Abstract
Introduction
Nuchal translucency prenatal ultrasound is widely used to screen for chromosomal abnormalities. An elevated nuchal translucency has been associated with adverse outcomes such as pregnancy loss; however, extant studies investigating these associations have had important limitations, including selection bias. This study aimed to investigate the association between nuchal translucency measurements and pregnancy outcome, specifically, a composite of pregnancy loss, termination, stillbirth, or neonatal death.
Material and Methods
This was a population‐based retrospective cohort study conducted with data from the prescribed perinatal registry in Ontario, Canada, Better Outcomes Registry & Network. All singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, and multiple marker screening including a nuchal translucency were included. Pregnancies with measurements 2.0‐ < 2.5 mm, 2.5‐ < 3.0 mm, 3.0‐ < 3.5 mm, 3.5‐ < 5.0 mm, 5.0‐ < 6.5 mm, and ≥6.5 mm were compared to a reference group with measurements <2.0 mm. We used multivariable modified Poisson regression models with robust variance estimation to estimate associations between nuchal translucency measurement and pregnancy outcome, with adjustment for age at estimated date of delivery and gestational age at screening.
Results
There were 414 268 singleton pregnancies included in the study. The risk of pregnancy loss, termination, stillbirth, or neonatal death increased with increasing levels of nuchal translucency measurements, with an adjusted risk ratio (aRR) of 11.9 (95% confidence interval (CI) 9.9, 14.3) in the group with measurements 3.5‐ < 5.0 mm. When pregnancies with diagnosed chromosomal abnormalities were excluded, this association remained strong, with an aRR of 6.4 (95% CI 4.8, 8.5). Among pregnancies with a live birth, those with a higher nuchal translucency measurement (>5.0 mm vs. <2.0 mm) were also at increased risk of adverse perinatal outcomes such as admission to the neonatal intensive care unit and APGAR score <7.
Conclusions
In this population‐based study using robust methods to reduce the risk of selection bias, we found that pregnancies with increased nuchal translucency measurements are less likely to result in a live birth, even with the exclusion of chromosomal abnormalities. Pregnancies with increased nuchal translucency measurements that resulted in a live birth may also be at increased risk of adverse perinatal outcomes.
Keywords: chromosomal abnormalities, nuchal translucency, perinatal outcomes, pregnancy outcome, prenatal screening
Studies investigating the association between nuchal translucency measurements and pregnancy outcomes have been subject to selection bias. This study provides robust evidence of the increased risk of pregnancy loss, termination, stillbirth, or neonatal death with increasing nuchal translucency measurements.
Abbreviations
- aRR
adjusted risk ratio
- aRD
adjusted risk difference
- 95%CI
95% confidence interval
Key message.
Studies investigating the association between nuchal translucency measurements and pregnancy outcomes have been subject to selection bias. This study provides robust evidence of the increased risk of pregnancy loss, termination, stillbirth, or neonatal death with increasing nuchal translucency measurements.
1. INTRODUCTION
Fetal nuchal translucency results from an accumulation of fluid located posteriorly to the fetal neck. 1 In many prenatal screening programs in Canada and internationally, pregnant individuals are offered multiple marker screening to detect trisomies 21 and 18, often incorporating information from this nuchal translucency ultrasound given its association with aneuploidy, first identified in the early 1990s. 2 , 3 When an increased nuchal translucency (traditionally defined as a measurement greater or equal to 3.5 mm 4 ) is identified in this context, follow‐up investigations such as prenatal diagnosis with cytogenetic testing or cell‐free DNA (cfDNA) screening are routinely offered to pregnant individuals to confirm chromosomal abnormalities.
Although the main purpose of the nuchal translucency measurement is to calculate the risk of trisomies 21 and 18 for the multiple marker screening result, an increased nuchal translucency measurement can be associated with other important outcomes. In a large population‐based study, 33.9% of pregnancies with a nuchal translucency measurement greater of equal to 3.5 mm were diagnosed with a chromosomal abnormality identified by traditional cytogenetic techniques, 30.1% of which were chromosomal abnormalities other than trisomies 21 and 18. 5 After excluding common aneuploidies, an additional diagnostic yield for copy number variants of up to 6.1% is reported for microarray analysis. 6 Additionally, an isolated increased nuchal translucency measurement can be associated with single‐gene conditions, with 1.0% of pregnancies being diagnosed through a RASopathy panel or 3.7% through exome sequencing. 7 , 8 An increased nuchal translucency measurement can also be predictive of a structural defect, most notably heart defects. 9 Given the association between an increased nuchal translucency measurement and conditions beyond the common aneuploidies, offering further investigations beyond cfDNA screening is warranted in this context.
Studies have also reported an increased risk of pregnancy loss with elevated nuchal translucency measurements. 10 , 11 , 12 However, studies investigating the outcomes of pregnancies with increased nuchal translucency have largely focused only on the minority of pregnancies where individuals received cytogenetic testing and/or additional ultrasound investigations conducted at tertiary care centers, and had normal results. 13 , 14 , 15 To fully understand the association of nuchal translucency levels with pregnancy outcomes, there is a need to investigate this relationship at the population level, that is, among all pregnancies receiving a nuchal translucency measurement as part of prenatal screening; and to understand whether increased nuchal translucency measurements are associated with additional risks in the perinatal period.
The primary objective of the present study was to estimate the association between nuchal translucency measurements and pregnancy outcomes in the fully screened population in Ontario by defining whether the pregnancy resulted in a loss, termination, stillbirth, or neonatal death. Understanding this association in an unselected sample of pregnant individuals, regardless of follow‐up confirmatory testing received, can support the interpretation of nuchal translucency measurement results at the time they are received. Our secondary objective was to estimate the relationship (overall and for pregnancies without diagnosed chromosomal abnormalities) between nuchal translucency measurements and outcomes indicative of perinatal complications (preterm birth, admission to the neonatal intensive care unit, APGAR score <7 and small for gestational age), for those pregnancies resulting in a live birth.
2. MATERIAL AND METHODS
This population‐based cohort study was approved by the research ethics board of the Children's Hospital of Eastern Ontario (protocol # 22/03PE), and the University of Ottawa (protocol # H‐06‐22‐8234). Given that this study was conducted with data from a prescribed registry, obtaining individual patient consent was not required. To comply with privacy requirements, numbers <6 are not presented. Reporting was guided by the RECORD statement. 16
2.1. Data sources
The Better Outcomes Registry & Network (BORN) is Ontario's prescribed perinatal registry and collects data directly from all prenatal screening and diagnostic laboratories in the province. 17 BORN Ontario also collects information on pregnancy and postnatal outcomes from labor and delivery units and neonatal intensive care units. 17 BORN data are linked to the hospital Discharge Abstract Database from the Canadian Institute for Health Information (CIHI), providing supplemental information from all Ontario hospital births on pregnancy outcomes and perinatal outcomes, including congenital anomalies (Table S1). 18
2.2. Setting and study population
In Ontario, prenatal genetic screening is publicly funded in the form of a mixed contingent model where multiple marker screening is offered to all pregnant individuals, and cfDNA screening is offered to those who meet specific eligibility criteria, including as a second‐tier screen for those with a positive multiple marker screening result. A nuchal translucency measurement is included in more than 90% of multiple marker screens. 19 The province has considerable variability in terms of socio‐economic status, race/ethnicity, and geography, which renders varying access to some aspects of prenatal care (eg nuchal translucency ultrasound is more difficult to access in some remote regions).
All sonographers providing nuchal translucency measurements in the context of multiple marker screening are enrolled in Ontario's Nuchal Translucency Quality Assurance Program. 20
We included all singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, and with a multiple marker screening test result including a nuchal translucency measurement. Pregnancies for which the nuchal translucency was measured outside the internationally recognized range of 45–84 mm crown‐rump length were excluded (Figure 1). 21
FIGURE 1.
Inclusion flow for pregnancies included in the study.
2.3. Study exposure
Nuchal translucency measurements were identified through multiple marker screening results in the registry and categorized as follows: <2.0 mm (reference group), 2.0‐ < 2.5 mm, 2.5‐ < 3.0 mm, 3.0‐ < 3.5 mm, 3.5‐ < 5.0 mm, 5.0‐ < 6.5 mm, and ≥6.5 mm.
2.4. Study outcome
Our primary outcome of interest was pregnancy outcome, defined as a composite of pregnancy loss, termination, stillbirth, or a neonatal death that occurred during the index pregnancy delivery admission. The outcome was identified through the registry's birth encounter data with supplementation from hospital discharge data. Pregnancies with diagnosed chromosomal abnormalities were identified based on prenatal or postnatal cytogenetic testing which included rapid aneuploidy detection techniques such as Fluorescent In Situ Hybridization (FISH) and Quantitative Fluorescent Polymerase Chain Reaction (QF‐PCR), karyotype, and microarray analysis; a detailed description of these pregnancies is provided in a previous publication. 22
Secondary outcomes were identified among the subgroup of pregnancies that resulted in a live birth and included: preterm birth, defined as a birth before 37 weeks' gestation; admission to the neonatal intensive care unit (NICU) for more than 12 hours; 5‐minute APGAR score below 7; and small for gestational age, defined as smaller than the 10th percentile for the corresponding gestational age. 23
2.5. Statistical analyses
We used means and standard deviations to describe continuous variables, and frequencies and proportions to describe categorical variables. We used multivariable modified Poisson regression models with robust variance estimation to generate risk ratios as well as risk differences to compare pregnancy outcomes among pregnancies with varying levels of nuchal translucency measurements relative to the reference group of pregnancies with measurements <2.0 mm. This analysis accounted for non‐independence of individuals with more than one pregnancy during the study period. We identified gestational age at screening and age of the pregnant individual at estimated date of delivery as potential confounders a priori and therefore included these variables as covariates in the adjusted models. The primary analysis was repeated excluding pregnancies with identified chromosomal abnormalities, to assess if any association was solely due to the increased risk of chromosomal abnormalities with increasing nuchal translucency.
While we mitigated against selection bias by including all pregnancies in the screened population, some potential for residual bias remained given that there were pregnancies for which no outcome was available in our registry data. This was particularly important to examine in sensitivity analyses given that the proportion of such pregnancies increased with increasing nuchal translucency measurements. These pregnancies that were lost to follow‐up could represent early pregnancy losses or terminations, or pregnant individuals who had multiple marker screening in Ontario but subsequently received care outside the province. Thus, in two sensitivity analyses we randomly assigned pregnancies for which no outcome was recorded (lost to follow‐up) to either experiencing or not experiencing the outcome. This was done under assumptions that pregnancies lost to follow‐up had half the risk of the composite pregnancy outcome compared to those for which an outcome was recorded within the same category of nuchal translucency measurement in a conservative approach; or twice the risk for a more theoretically realistic approach, respectively (Figure S1). This analysis was also conducted with the exclusion of pregnancies with identified chromosomal abnormalities (Figure S2).
We conducted a further sensitivity analysis to qualitatively evaluate the potential for bias in analyses that are restricted to only those pregnancies receiving cytogenetic testing, with normal results, as has been common practice in previous studies on this topic (Table S2).
While the registry routinely captures pregnancy outcomes after 20 weeks' gestation, early losses or terminations before 20 weeks' gestation are not systematically captured. While we wanted to capture those early pregnancy losses that were included in the registry, pregnancies with an increased nuchal translucency measurement (defined as a measurement greater or equal to 3.5 mm) may be subject to closer ascertainment of these outcomes. A sensitivity analysis including only those pregnancies with outcomes recorded after 20 weeks' gestation was, therefore, performed to account for this potential ascertainment bias (Table S3).
Additional sensitivity analyses explored different lengths of stay for NICU admissions (Table S4).
We performed all study analyses using SAS, version 9.4 (SAS Institute Inc, Cary, NC).
3. RESULTS
From 643 146 singleton pregnancies recorded in the registry during the study period, 458 240 pregnant individuals had multiple marker screening, of which 414 268 received a valid multiple marker screening result that included a nuchal translucency measurement and were included in this study (Figure 1). Most pregnancies (359 807, 86.9%) had a nuchal translucency measurement <2.0 mm and comprised the reference group, while 10.4% were in the category 2.0‐ < 2.5 mm, 1.8% in 2.5‐ < 3.0 mm, 0.4% in 3.0‐ < 3.5 mm, 0.3% in 3.5‐ < 5.0 mm, 0.1% in 5.0‐ < 6.5 mm and 0.1% in ≥6.5 mm (Table 1). The mean age of pregnant individuals increased with increasing nuchal translucency categories; no other trends in characteristics of the population by nuchal translucency were apparent. The proportion of pregnancies with missing data regarding parity and method of conception increased with increasing nuchal translucency measurement; the distribution of these characteristics should therefore be interpreted with caution.
TABLE 1.
Characteristics of study population by nuchal translucency measurement.
Characteristic | Pregnancies with nuchal translucency measurement | Nuchal translucency measurement (mm) | ||||||
---|---|---|---|---|---|---|---|---|
<2.0 | 2.0‐ < 2.5 | 2.5‐ < 3.0 | 3.0‐ < 3.5 | 3.5‐ < 5.0 | 5.0‐ < 6.5 | ≥6.5 | ||
Total | 414 268 | 359 807 | 43 219 | 7474 | 1789 | 1088 | 404 | 487 |
Age, EDD Mean years (SD) | 31.5 (4.7) | 31.5 (4.7) | 31.6 (4.8) | 31.9 (4.8) | 32.2 (4.8) | 32.8 (5.0) | 33.0 (5.5) | 33.3 (5.4) |
Gestational age at screening Mean days (SD) | 87.8 (3.3) | 87.5 (3.3) | 90.0 (2.6) | 90.0 (3.0) | 88.9 (3.4) | 87.3 (3.6) | 86.4 (3.6) | 86.9 (3.1) |
Weight Mean kg (SD) | 68 (17.0) | 67.9 (16.9) | 68.5 (17.4) | 68.3 (17.3) | 68.1 (17.0) | 67.2 (16.6) | 68.8 (17.8) | 67.0 (14.0) |
Parity, n(%) | ||||||||
Nulliparous | 183 587 (46.2) | 161 994 (46.8) | 17 689 (42.7) | 2847 (40.3) | 595 (37.5) | 314 (39.4) | 81 (46.0) | 67 (45.6) |
Primiparous | 143 190 (36.0) | 123 661 (35.7) | 15 760 (38.0) | 2739 (38.7) | 614 (38.7) | 320 (40.2) | 56 (31.8) | 40 (27.2) |
Multiparous | 70 967 (17.8) | 60 848 (17.6) | 8012 (19.3) | 1487 (21.0) | 378 (23.8) | 163 (20.5) | 39 (22.2) | 40 (27.2) |
Missing | 16 524 | 13 304 | 1758 | 401 | 202 a | 291 a | 228 a | 340 a |
Conception, n(%) | ||||||||
Spontaneous | 374 873 (96.0) | 326 450 (96.0) | 38 712 (95.9) | 6685 (95.9) | 1568 (96.1) | 876 (96.4) | 275 (96.8) | 307 (97.5) |
IVF | 12 025 (3.1) | 10 429 (3.1) | 1289 (3.2) | 220 (3.2) | 49 (3.0) | 22 (2.4) | 8 (2.8) | 8 (2.5) |
Other ART | 3659 (0.9) | 3188 (0.9) | 378 (0.9) | 66 (0.9) | 15 (0.9) | 11 (1.2) | <6 (S) | 0 (0.0) |
Missing | 23 711 | 19 740 | 2840 | 503 | 157 | 179 a | 120 a | 172 a |
Smoking, n(%) | ||||||||
Nonsmoker | 358 781 (91.8) | 312 038 (92.0) | 37 006 (90.5) | 6458 (90.3) | 1542 (90.5) | 953 (92.9) | 364 (94.5) | 420 (93.1) |
Smoker | 32 117 (8.2) | 27 264 (8.0) | 3874 (9.5) | 693 (9.7) | 161 (9.5) | 73 (7.1) | 21 (5.5) | 31 (6.9) |
Missing | 23 370 | 20 505 | 2339 | 323 | 86 | 62 | 19 | 36 |
Neighborhood Income Quintile, n(%) | ||||||||
First | 84 356 (20.7) | 73 001 (20.6) | 9057 (21.3) | 1564 (21.3) | 343 (19.6) | 217 (20.4) | 91 (23.0) | 83 (17.4) |
Second | 84 977 (20.9) | 73 596 (20.8) | 8929 (21.0) | 1647 (22.4) | 382 (21.8) | 224 (21.1) | 95 (24.0) | 104 (21.8) |
Third | 87 373 (21.4) | 76 165 (21.5) | 8984 (21.2) | 1476 (20.1) | 365 (20.9) | 209 (19.7) | 63 (15.9) | 111 (23.3) |
Fourth | 83 373 (20.5) | 72 711 (20.5) | 8496 (20.0) | 1407 (19.1) | 364 (20.8) | 216 (20.3) | 79 (19.9) | 100 (21.0) |
Fifth | 67 279 (16.5) | 58 379 (16.5) | 7001 (16.5) | 1259 (17.1) | 296 (16.9) | 197 (18.5) | 68 (17.2) | 79 (16.6) |
Missing | 6910 | 5955 | 752 | 121 | 39 | 25 | 8 | 10 |
Neighborhood Education Quintile, n(%) | ||||||||
First | 51 317 (13.6) | 44 203 (13.5) | 5677 (14.5) | 968 (14.3) | 236 (14.6) | 143 (14.6) | 43 (12.1) | 47 (10.5) |
Second | 69 246 (18.4) | 59 896 (18.3) | 7431 (19.0) | 1259 (18.5) | 333 (20.7) | 165 (16.8) | 77 (21.8) | 85 (18.9) |
Third | 83 534 (22.2) | 72 957 (22.3) | 8396 (21.4) | 1474 (21.7) | 313 (19.4) | 218 (22.2) | 72 (20.3) | 104 (23.2) |
Fourth | 94 749 (25.2) | 82 688 (25.3) | 9496 (24.2) | 1665 (24.5) | 422 (26.2) | 264 (26.9) | 97 (27.4) | 117 (26.1) |
Fifth | 77 202 (20.5) | 66 954 (20.5) | 8165 (20.8) | 1423 (21.0) | 308 (19.1) | 191 (19.5) | 65 (18.4) | 96 (21.4) |
Missing | 38 220 | 33 109 | 4054 | 685 | 177 | 107 | 50 a | 38 |
Abbreviations: ART, Assisted reproductive technology; EDD, Estimated date of delivery; IVF, in vitro fertilization; SD, standard deviation.
Missing data for more than 10.0% of the pregnancies.
The proportion of pregnancies experiencing the composite outcome of pregnancy loss, termination, stillbirth, or neonatal death among those for which an outcome was recorded increased with increasing nuchal translucency measurements, from 1.0% in the group with measurements <2.0 mm to 57.7% in the group with the highest nuchal translucency measurements (≥6.5 mm) (Table 2). After excluding pregnancies for which a chromosomal abnormality was identified, the same trend was observed with some attenuation in the magnitude of the increase: 1.0% in the group with nuchal translucencies <2.0 mm experienced the composite outcome of either pregnancy loss, termination, stillbirth, or neonatal death, increasing to 41.8% in the group with measurements ≥6.5 mm. The proportion of pregnancies for which outcomes were unavailable (lost to follow‐up) increased with nuchal translucency measurements, from 3.0% in pregnancies with a measurement <2.0 mm to 65.5% in the group with a measurement ≥6.5 mm. With increasing nuchal translucency, the proportion of pregnancies experiencing each individual outcome included in the composite also increased. The most common of these component outcomes were pregnancy loss and termination; pregnancy termination comprised an increasing proportion of outcomes in the composite with increasing nuchal translucency (Table 2).
TABLE 2.
Overall pregnancy outcomes by nuchal translucency measurement category.
Overall | Nuchal translucency measurement (mm) | |||||||
---|---|---|---|---|---|---|---|---|
<2.0 | 2.0‐ < 2.5 | 2.5‐ < 3.0 | 3.0‐ < 3.5 | 3.5‐ < 5.0 | 5.0‐ < 6.5 | ≥6.5 | ||
A. All pregnancies | 414 268 | 359 807 | 43 219 | 7474 | 1789 | 1088 | 404 | 487 |
Pregnancies with a recorded outcome | 400 625 (96.7) | 348 947 (97.0) | 41 753 (96.6) | 7133 (95.4) | 1608 (89.9) | 824 (75.7) | 192 (47.5) | 168 (34.5) |
Live birth without neonatal death, n (%) | 396 148 (98.9) | 345 404 (99.0) | 41 313 (98.9) | 6988 (98.0) | 1527 (95.0) | 722 (87.6) | 123 (64.1) | 71 (42.3) |
Total composite outcome | 4477 (1.1) | 3543 (1.0) | 440 (1.1) | 145 (2.0) | 81 (5.0) | 102 (12.4) | 69 (35.9) | 97 (57.7) |
Pregnancy loss, n (%) | 468 (0.1) | 381 (0.1) | 37 (0.1) | 14 (0.2) | 6 (0.4) | 8 (1.0) | 6 (3.1) | 16 (9.5) |
Stillbirth, n (%) | 1602 (0.4) | 1356 (0.4) | 168 (0.4) | 40 (0.6) | 9 (0.6) | 8 (1.0) | 11 (5.7) | 10 (6.0) |
Termination, n (%) | 1396 (0.3) | 961 (0.3) | 134 (0.3) | 66 (0.9) | 54 (3.4) | 73 (8.9) | 45 (23.4) | 63 (37.5) |
Neonatal death, n (%) | 1011 (0.3) | 845 (0.2) | 101 (0.2) | 25 (0.4) | 12 (0.7) | 13 (1.6) | 7 (3.6) | 8 (4.8) |
Pregnancies with no recorded outcome (lost to follow‐up) | 13 643 (3.3) | 10 860 (3.0) | 1466 (3.4) | 341 (4.6) | 181 (10.1) | 264 (24.3) | 212 (52.5) | 319 (65.5) |
B. Pregnancies with chromosomal abnormalities excluded | ||||||||
Total pregnancies, chromosomal abnormalities excluded | 410 836 | 357 894 | 42 763 | 7276 | 1610 | 832 | 230 | 231 |
Pregnancies with a recorded outcome | 398 235 (96.9) | 347 338 (97.1) | 41 414 (96.8) | 7006 (96.3) | 1529 (95.0) | 718 (86.3) | 132 (57.4) | 98 (42.4) |
Live birth without neonatal death, n (%) | 394 302 (99.0) | 344 022 (99.0) | 41 052 (99.1) | 6905 (98.6) | 1487 (97.3) | 674 (93.9) | 105 (79.5) | 57 (58.2) |
Total composite outcome | 3933 (1.0) | 3316 (1.0) | 362 (0.9) | 101 (1.4) | 42 (2.7) | 44 (6.1) | 27 (20.5) | 41 (41.8) |
Pregnancy loss, n (%) | 432 (0.1) | 372 (0.1) | 33 (0.1) | 14 (0.2) | <6 (S) | <6 (S) | <6 (S) | <6 (S) |
Stillbirth, n (%) | 1549 (0.4) | 1327 (0.4) | 164 (0.4) | 35 (0.5) | 7 (0.5) | 6 (0.8) | <6 (S) | <6 (S) |
Termination, n (%) | 1001 (0.3) | 804 (0.2) | 76 (0.2) | 31 (0.4) | 22 (1.4) | 26 (3.6) | 15 (11.4) | 27 (27.6) |
Neonatal death, n (%) | 951 (0.2) | 813 (0.2) | 89 (0.2) | 21 (0.3) | 8 (0.5) | 8 (1.1) | <6 (S) | 7 (7.1) |
Pregnancies with no recorded outcome (lost to follow‐up) | 12 601 (3.1) | 10 556 (3.0) | 1349 (3.2) | 270 (3.7) | 81 (5.0) | 114 (13.7) | 98 (42.6) | 133 (57.6) |
Note: a visual representation of the incidence of perinatal outcomes by nuchal translucency measurement category is presented in Figure S3.
3.1. Results for primary outcomes
The analysis of the full cohort of pregnancies showed an increased risk of the composite of pregnancy loss, termination, stillbirth, or neonatal death with increasing nuchal translucency measurements (Figure 2), with an aRD of 11.2% (95% CI 9.0, 13.5) and aRR of 11.9 (95% CI 9.9, 14.3) for pregnancies with nuchal translucency measurements from 3.5 to <5.0 mm. Sensitivity analyses conducted to account for losses to follow‐up showed similar results with slight attenuation or accentuation of the association depending on whether the losses to follow‐up were assumed to have either half or twice the risk of the composite outcome compared to those for which an outcome was recorded, respectively, within each category of nuchal translucency measurement (Figure S1).
FIGURE 2.
Pregnancy outcomes by nuchal translucency measurement, main analysis and analysis excluding pregnancies with identified chromosomal abnormalities.
The regression models were also performed with the exclusion of pregnancies for which a chromosomal abnormality had been identified to determine if the nuchal translucency measurement was associated with pregnancy outcomes independently of chromosomal abnormalities. Although attenuated, the association remained significant in all groups relative to the reference category of <2.0 mm, apart from pregnancies with a nuchal translucency measurement between 2.0 and <2.5 mm (Figure 2).
The sensitivity analysis restricted to pregnancies with cytogenetic testing results available, and with normal results, yielded different findings, with a very attenuated association between nuchal translucency and the composite outcome of pregnancy loss, termination, stillbirth, or neonatal death that was apparent only in pregnancies with nuchal translucency measurements ≥5.0 mm (Table S2).
The results of the sensitivity analysis including only pregnancy outcomes captured after 20 weeks' gestation were mildly attenuated, but not qualitatively different from the main findings (Table S3).
3.2. Results for secondary outcomes
We also performed a series of analyses to assess the relationship between nuchal translucency measurements and perinatal outcomes among pregnancies that resulted in a live birth. Pregnancies with very high nuchal translucency measurements (i.e., ≥5.0 mm) were at risk of some adverse perinatal outcomes such as neonatal intensive care unit admission or having an APGAR score below 7, even when pregnancies with identified chromosomal abnormalities were excluded (Table 3).
TABLE 3.
Perinatal outcomes by nuchal translucency measurement among pregnancies with a recorded live birth.
Main model, full analytical sample | Sample excluding chromosomal abnormalities | |||||
---|---|---|---|---|---|---|
No. (%) | RD, %, (95% CI) | RR, (95% CI) | No. (%) | RD, %, (95% CI) | RR, (95% CI) | |
Preterm birth | ||||||
NT <2.0 mm | 21 022 (6.1) | Ref. | Ref. | 20 796 (6.1) | Ref. | Ref. |
NT 2.0‐ < 2.5 mm | 2363 (5.7) | −0.4 (−0.6 to −0.1) | 0.9 (0.9 to 1.0) | 2318 (5.7) | −0.4 (−0.6 to −0.2) | 0.9 (0.9 to 1.0) |
NT 2.5‐ < 3.0 mm | 391 (5.6) | −0.5 (−1.1 to 0.1) | 0.9 (0.8 to 1.0) | 379 (5.5) | −0.6 (−1.1 to 0.0) | 0.9 (0.8 to 1.0) |
NT 3.0‐ < 3.5 mm | 97 (6.4) | 0.3 (−1.0 to 1.5) | 1.0 (0.9 to 1.3) | 86 (5.8) | −0.3 (−1.5 to 0.9) | 1.0 (0.8 to 1.2) |
NT 3.5‐ < 5.0 mm | 57 (7.8) | 1.8 (−0.2 to 3.7) | 1.3 (1.0 to 1.7) | 40 (6.0) | −0.1 (−1.9 to 1.7) | 1.0 (0.7 to 1.3) |
NT 5.0‐ < 6.5 mm | 18 (14.1) | 8.0 (1.9 to 14.0) | 2.3 (1.5 to 3.5) | 14 (13.0) | 6.9 (0.6 to 13.2) | 2.1 (1.3 to 3.5) |
NT ≥6.5 mm | 9 (12.3) | 6.2 (−1.3 to 13.8) | 2.0 (1.1 to 3.7) | 6 (10.0) | 3.9 (−3.7 to 11.5) | 1.6 (0.8 to 3.5) |
Missing | 2939 | 2888 | ||||
NICU admission | ||||||
NT <2.0 mm | 34 322 (10.0) | Ref. | Ref. | 33 875 (9.9) | Ref. | Ref. |
NT 2.0‐ < 2.5 mm | 3852 (9.4) | −0.6 (−0.9 to −0.3) | 0.9 (0.9 to 1.0) | 3771 (9.2) | −0.7 (−1.0 to −0.4) | 0.9 (0.9 to 1.0) |
NT 2.5‐ < 3.0 mm | 720 (10.4) | 0.4 (−0.4 to 1.1) | 1.0 (0.9 to 1.1) | 684 (10.0) | 0.1 (−0.7 to 0.8) | 1.0 (0.9 to 1.1) |
NT 3.0‐ < 3.5 mm | 173 (11.4) | 1.4 (−0.2 to 3.0) | 1.1 (0.9 to 1.3) | 154 (10.4) | 0.5 (−1.1 to 2.1) | 1.1 (0.9 to 1.2) |
NT 3.5‐ < 5.0 mm | 114 (15.9) | 5.9 (3.2 to 8.5) | 1.6 (1.3 to 1.9) | 84 (12.5) | 2.6 (0.1 to 5.1) | 1.3 (1.0 to 1.5) |
NT 5.0‐ < 6.5 mm | 31 (24.4) | 14.4 (6.9 to 21.9) | 2.4 (1.8 to 3.3) | 19 (17.8) | 7.9 (0.6 to 15.1) | 1.8 (1.2 to 2.7) |
NT ≥6.5 mm | 20 (27.4) | 17.4 (7.2 to 27.6) | 2.7 (1.9 to 4.0) | 12 (20.0) | 10.1 (0.0 to 20.2) | 2.0 (1.2 to 3.3) |
Missing | 3495 | 3425 | ||||
APGAR <7 | ||||||
NT <2.0 mm | 6124 (1.8) | Ref. | Ref. | 6042 (1.8) | Ref. | Ref. |
NT 2.0‐ < 2.5 mm | 784 (1.9) | 0.1 (0.0 to 0.3) | 1.1 (1.0 to 1.2) | 765 (1.9) | 0.1 (0.0 to 0.3) | 1.1 (1.0 to 1.1) |
NT 2.5‐ < 3.0 mm | 139 (2.0) | 0.2 (−0.1 to 0.5) | 1.1 (0.9 to 1.3) | 135 (2.0) | 0.2 (−0.1 to 0.5) | 1.1 (0.9 to 1.3) |
NT 3.0‐ < 3.5 mm | 27 (1.8) | 0.0 (−0.7 to 0.7) | 1.0 (0.7 to 1.4) | 22 (1.5) | −0.3 (−0.9 to 0.3) | 0.8 (0.6 to 1.3) |
NT 3.5‐ < 5.0 mm | 23 (3.2) | 1.5 (0.1 to 2.8) | 1.8 (1.2 to 2.7) | 17 (2.6) | 0.8 (−0.4 to 2.0) | 1.4 (0.9 to 2.3) |
NT 5.0‐ < 6.5 mm | 10 (8.1) | 6.3 (1.5 to 11.2) | 4.5 (2.5 to 8.2) | 8 (7.8) | 6.0 (0.8 to 11.2) | 4.4 (2.2 to 8.5) |
NT ≥6.5 mm | 8 (11.1) | 9.3 (2.1 to 16.6) | 6.2 (3.2 to 11.9) | 8 (13.6) | 11.8 (3.0 to 20.5) | 7.6 (4.0 to 14.5) |
Missing | 7311 | 7230 | ||||
Small for gestational age | ||||||
NT <2.0 mm | 34 101 (10.0) | Ref. | Ref. | 33 777 (9.9) | Ref. | Ref. |
NT 2.0‐ < 2.5 mm | 2971 (7.3) | −2.7 (−3.0 to −2.4) | 0.7 (0.7 to 0.8) | 2921 (7.2) | −2.7 (−3.0 to −2.5) | 0.7 (0.7 to 0.8) |
NT 2.5‐ < 3.0 mm | 455 (6.6) | −3.4 (−4.0 to −2.8) | 0.7 (0.6 to 0.7) | 436 (6.4) | −3.5 (−4.1 to −2.9) | 0.6 (0.6 to 0.7) |
NT 3.0‐ < 3.5 mm | 101 (6.7) | −3.3 (−4.6 to −2.1) | 0.7 (0.6 to 0.8) | 89 (6.1) | −3.9 (−5.1 to −2.7) | 0.6 (0.5 to 0.7) |
NT 3.5‐ < 5.0 mm | 58 (8.2) | −1.8 (−3.9 to 0.2) | 0.8 (0.6 to 1.0) | 48 (7.2) | −2.7 (−4.7 to −0.7) | 0.7 (0.6 to 1.0) |
NT 5.0‐ < 6.5 mm | 16 (13.0) | 3.0 (−2.9 to 9.0) | 1.3 (0.8 to 2.1) | 10 (9.7) | −0.2 (−5.9 to 5.5) | 1.0 (0.5 to 1.8) |
NT ≥6.5 mm | 8 (11.4) | 1.4 (−6.0 to 8.9) | 1.1 (0.6 to 2.2) | 6 (10.2) | 0.2 (−7.5 to 8.0) | 1.0 (0.5 to 2.2) |
Missing | 5595 | 5510 |
Note: a visual representation of the incidence of perinatal outcomes by nuchal translucency measurement category is presented in Figure S4.
Abbreviations: CI, confidence interval; NICU, neonatal intensive care unit; NT, nuchal translucency measurement; RD, risk difference; Ref., reference group; RR, risk ratio.
4. DISCUSSION
In this population‐based study of pregnancies receiving prenatal screening, the risk of a composite of pregnancy loss, termination, stillbirth, or neonatal death increased with increasing nuchal translucency measurements. This association remained, though attenuated when excluding pregnancies with identified chromosomal abnormalities. This association also persisted in sensitivity analyses with different assumptions about the pregnancies for which no outcome was recorded, which was important given that the proportion of pregnancies with an unknown outcome was positively associated with the nuchal translucency measurement. Further, among pregnancies that resulted in a live birth, our study showed a potential association between higher nuchal translucency measurement (>5.0 mm) and some adverse perinatal outcomes such as admission to the neonatal intensive care unit and APGAR scores below 7.
Because previous studies have typically focused on selected groups of pregnant individuals seen in tertiary care centers, or who opted to have diagnostic investigations prenatally, the results of this study are difficult to situate in the context of existing literature. Among studies performed in unselected pregnancies, which would be more comparable to our results, Cheng et al. reported that 70.6% of pregnancies with nuchal translucency measurements ≥3.0 mm resulted in a live birth after excluding chromosomal abnormalities, whereas in our study 80.0% (2323/2903) of pregnancies with measurements ≥3.0 mm had a recorded live birth. 24 Westin et al. calculated a six‐fold increased risk of adverse outcomes in pregnancies with measurements ≥3.0 mm compared to pregnancies with measurements <3.0 mm, mirroring the six‐fold increase in our study (6.2% compared to 1.0%). 25 Additionally, in descriptive studies of unselected pregnancies with very high nuchal translucency measurements of ≥6.5 mm, after excluding those with identified chromosomal abnormalities, Scott et al. and Pitkanen et al. reported 29.6% (8/27) and 20.0% (1/5) resulted in a live birth, respectively, compared to 24.7% (57/231) in our study. 26 , 27 Shakoor et al. and Tahmasebpour et al. included multiple detailed thresholds but were limited to a small sample size with increasing levels of nuchal translucency, though a strength of the study by Shakoor et al. was including a reference group of pregnancies <2.5 mm where 94.6% (1780/1882) resulted in a live birth, similarly to the 96.1% (358 074/400 657) in our study 28 , 29 ; none of the other studies cited here included a reference group.
This study represents, to our knowledge, the first report of pregnancy outcomes at all nuchal translucency measurements at a population level, generating more accurate and generalizable risk estimates that are more applicable to the general population. This provides valuable information for patient counseling on the elevated risk of adverse pregnancy outcomes and some perinatal outcomes when an increased nuchal translucency is identified, and also when chromosomal abnormalities are not diagnosed. These results offer risk estimates to support an accurate interpretation of the results of the nuchal translucency measurement at all levels, at the time that the nuchal translucency measurement is disclosed, where previous risk estimates used in counseling were dependent on the hypothetical that all future follow‐up investigations would be performed and normal. These results therefore also provide important information for the counseling of pregnant individuals who decline prenatal diagnostic investigations following the nuchal translucency measurement but are still interested in the meaning of the nuchal translucency measurement for the pregnancy outcome. Further, this illustrates the importance of the nuchal translucency ultrasound beyond its role in screening for chromosomal abnormalities at a time where prenatal screening programs may be considering moving away from multiple marker screening algorithms including a nuchal translucency measurement towards offering universal cell‐free DNA screening and discontinuing the offer of nuchal translucency.
While in theory the 99th percentile for nuchal translucency measurement is measured at 3.5 mm, in this study pregnancies with measurements ≥3.5 mm represented only (1979) 0.5% of the study population. Although some pregnancies with very high nuchal translucency measurements may have been excluded from the study, by discontinuing the multiple marker screening process for instance, this points to a chronic undermeasurement of nuchal translucency as has been reported by other jurisdictions and underlines the importance of continued quality assurance of nuchal translucency. 30 , 31 This was, however, comparable to two population‐based studies, with pregnancies with measurements ≥3.5 mm representing 0.5% of the population in a Californian study by Berger et al., compared to 0.6% in an Australian study by Hui et al. 5 , 6 Key strengths of our study include the ascertainment of pregnancies in the first trimester, at the time of the nuchal translucency ultrasound; the population‐based nature of the data; and the large sample size, including 1979 pregnancies with nuchal translucency measurements of 3.5 mm or greater. These features allowed us to overcome key limitations of previous studies on this topic, including: (i) restriction to outcomes among pregnant individuals referred to specialty care and seen at academic centers, 10 , 11 , 13 , 14 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 where survivor bias could mask an association between increased nuchal translucency measurements and early pregnancy loss; (ii) restriction to pregnant individuals who opted to have prenatal diagnosis and had normal cytogenetic investigations, 13 , 14 , 15 , 36 , 39 , 40 , 42 , 43 , 44 , 45 , 46 which could lead to selection bias to the extent that those receiving prenatal diagnosis are more likely to have additional clinical indications beyond an elevated nuchal translucency prompting the procedure; and (iii) small sample sizes, including fewer than 200 pregnancies with increased nuchal translucency measurements, 10 , 14 , 15 , 24 , 26 , 27 , 28 , 29 , 33 , 38 , 39 , 40 , 43 , 44 , 45 , 47 , 48 , 49 , 50 rendering it challenging to understand the association of narrow bands of nuchal translucency measurement with rare outcomes.
This study also had several limitations. Information on pregnancy outcomes was missing for some individuals included in the study. To address this limitation, we conducted sensitivity analyses with the assumptions that these losses to follow‐up either experienced the composite outcome of pregnancy loss, termination, stillbirth, or neonatal death at either half or twice the risk of those for which an outcome was recorded within each corresponding nuchal translucency category. The results did not change the interpretation of the associations. Further, not all pregnancies in our analysis received cytogenetic testing, as expected on a population level, therefore, we may have failed to identify some individuals who had a chromosomal abnormality. This misclassification, particularly for pregnancies not resulting in a live birth, may have overestimated the risk estimates in the subgroup analyses where pregnancies with chromosomal abnormalities were excluded.
Additionally, the registry does not systematically capture structural defects identified on the 18‐to‐20‐week detailed ultrasound and fetal echocardiogram that are routinely offered in Ontario when an increased nuchal translucency measurement is identified (≥3.5 mm), or the diagnosis of single‐gene conditions, which precluded us from incorporating this information in our analysis. We hypothesize that these conditions play an important role in the underlying pathophysiological explanation of the association between nuchal translucency values and perinatal complications, particularly when chromosomal abnormalities have been excluded. Additionally, the indication for the termination of pregnancy was not available in the registry and could therefore not be incorporated in the interpretation of the findings. This precluded us from distinguishing between terminations that were performed due to the identification of a structural defect, or based on the nuchal translucency measurement alone, vs terminations performed for social reasons.
Finally, not all pregnant individuals in Ontario receive multiple marker screening, with an uptake of a valid multiple marker screening result with a nuchal translucency measurement in 65.3% of the population of singleton pregnancies; most of those pregnancies without such a result were among individuals who did not receive multiple marker screening. Although there is evidence that there are differences among pregnant individuals who do and do not receive prenatal genetic screening (eg maternal age, living in rural areas of Ontario) 19 , 51 there is no reason to expect the association between the nuchal translucency measurement and pregnancy outcome to differ in this population excluded from our study.
5. CONCLUSION
This study reports on the increasing risk of a composite of pregnancy loss, termination, stillbirth, or neonatal death with increasing nuchal translucency measurements on a population level. This association was found to persist when pregnancies with chromosomal abnormalities were excluded, and under different scenarios accounting for the pregnancies for which no outcome was recorded. Pregnancies with high nuchal translucency measurements were also at risk for some adverse perinatal health outcomes even if cytogenetic investigations were normal.
These findings will provide valuable information for patient counseling on overall pregnancy outcomes, rather than specifically in the situation where prenatal diagnosis has already taken place and resulted in normal findings. Further studies on a population level are required to understand the underlying mechanisms responsible for the increased risk of these adverse perinatal complications with increasing nuchal translucency levels, including the role of structural defects and single‐gene conditions and, for perinatal outcomes, factors related to placental insufficiency.
AUTHOR CONTRIBUTIONS
Kara Bellai‐Dussault designed the study, performed all analyses, interpreted the findings, and drafted the manuscript. The co‐authors Beth K Potter, Shelley D Dougan, Deshayne B Fell, Carolina Lavin Venegas, Julian Little, Lynn Meng, Mark Walker, Nan Okun, and Christine M Armour were involved in the conceptualization of study, interpretation of the results, and critical review of the article. All authors made significant contributions to the manuscript, and approved the final version submitted to the journal.
FUNDING INFORMATION
Canadian Institutes of Health Research: Doctoral Award Frederick Banting and Charles Best Canada Graduate Scholarships (Funding Reference Number FBD‐170866).
CONFLICT OF INTEREST STATEMENT
During the conduct of this work, Dr. Deshayne B Fell was employed by the University of Ottawa and had an academic appointment at the Children's Hospital of Eastern Ontario Research Institute. Although she maintains those academic affiliations, she is now employed by Pfizer and works on an unrelated topic. The other authors report no conflict of interest.
ETHICS STATEMENT
This study received approval by the Children's Hospital of Eastern Ontario Research Ethics Board (protocol #22/03PE) on June 7, 2022, and University of Ottawa Research Ethics Board (protocol #H‐06‐22‐8234) on June 24, 2022. Given that this study was conducted with data from a prescribed registry, obtaining individual patient consent was not required.
Supporting information
Supinfo
Bellai‐Dussault K, Dougan SD, Fell DB, et al. Outcomes of pregnancies with varying levels of nuchal translucency measurements: A population‐based retrospective study in Ontario, Canada. Acta Obstet Gynecol Scand. 2024;103:2499‐2510. doi: 10.1111/aogs.14965
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