply and quality decline, leading to decreased fecundity and increased risks of adverse pregnancy outcome and chromosomal anomalies of the fetus. 2 , 3 , 4 , 5 , 6 Newer studies, however, demonstrate a U‐shaped curve of aneuploidy indicating that increased risk may also affect the very young. 7 Chromosomal anomalies are relatively common in human embryos. 8 , 9 However, a considerable proportion of these conceptions will likely result in early miscarriage, 10 or, if detected early, in a parental decision to terminate the pregnancy. 11 , 12
Consequently, fewer children are born with chromosomal anomalies, but with large variations in live‐birth prevalence between countries depending on age and on prenatal screening policy, provision and uptake. 13 The literature lack investigation on how translocations and mosaicisms affect the association between aneuploidy and advanced maternal age, as well as the age‐related association with less common fetal aneuploidies. 14 , 15 , 16 , 17 , 18 , 19 , 20 Moreover, previous studies exploring an association between maternal age and fetal aneuploidies have been methodologically limited by investigating prevalence at a late gestational age (eg >20 weeks of gestation) or on live birth prevalence, thus failing to include cases which result in fetal loss or elective terminations. 13 , 14 , 15 , 17 , 21 , 22
To address these gaps in the existing knowledge, we conducted a nationwide study of pregnant women in Denmark followed from first trimester screening to assess the association between maternal age and risk of aneuploidies of the fetus, including trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations. This study further aims to disentangle whether the maternal age‐related effect on fetal aneuploidies is influenced by cases with translocation trisomies and mosaicisms.
2. MATERIAL AND METHODS
2.1. Study population and setting
We conducted a nationwide register‐based cohort study of singleton pregnancies followed from first trimester screening performed at a public hospital in Denmark between 1 January 2008 and 31 December 2017. We followed these pregnancies until delivery, miscarriage or termination of pregnancy. After applying different exclusion criteria (Figure S1), our final study population consisted of 542 375 pregnancies.
Since 2004, Denmark has had a national antenatal screening program that offers first‐trimester screening for chromosomal anomalies at 11–14 weeks of gestation and a second trimester screening for fetal malformations at 18–20 weeks of gestation to all pregnant women. 11
The unique personal identification number assigned to all individuals born in, or a resident of, Denmark enables accurate linkage of individual‐level information on our study population across various nationwide data sources. Clinical data and maternal characteristics from the antenatal screening program is prospectively registered in the national clinical database; Danish Fetal Medicine Database, established in 2008 and covering all obstetric departments in Denmark. 23 This database collects information on maternal age, smoking status, body mass index, ethnicity, parity, use of assisted reproductive technology and data from the prenatal ultrasound scans, which are registered locally (Astraia software gmbh). Furthermore, the database collects information on pregnancy outcomes, including fetal losses and postnatal congenital malformations from the national patient register, information about pregnancy complications and delivery from the national medical birth register, and results from prenatal, abortion and postnatal chromosome analyses from the national cytogenetic register (DCCR). 23
The antenatal screening program in Denmark has a high population support with more than 90% of all pregnant women in Denmark participating in both first and second trimester screening, and more than 95% of the pregnancies have an outcome registered in the Danish Fetal Medicine Database. 23
2.2. Maternal age
Maternal age of each pregnancy was defined at time of first‐trimester scan. We included all maternal ages and grouped it into six maternal age categories (<20 years; 20–29 years; 30–34 years, 35–39 years; 40–44 years; ≥45 years). The reference group was defined as pregnant women between 20 and 29 years of age. Pregnant women conceiving with donor eggs were excluded from our analyses as we did not have complete information on age of the donor.
2.3. Aneuploidies of the fetus and infant
We retrieved prospectively collected information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. This included prenatally detected cases of aneuploidies from first trimester scanning onwards, as well as postnatally detected cases among stillborn and live born children within 1–2 years after birth. In Denmark, all live born children are assessed by a midwife after birth and again by a doctor at age 5 weeks and referred for further testing if a syndrome is suspected.
For all pregnancies with a cytogenetic or molecular analysis performed, we used an algorithm developed by Vogel and colleagues to sort chromosomal anomalies in our study population. 24 Additionally, two genetic experts (I.V. and L.R.) manually checked all karyotypes to assign them into the following six different groups of aneuploidies to be assessed in this study: Trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X, and other sex chromosome aberrations. The aneuploidies assessed in our study included cases with translocation trisomies and mosaicisms. We identified those specific cases for further analytical investigations. Throughout the study, we refer to trisomy 21, trisomy 18 and trisomy 13 as trisomies despite the inclusion of translocations in these groups. The samples were analyzed in five different centers in Denmark, and analyzed with conventional karyotype, aneuploidy screening only (multiplex ligation‐dependent probe amplification [MLPA], quatitative fluorescence PCR [QF‐PCR], fluorescence in situ hybridization [FISH]) or chromosomal microarray. Over the time period the first‐line method used on invasive samples has gradually changed from conventional karyotyping to chromosomal microarray. This has increased resolution but has the drawback that one may not be able to discern between translocation trisomies and trisomies with three chromosomes, by restriction of data prior to 2015 we investigated how this affect results.
2.4. Statistical analyses
To compare the distribution of sociodemographic and maternal characteristics by maternal age groups, we used Pearson's chi‐squared tests.
All aneuploidies were formed into a composite outcome for an overall assessment of any aneuploidy (none vs. any). Additionally, we assessed the risk of trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X, and other sex chromosome aberrations, separately.
We descriptively calculated and visually plotted the proportional probabilities of any aneuploidy and of specific groups of aneuploidies by maternal age.
To explore the association between maternal age groups and risk of fetal aneuploidies, we performed logistic regression analyses, estimating odds ratio (OR) and 95% confidence levels (CI) for each of the maternal age groups relative to the group of pregnant women aged 20–29 years (reference group). These analyses were performed for all aneuploidies as a composite outcome, and for each of the six groups of aneuploidies. Due to the rare nature of chromosomal anomalies, odds ratio estimates are interpreted as relative risk estimates. We did not adjust our models for any potential confounders. However, to take potential effect modification by assisted reproductive technology into consideration, we stratified our logistic regression models by pregnancies conceived with assisted reproductive technology (yes, no). As the maternal age‐related effect on aneuploidies is a nonlinear function in where log odds do not increase uniformly each year of age, we did not assess maternal age as a continuous variable in the logistic regression models. 25 , 26
To assess the impact of translocations on the maternal age‐related risk of fetal aneuploidies, we calculated and compared the median maternal age for translocation trisomies and for free trisomies, respectively. Similarly, we assessed the impact of mosaicisms by calculating and comparing the median maternal age for cases with and without chromosomal mosaicism, respectively. Additionally, we ran sensitivity analyses excluding cases of aneuploidies with translocations and mosaicisms from our logistic regression models.
All analyses were performed using Stata 14.
3. RESULTS
Our study population consisted of 542 375 singleton‐pregnant women attending first trimester screening, with a mean age of 30 years (range 13;54) (Figure S1). The annual number of first trimester scans performed was similar throughout the study period, ranging from a minimum of 50 905 to a maximum of 56 694 pregnancies with a first trimester scan per year (data not shown). The distribution of sociodemographic and maternal characteristics of our study population differed by maternal age groups (Table 1).
TABLE 1.
Characteristics of study population (n, %) of singleton pregnant women attending first trimester screening in Denmark from 2008 to 2017.
| Total | <20 years | 20–29 years | 30–34 years | 35–39 years | 40–44 years | ≥45 years | p a | |
|---|---|---|---|---|---|---|---|---|
| N | 542 375 | 8115 | 251 756 | 185 025 | 83 485 | 13 652 | 342 | |
| Body mass index at first trimester scan b | ||||||||
| Underweight <18.5 | 34 731 (6.6) | 1194 (15.2) | 18 179 (7.4) | 10 722 (5.9) | 4041 (5.0) | 590 (4.5) | 5 (1.6) | <0.001 |
| Normal weight 18.5–25 | 312 028 (58.9) | 4273 (54.3) | 141 927 (57.6) | 109 951 (60.8) | 48 146 (59.1) | 7570 (57.0) | 161 (50.6) | |
| Overweight 25–30 | 114 756 (21.6) | 1520 (19.3) | 53 065 (21.5) | 38 355 (21.2) | 18 540 (22.8) | 3192 (24.1) | 84 (26.4) | |
| Obese >30 | 68 714 (13.0) | 888 (11.3) | 33 310 (13.5) | 21 805 (12.1) | 10 722 (13.2) | 1921 (14.5) | 68 (21.4) | |
| Smoking at first trimester scan b | ||||||||
| No | 480 (89.1) | 4856 (60.4) | 216 680 (86.5) | 170 104 (92.4) | 76 318 (92.0) | 12 405 (91.5) | 311 (93.1) | <0.001 |
| Stopped | 8905 (1.7) | 386 (4.8) | 5192 (2.1) | 2346 (1.3) | 855 (1.0) | 121 (0.9) | 5 (1.5) | |
| Yes | 50 051 (9.3) | 2805 (34.9) | 28 679 (11.5) | 11 717 (6.4) | 5806 (7.0) | 1026 (7.6) | 18 (5.4) | |
| Ethnicity | ||||||||
| Non‐Caucasian | 34 517 (6.5) | 525 (6.5) | 15 580 (6.3) | 11 791 (6.5) | 5529 (6.7) | 1035 (7.8) | 57 (17.1) | <0.001 |
| Caucasian | 499 685 (93.5) | 7522 (93.5) | 233 010 (93.7) | 170 130 (93.5) | 76 495 (93.3) | 12 252 (92.2) | 276 (82.9) | |
| Parity | ||||||||
| Nulliparous | 184 037 (33.9) | 5038 (62.1) | 114 66 (45.5) | 46 460 (25.1) | 15 444 (18.5) | 2482 (18.2) | 47 (13.7) | <0.001 |
| Primiparous | 157 372 (29.0) | 615 (7.6) | 64 007 (25.4) | 63 504 (34.3) | 25 409 (30.4) | 3767 (27.6) | 70 (20.5) | |
| Multiparous | 72 143 (13.3) | 34 (0.4) | 14 549 (5.8) | 29 468 (15.9) | 23 298 (27.9) | 4642 (34.0) | 152 (44.4) | |
| Missing | 128 823 (23.8) | 2428 (29.9) | 58 634 (23.3) | 45 593 (24.6) | 19 334 (23.2) | 2761 (20.2) | 73 (21.4) | |
| Mode of conception b | ||||||||
| Spontaneous | 499 384 (93.7) | 7927 (99.7) | 238 531 (96.3) | 169 139 (93.0) | 72 444 (88.4) | 11 049 (82.6) | 294 (88.8) | <0.001 |
| Assisted reproductive technology | 33 678 (6.3) | 23 (0.3) | 9058 (3.7) | 12 730 (7.0) | 9507 (11.6) | 2323 (17,4) | 37 (11.2) | |
p‐values from chi‐squared tests.
Less than 5% missing.
In our study population, 33 606 (6.2%) had a cytogenetic or molecular analysis performed pre‐ or postnatally; of these, 89% was by conventional karyotyping, 7% aneuploidy screening only (MLPA, QF‐PCR, FISH) and 6% chromosomal microarray. A total of 2358 (0.43% of total study population) of the pregnancies had a confirmed aneuploidy. A large majority of these aneuploidies were trisomy 21 (1415/2358, 60.0%) and trisomy 18 (377/2358, 16.0%), whereas trisomy 13 (128/2358, 5.4%), triploidy (117/2358, 5.0%), monosomy X (205/2358, 8.7%) and other sex chromosome aberrations (116/2358, 4.9%) occurred more rarely in all age groups (Table 2). Trisomies involving other chromosomes than chromosome 13, 18, 21 were not analyzed in this study. In our study, the prevalence per 10 000 pregnancies was 26.1 for trisomy 21, 7.0 for trisomy 18 and 2.4 for trisomy 13.
TABLE 2.
Frequencies, n (%) and risk odds ratios (OR), 95% CI of aneuploidies in singleton pregnancies in Denmark from 2008 to 2017 by median maternal age and maternal age groups.
| Total | Median age (years) | <20 years | 20–29 years | 30–34 years | 35–39 years | 40–44 years | ≥45 years | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 542 375 | 30 | 8115 | 251 756 | 185 025 | 83 485 | 13 652 | 342 | ||||||
| N (%) | OR (95% CI) | N (%) | OR | N (%) | OR (95% CI) | N (%) | OR (95% CI) | N (%) | OR (95% CI) | N (%) | OR (95% CI) | |||
| No aneuploidy | 540 017 (99.57) | 30 | 8102 (99.84) | 251 255 (99.80) | 184 404 (99.66) | 82 714 (99.08) | 13 223 (96.86) | 319 (93.27) | ||||||
| Any aneuploidy | 2358 (0.43) | 35 | 13 (0.16) | 0.80 (0.46–1.40) | 501 (0.20) | Ref. | 621 (0.34) | 1.69 (1.50–1.90) | 771 (0.92) | 4.67 (4.18–5.23) | 429 (3.14) | 16.27 (14.29–18.53) | 23 (6.73) | 36.16 (23.47–55.70) |
| Trisomy 21 | 1415 (0.26) | 36 | 7 (0.09) | 0.88 (0.42–1.87) | 246 (0.10) | Ref. | 343 (0.19) | 1.90 (1.61–2.24) | 516 (0.62) | 6.36 (5.46–7.40) | 292 (2.14) | 22.35 (18.84–26.50) | 11 (3.22) | 33.98 (18.40–62.76) |
| Trisomy 18 | 377 (0.07) | 36 | 3 (0.04) | 1.76 (0.55–5.62) | 53 (0.02) | Ref. | 87 (0.05) | 2.23 (1.59–3.14) | 132 (0.16) | 7.52 (5.47–10.34) | 94 (0.69) | 32.93 (23.50–46.13) | 8 (2.34) | 113.75 (53.67–241.08) |
| Trisomy 13 | 128 (0.02) | 34 | <3 | — | 33 (0.01) | Ref. | 33 (0.02) | 1.36 (0.84–2.20) | 45 (0.05) | 4.11 (2.63–6.45) | 14 (0.10) | 7.83 (4.19–14.63) | <3 | — |
| Triploidy | 117 (0.02) | 30 | <3 | — | 52 (0.02) | Ref. | 41 (0.02) | 1.07 (0.71–1.62) | 20 (0.02) | 1.16 (0.69–1.94) | 4 (0.03) | 1.42 (0.51–3.92) | <3 | — |
| Monosomy X | 205 (0.04) | 30 | <3 | — | 91 (0.04) | Ref. | 69 (0.04) | 1.03 (0.75–1.41) | 37 (0.04) | 1.23 (0.84–1.80) | 7 (0.05) | 1.42 (0.66–3.06) | <3 | — |
| Other sex chromosome aberrations | 116 (0.02) | 33 | <3 | — | 26 (0.01) | Ref. | 48 (0.03) | 2.51 (1.56–4.05) | 21 (0.03) | 2.44 (1.37–4.33) | 18 (0.13) | 12.78 (7.01–23.32) | < 3 | — |
Note: —meaning fewer than three cases and therefore not meaningful to report relative effect estimates. Absolute numbers can be found in Table 2.
Abbreviation: CI, confidence interval.
Overall, we found that the probability of aneuploidy increased by advancing maternal age (Figures 1 and 2; Table 2). Using pregnant women between 20 and 29 years of age as reference, pregnant women between 30 and 34 years had less than a two‐fold increased risk (OR 1.69, 95% CI: 1.50–1.90), pregnant women between 35 and 39 years had a fourfold increased risk (OR 4.67, 95% CI: 4.18–5.23), 40–44 years had a 16‐fold increased risk (OR 16.27, 95% CI: 14.29–18.53), and pregnant women ≥45 years had a 36‐fold increased risk (OR 36.16, 95% CI: 23.47–55.70) of any aneuploidy. Young pregnant women below 20 years did not have an increased risk of trisomy 13, 18 or 21 (Table 2). When stratifying our models by whether the pregnancy was achieved by assisted reproductive technology, we found similar effect estimates for the overall risk of aneuploidies by maternal age groups (data not shown).
FIGURE 1.
Probabilities of aneuploidies in singleton pregnancies by maternal ages.
FIGURE 2.
Probabilities (%) of specific aneuploidies by maternal ages.
Regarding specific aneuploidies, we observed significantly increased risks of trisomy 21, 18, 13 and other sex chromosome aberrations than monosomy X by maternal ages above 35 years compared with pregnant women aged 20–29 years. In contrast, we did not find any significant associations between maternal age and the risk of triploidy or monosomy X (Table 2; Figure 2).
To improve precision entailing the maternal age‐related risks of aneuploidies reported above, we looked further into those aneuploidies caused by translocations and mosaicism (Table 3). Trisomies due to translocations occurred at a lower median maternal age compared with other trisomies (Table 3). Similarly, cases of aneuploidies with mosaicism had a lower median maternal age compared with aneuploidies without mosaicism (Table 3). We examined our effect estimates after exclusions of translocation trisomies and mosaicisms in our logistic regression models. These sensitivity analyses yielded very similar effect estimates, thereby implying that cases with translation trisomies and mosaicisms were not likely to have an impact on the overall maternal age‐related risk of aneuploidies reported in our study population (Table S1). These subtypes, however, comprise only a very small proportion of all aneuploidies. Restricting analyses to data before 2015, to restrict misclassification error due to chromosomal microarray, did not affect the results.
TABLE 3.
Median maternal age for translocation trisomies and chromosomal mosaicism occurring in singleton pregnancies.
| Any aneuploidy | Down syndrome | Edward syndrome | Patau syndrome | Triploids | Turner syndrome | Other sex chromosome aberrations | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N a | Median maternal age (years) | N a | Median maternal age (years) | N a | Median maternal age (years) | N a | Median maternal age (years) | N a | Median maternal age (years) | N a | Median maternal age (years) | N a | Median maternal age (years) | |
| Translocation trisomy | ||||||||||||||
| No | 1866 | 36 | 1381 | 36 | 369 | 37 | 116 | 34.5 | — | — | — | — | — | — |
| Yes | 54 | 30 | 34 | 29 | 8 | 31.5 | 12 | 29.5 | — | — | — | — | — | — |
| Chromosomal mosaicism | ||||||||||||||
| No | 2233 | 35 | 1387 | 36 | 367 | 36 | 124 | 34 | 116 | 27.5 | 135 | 29 | 104 | 33 |
| Yes | 125 | 31 | 28 | 30.5 | 10 | 38 | 4 | 27 | < 3 | 20 | 70 | 31.5 | 12 | 31 |
Note: N a = number of chromosomal anomalies combined with either translocation trisomy or mosaicism. Restricting analyses to data before 2015, to restrict misclassification error due to chromosomal microarray, did not affect results.
4. DISCUSSION
In this large nationwide cohort of 542 375 singleton pregnancies followed from first trimester screening, we confirm the well‐known increased risk for the most common types of aneuploidies of the fetus, such as trisomy 21 and 18 by maternal ages above 30 years, and with a substantially higher risk observed for pregnant women above 35 years of age.
This study contributes novel findings on more rare aneuploidies, where we found increased risks of trisomy 13 and other sex chromosome aberrations by maternal ages above 35 years and verify that the risks of triploidy or monosomy X are age independent. Furthermore, we add knowledge regarding subtypes of aneuploidies; translocation trisomies and mosaicisms. Although we observed lower median maternal ages for these few subtypes, they did not appear to influence the overall reported association between maternal age and aneuploidies in the entire cohort.
A previous study of pregnant women in Denmark between 2005 and 2014 reported an overall first‐trimester prevalence per 10 000 pregnancies for trisomy 21, 18 and 13 similar to our reported prevalence. 26 This prevalence is very similar to our study findings. Our study also included pregnant women below 20 years of age and included the data on pregnant women with antenatal screening in more recent years. In addition to the study by Hartwig and colleagues, 26 we focused on disentangling the maternal age‐related effect on aneuploidies that were attributable to subtypes of translocation trisomies or mosaicisms. In line with our findings, Zhang et al. reported relative risk for trisomy 21 of 6.64 (95% CI: 5.55–7.93) and for trisomy 18 of 6.83 (95% CI: 5.63–8.30) for trisomy 18 in pregnant women aged ≥35 years in comparison with pregnant women aged 25–29 years. 16 Contrary to our study, Kim et al. observed no significant association between maternal age and risk of trisomy 13. 15 However, their study was based on data from a high‐risk group of pregnant women who underwent amniocentesis or chorionic villous sampling. Many prior studies have had too limited power to provide meaningful estimates on a maternal age‐related risk of more specific and rare types of aneuploidies, such as triploidy, monosomy X and other sex chromosome aberrations, 14 , 15 and therefore this study fills a needed gap in the existing literature.
Our study included a large nationwide and unselected cohort of singleton pregnant women with virtually complete information on pregnancy outcomes, thereby minimizing selection bias. 27 Moreover, the very high participation rate in first‐trimester screening in Denmark contributed to a highly representative study population, and our findings therefore apply to the general population of pregnant women. Information on chromosomal anomalies of the fetus was prospectively collected and reported by clinical experts, which reduce the risk of information bias. Additionally, two genetic experts (I.V. and L.R.) validated all karyotypes used for this study. A considerable strength of this study was the ability to follow the pregnant women from an early gestational age and include also prenatally detected fetuses with aneuploidies. In Denmark, a considerable proportion of fetuses are cytogenetically examined in case of a late miscarriage or stillbirth. Therefore, our findings suggest a more accurate association and an important contribution to the existing literature, whereas most studies have only previously assessed the association only among live born children.
The findings of this study should also be interpreted in light of certain limitations. Despite our large cohort of pregnant women, the reported estimates of trisomy 13 in the more advanced maternal age groups are based on low numbers and should be interpreted with caution.
As we included the pregnancies at the time of first‐trimester screening (GA 11–13), this study does not include cases of aneuploidies that resulted in miscarriages prior to this, and since a great proportion of very early miscarriages will have chromosomal abnormalities, this study does not report the overall risk of aneuploidy in pregnancy, but the age‐related risk at the end of first trimester. However, we did include postnatally detected cases among live born children within 1–2 years after birth. Sex chromosome aberrations are also likely to be diagnosed at much later ages postnatally and were thereby likely not included in our study. As a result, the absolute risk of sex chromosome abnormalities might be higher than observed in this study. We did not adjust for any confounders. A previous study from Denmark found no evidence that body mass index, smoking or ethnicity was a confounding factor in the association between advanced maternal age and the risk of chromosomal abnormalities. 2
Second, the absolute numbers of aneuploidies reported in this study should be interpreted with caution considering the available screening techniques. Since free trisomies and translocation trisomies can only be distinguished with chromosome analysis and not with molecular techniques such as MLPA or array comparative genomic hybridization (CGH), we may have underestimated the number of cases with translocation trisomies in the later years, but restriction of data prior to 2015 did not affect the results.
5. CONCLUSION
In this study we provide insight into the accurate risk of fetal aneuploidy that pregnant women of advanced age encounter at the end of the first trimester. We confirm the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially among pregnant women aged ≥35 years, whereas we found no age‐related associations with triploidy or monosomy X. Our reported associations between maternal age and aneuploidies were not substantially influenced by subtypes of trisomies such as translocations or mosaicisms.
The maternal age‐related risk is already included in the well‐established combined first trimester screening program in Denmark. In the future, the first trimester screening program may be extended to include a more comprehensive screening for more chromosomal aberrations than trisomy 13, 18 and 21 using appropriately designed algorithms which includes age‐related risk estimates, as provided by this study. Improved antenatal screening and care services are of high clinical and public health importance considering the growing number of pregnant women conceiving at an advanced maternal age.
AUTHOR CONTRIBUTIONS
LEF retrieved the data and performed the majority of the data analyses, SMØ reviewed the data and completed the manuscript. LR and IV reviewed and grouped the genetics data. All authors contributed to the manuscript and revisions.
FUNDING INFORMATION
Olav Bjørn Petersen holds a professorship funded by Novo Nordisk Foundation grant NNFSA170030576 and Ida Vogel by Novo Nordisk Foundation grant NNF16OC0018772.
CONFLICT OF INTEREST STATEMENT
None of the authors have any conflicts of interest to report.
6. Ethics statement
The study was originally approved by the Danish Data Protection Agency (2018‐521‐0047) and the Danish Fetal Medicine Database (FØTO‐2018‐12‐21) on December 21, 2018. The project is listed in the local archive list DCS‐DCRC‐2100 (2018‐DCRC‐0048).
Supporting information
Figure S1.
Table S1.
ACKNOWLEDGMENTS
The Danish Fetal Medicine Database and the Danish Central Cytogenetic Registry contributed data to this study.
Elmerdahl Frederiksen L, Ølgaard SM, Roos L, et al. Maternal age and the risk of fetal aneuploidy: A nationwide cohort study of more than 500 000 singleton pregnancies in Denmark from 2008 to 2017. Acta Obstet Gynecol Scand. 2024;103:351‐359. doi: 10.1111/aogs.14713
Line Elmerdahl Frederiksen and Sofie Møller Ølgaard contributed equally.
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Supplementary Materials
Figure S1.
Table S1.