Risk of critical congenital heart defects by nuchal translucency norms




Objective


The purpose of this study was to compare the performance of first-trimester nuchal translucency (NT) cutoff of ≥3.5 mm with NT percentiles that were calculated for crown-rump length to identify fetuses with critical congenital heart defects (CCHDs).


Study Design


This was a population-level study of singleton pregnancies in California with NT measurements performed between 11 and 14 weeks of gestation. Eligible cases were those that resulted in live births from 2009-2010 and had information about the presence or absence of CCHDs available in the hospital discharge records through age 1 year (n = 76,089). Logistic binomial regression methods were used to compare the rate of CCHDs by an NT percentile for crown-rump length and millimeter cutpoints.


Results


Compared with fetuses with an NT measurement of <90th percentile, fetuses with an NT of ≥99th percentile were >5 times as likely to have a CCHD (1.3% vs 0.2%; relative risk, 5.66; 95% confidence interval, 3.19–10.04) and fetuses with an NT measurement ≥3.5 mm were >12 times as likely to have a CCHD (2.8% vs 0.2%; relative risk, 12.28; 95% confidence interval, 5.11–29.51). NT ≥99th percentile had a sensitivity of 5.8% and a specificity of 98.9% for the detection of CCHDs compared with 2.6% and 99.8% for NT ≥3.5 mm.


Conclusion


Results show that NT measurements of ≥99th percentile and ≥3.5 mm are not equivalent and that substantial risk for CCHD extends to the less restrictive ≥99th percentile cutpoint. Data suggest that the use of this cutpoint compared with the current standard could double the number of CCHDs that are identified based on NT risk.


Congenital heart defects affect approximately 1% of newborn infants. Critical congenital heart defects (CCHDs), which are the most serious of these, typically require surgical repair within the first year of life to avoid death or permanent morbidity. Prenatal detection is therefore particularly important for these newborn infants. Over the past decade, first-trimester nuchal translucency (NT) measurement has been used increasingly for prenatal detection of chromosomal abnormalities and has been associated with CCHDs in pregnancies with and without aneuploidy. Although an enlarged NT has been associated with CCHDs (defined by either an NT measurement percentile for crown-rump-length [CRL] or by a specific NT measurement in millimeters), having an NT measurement of ≥3.5 mm is the most commonly applied cutoff at which fetal echocardiography is recommended, based on guidelines of the American College of Obstetricians and Gynecologists. Here we evaluate how well an NT cutoff of ≥3.5 mm performs in comparison with NT percentile by CRL for identifying pregnancies carrying fetuses with CCHDs in a large, diverse population-based sample of live-born singleton pregnancies (n = 76,089) with complete CCHD ascertainment.


Materials and Methods


All pregnancies included in the study were participants in the California Prenatal Screening Program that was administered by the Genetic Disease Screening Program within the California Department of Public Health. Included pregnancies had CRLs from 45.0-84.0 mm and had NT measurements performed as part of routine screening for chromosomal defects.


Study pregnancies were drawn from a larger sample of all singleton pregnancies with NT results and estimated dates of delivery between July 2009 and December 2010 based on CRL (n = 163,899). The study was restricted to pregnancies with linked newborn infant screening records (n = 127,259) and linked birth certificate and hospital discharge records (n = 117,717). We further restricted the study sample to pregnancies for which NT measurements were done by clinicians who had practitioner-specific NT medians (n = 76,286) and to pregnancies without chromosomal defects (n = 76,089; Figure 1 ). Details regarding how practitioner-specific medians are calculated as part of the California Prenatal Screening Program are described elsewhere. All California NT practitioners are credentialed by the Nuchal Translucency Quality Review Program or the Fetal Medicine Foundation. Clinicians who had practitioner-specific medians are those who had a minimum of 75 examinations for whom the slope of their NT measurements increased by at least 11% across gestational weeks. In California, practitioner-specific medians have been shown to help control for less experienced practitioners who were tending towards smaller NT measurements.




Figure 1


Singleton pregnancies with first trimester nuchal translucency

The flow chart delineates the measurement of singleton pregnancies with first-trimester nuchal translucency that were included in our study.

NT , nuchal translucency.

Jelliffe-Pawlowski. Risk of CCHDs by nuchal translucency norms. Am J Obstet Gynecol 2015 .


Data that were used to exclude newborn infants from the analyses based on the presence of a chromosomal abnormality were obtained by a search of the Genetic Disease Screening Program Chromosome Registry. The registry collects information on chromosomal abnormalities from multiple ascertainment sources (physicians, laboratories, hospitals, and prenatal diagnostic centers) on all births in the state. All sources are mandated by California law to report diagnosed chromosomal abnormalities (whether diagnosed by karyotype or microarray) to the program.


Information on CCHDs was collected by the linkage of screening records with all hospital discharge records through 1 year of age for each study infant (wherein records were linked with the use of multiple identifiers [baby and mother date of birth; baby first and last name; mother first, last, and maiden name, address, phone number, and hospital of baby birth]). These records include all inpatient discharge information that is submitted to the state each time a patient is treated in a licensed general acute care hospital in California and includes all diagnoses present at the time of discharge based on 4- or 5-digit codes from the Ninth Revision of the International Classification of Diseases. For this study, CCHDs were considered to be those associated with substantive morbidity and mortality rates that included “common truncus,” “transposition of great vessels,” “Tetralogy of Fallot,” “common ventricle,” “endocardial cushion defects,” “anomalies of pulmonary valve,” “tricuspid atresia and stenosis,” “Ebstein’s anomaly,” “congenital stenosis of aortic valve,” “hypoplastic left heart syndrome,” “coarctation of the aorta,” and “anomalies of the great veins.” Hospital discharge records were considered the reference standard (gold standard) for the presence of a CCHD in our analyses.


All NT measurements are submitted to the California Prenatal Screening Program as part of routine first- and second-trimester screening for aneuploidies. Screening requires submission of a single valid NT measurement that then generates an interpretation for aneuploidy risk when accompanied by first- and/or second-trimester serum analyte results. All requisitions for screening include information on maternal race/ethnicity, weight, smoking status, and self-reported presence of pregestational diabetes mellitus. We used the prenatal screening records that were associated with the NT measurement to identify these sociodemographic factors.


To compare performance of an NT cutoff of ≥3.5 mm to NT percentile by CRL for the identification of fetuses with CCHDs, we first categorized each pregnancy as having an NT measurement of ≥3.5 mm and/or an NT measurement <90th, ≥ 90th, 90-94th, 95-99th, or ≥99th percentile for CRL. NT percentiles by CRL were computed for all pregnancies with NT that had been submitted by clinicians with practitioner-specific NT medians available and included pregnancies with and without chromosomal defects so as to best reflect the distribution of NT at the time of measurement (n = 76,286; Table 1 ).



Table 1

Distribution of nuchal translucency a





































































































































































































































































































































































































































































































































































































Crown-rump length Gestational age n Mean Median Standard deviation Percentile cutpoint, mm Percentile cutpoint, multiples of the median Percentile equivalent at 3.5 mm
90th 95th 99th 90th 95th 99th
45.0 11.3 404 1.17 1.1 0.31 1.5 1.7 2.0 1.31 1.42 1.82 99.8
46.0 11.4 620 1.22 1.2 0.38 1.6 1.8 2.9 1.37 1.58 2.45 99.6
47.0 11.5 667 1.21 1.2 0.33 1.6 1.8 2.2 1.30 1.44 2.02 99.8
48.0 11.6 796 1.26 1.2 0.39 1.7 1.9 2.9 1.35 1.55 2.32 99.6
49.0 11.7 853 1.25 1.2 0.33 1.6 1.8 2.5 1.28 1.45 1.90 99.8
50.0 11.7 1048 1.29 1.2 0.36 1.7 1.8 2.6 1.34 1.49 2.08 99.7
51.0 11.8 1256 1.31 1.2 0.38 1.7 1.9 2.8 1.34 1.53 2.17 99.8
52.0 11.9 1401 1.31 1.3 0.30 1.7 1.8 2.3 1.29 1.40 1.71 99.9
53.0 12.0 1783 1.35 1.3 0.39 1.7 1.9 2.6 1.32 1.44 1.98 99.7
54.0 12.0 1919 1.37 1.3 0.34 1.8 2.0 2.4 1.33 1.47 1.83 99.8
55.0 12.1 2089 1.41 1.4 0.42 1.8 2.0 2.6 1.32 1.46 2.02 99.6
56.0 12.2 2247 1.42 1.4 0.36 1.8 2.0 2.6 1.33 1.45 1.89 99.7
57.0 12.3 2439 1.44 1.4 0.35 1.8 2.0 2.5 1.33 1.46 1.85 99.9
58.0 12.3 2695 1.48 1.4 0.39 1.9 2.1 2.6 1.35 1.48 1.92 99.6
59.0 12.4 2831 1.51 1.5 0.42 1.9 2.1 2.8 1.35 1.49 1.93 99.6
60.0 12.5 3011 1.54 1.5 0.39 2.0 2.2 2.7 1.38 1.50 1.98 99.7
61.0 12.6 3050 1.55 1.5 0.37 2.0 2.2 2.6 1.35 1.50 1.79 99.8
62.0 12.6 3185 1.57 1.5 0.37 2.0 2.2 2.8 1.36 1.48 1.91 99.8
63.0 12.7 3156 1.60 1.5 0.38 2.1 2.3 2.7 1.35 1.48 1.85 99.8
64.0 12.8 3217 1.62 1.6 0.41 2.1 2.3 2.8 1.38 1.51 1.81 99.8
65.0 12.8 3125 1.64 1.6 0.39 2.1 2.3 2.8 1.35 1.47 1.83 99.7
66.0 12.9 3171 1.67 1.6 0.42 2.2 2.4 2.9 1.37 1.50 1.91 99.6
67.0 13.0 3083 1.69 1.6 0.42 2.2 2.4 2.8 1.37 1.51 1.81 99.7
68.0 13.1 2872 1.70 1.7 0.40 2.2 2.4 2.8 1.35 1.50 1.76 99.9
69.0 13.1 2779 1.72 1.7 0.41 2.2 2.4 2.9 1.35 1.46 1.80 99.8
70.0 13.2 2662 1.74 1.7 0.40 2.2 2.4 2.9 1.35 1.46 1.78 99.8
71.0 13.3 2483 1.79 1.7 0.41 2.3 2.5 3.0 1.37 1.48 1.77 99.7
72.0 13.4 2337 1.78 1.7 0.43 2.3 2.5 3.0 1.34 1.48 1.79 99.7
73.0 13.4 2150 1.79 1.8 0.43 2.3 2.5 2.9 1.34 1.45 1.74 99.7
74.0 13.5 2015 1.82 1.8 0.44 2.3 2.5 3.0 1.34 1.45 1.83 99.7
75.0 13.6 1920 1.80 1.8 0.43 2.3 2.5 3.1 1.31 1.49 1.75 99.7
76.0 13.7 1799 1.83 1.8 0.44 2.4 2.6 3.1 1.30 1.42 1.75 99.6
77.0 13.8 1542 1.85 1.8 0.45 2.4 2.6 3.3 1.30 1.43 1.75 99.4
78.0 13.8 1477 1.81 1.8 0.44 2.4 2.5 3.1 1.29 1.42 1.73 99.5
79.0 13.9 1215 1.85 1.8 0.47 2.4 2.5 3.0 1.27 1.38 1.65 99.7
80.0 14.0 778 1.84 1.8 0.43 2.4 2.7 3.1 1.27 1.39 1.69 99.8
81.0 14.1 625 1.86 1.8 0.45 2.4 2.7 3.2 1.24 1.39 1.67 99.6
82.0 14.2 592 1.86 1.8 0.45 2.4 2.6 3.3 1.23 1.33 1.66 99.4
83.0 14.2 611 1.85 1.8 0.44 2.4 2.6 2.8 1.18 1.27 1.47 99.8
84.0 14.2 383 1.86 1.8 0.45 2.5 2.6 3.1 1.23 1.35 1.84 99.7

Jelliffe-Pawlowski. Risk of CCHDs by nuchal translucency norms. Am J Obstet Gynecol 2015 .

a Nuchal translucency measurement (in millimeters) and multiple of the median equivalents by crown-rump length at testing (all pregnancies with nuchal translucency measurement where crown-rump length was 45.0-84.0 mm (n =76,286).



Analyses used logistic binomial regression methods (relative risks [RRs] and their associated 95% confidence intervals [CIs]; 2-tailed, significance threshold probability value of < .05) to measure whether maternal characteristics were associated with having an increased NT measurement (grouped by 90-94th, 95-99th, or ≥99th percentile and/or ≥3.5 mm), compared with <90th percentile. The rate of increased NT by different criteria was calculated for self-reported Hispanic, black, Asian, and “other” race/ethnicity relative to white not-Hispanic race/ethnicity, for maternal age <18 or ≥35 years relative to maternal age 18-34 years, maternal weight ≤5th or ≥95th weight percentiles relative to the weight between the 5th and 95th percentile (based on weight for gestational age by race/ethnicity at NT), smoking status, and self-reported pregestational diabetes mellitus (yes/no). The association between increased NT by different criteria and CCHDs was measured by a comparison of the rate of CCHDs in each increased NT group, with the rate in the NT <90th percentile group adjusted for maternal characteristics that have been found to be significantly associated with increased NT.


The performance of different cutoffs for the definition of increased NT and for the prediction of CCHD was assessed by sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (LR+), negative likelihood ratio, associated 95% CIs, and receiver operator curves (ROCs) and their associated area under the curve statistics. Analyses also evaluated the detection of specific CCHDs by NT cutoff criteria.


All analyses were done with Statistical Analysis Software (version 9.2; SAS Institute Inc, Cary, NC). Methods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California, which included a waiver of informed consent. All analyses were based on data received by the screening program as of Dec. 31, 2012.




Results


We identified 76,089 eligible, chromosomally normal pregnancies with NT measurements that had been performed by clinicians who had practitioner-specific NT medians. Most women were Hispanic or not-Hispanic white (41.2 and 34.8%) and 18-34 years old (68.1%). Less than 1% of all pregnancies (0.2%) had NT measurements ≥3.5 mm. Mean NT measurements increased as the CRL increased. A NT measurement of 3.5 mm corresponded to the 99.8 percentile at a CRL of 45 mm and the 99.7 percentile at 84 mm ( Table 1 ). Overall, the rate of CCHDs was 2.5 per 1000 pregnancies, with the most common cardiac lesions consisting of anomalies of the pulmonary valve, 0.8 per 1000 ( Table 2 ).



Table 2

Critical congenital heart defects in study sample (n = 76,089)








































































Variable n Percentage per 1000
Any critical congenital heart defect 190 2.50
Isolated critical congenital heart defect 143 1.88
Multiple critical congenital heart defect 47 0.62
Subtype a
Common truncus (745.0) 5 0.07
Transposition of the great arteries (745.1) 28 0.37
Tetralogy of Fallot (745.2) 29 0.38
Common ventricle (745.3) 6 0.08
Endocardial cushion defect (745.6) 15 0.20
Anomalies of the pulmonary valve (746.0) 61 0.80
Tricuspid atresia and stenosis (746.1) 9 0.12
Ebstein’s anomaly (746.2) 2 0.03
Congenital stenosis of the aortic valve (746.3) 10 0.13
Hypoplastic left heart syndrome (746.7) 16 0.21
Coarctation of the aorta (747.1) 53 0.70
Anomalies of the great veins (747.4) 20 0.26

CCHD , critical congenital heart defect.

Jelliffe-Pawlowski. Risk of CCHDs by nuchal translucency norms. Am J Obstet Gynecol 2015 .

a By 4-digit International Classification of Diseases, 9th revision .



Pregnancies with increased second-trimester NT measures (by percentile groupings at or above the 95th percentile and/or by ≥3.5mm) were more likely than pregnancies with NT measures <90th percentile to be of women of Asian race/ethnicity or Hispanic race/ethnicity, who are ≥35 years old, and who have weights for gestational age at NT measurement by race/ethnicity grouping that were ≥95th percentile. The highest risks were observed for Asian race/ethnicity relative to white not-Hispanic race/ethnicity. For example, 19.8% of those with an NT measurement ≥99th percentile were Asian compared with 10.4% Asian in the <90th percentile grouping (relative to 35.4% of those in the ≥99th and 28.9% in the <90th percentile grouping being white not-Hispanic; RR, 2.24; 95% CI, 1.84–2.73). Pregnancies with NT ≥95th percentile were less likely than pregnancies with NT measures <90th percentile to be of black race/ethnicity relative to white not-Hispanic race/ethnicity (eg, 1.6% of pregnancies with NT measures ≥99th percentile were black, and 4.4% of those with NT measurements <90th percentile were black (relative to 35.4% of those in the ≥99th percentile grouping and 28.9% in the <90th percentile grouping were white not-Hispanic; RR, 0.43; 95% CI, 0.25–0.78; Table 3 ).



Table 3

Maternal characteristics by nuchal translucency measurement a




















































































































































































































































































Variable Nuchal translucency, %
<90th 90-94th 95-99th ≥99th ≥3.5
n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI)
Sample (n = 76,089) 66,950 4577 3728 834 177
Race/ethnicity
White not Hispanic (n = 26,495) 23,701 (35.4) Reference 1425 (31.1) 1128 (30.3) 241 (28.9) 54 (30.5)
Hispanic (n = 31,319) 27,447 (41.0) 1900 (41.5) 1.14 (1.07–1.22) 1624 (43.6) 1.23 (1.14–1.32) 348 (41.7) 1.24 (1.06–1.47) 71 (40.1) 1.12 (0.80–1.60)
Black (n = 3222) 2960 (4.4) 143 (3.1) 0.81 (0.69–0.97) 106 (2.8) 0.76 (0.63–0.93) 13 (1.6) 0.43 (0.25–0.78) 5 (2.8) 0.76 (0.30–1.89)
Asian (n = 8425) 6940 (10.4) 721 (15.8) 1.66 (1.52–1.81) 604 (16.2) 1.76 (1.60–1.94) 160 (19.8) 2.24 (1.84–2.73) 31 (17.5) 1.85 (1.19–2.88)
Other b (n = 4729) 4237 (6.3) 258 (5.6) 1.01 (0.89–1.15) 182 (4.9) 0.91 (0.78–1.06) 52 (6.2) 1.21 (0.89–1.62) 12 (6.8) 1.25(0.67–2.33)
Maternal age, y
≤18 (n = 420) 381 (0.6) 19 (0.4) 0.75 (0.49–1.17) 17 (0.5) 0.82 (0.52–1.31) 3 (0.4) 0.69 (0.22–2.13) 1 (0.6) 1.08 (0.15–7.74)
18-34 (n = 51,843) 45,744 (68.3) Reference 3074 (67.2) 2500 (67.1) 525 (63.0) 113 (63.8)
≥35 (n = 23,811) 20,812 (31.1) 1484 (32.4) 1.06 (0.99–1.12) 1209 (32.4) 1.06 (0.99–1.13) 306 (36.7) 1.28 (1.11–1.47) 63 (35.6) 1.22 (0.90–1.66)
Maternal weight, percentile c
≤5th (n = 3276) 2878 (4.3) 206 (4.5) 1.05 (0.92–1.20) 157 (4.2) 0.99 (0.85–1.16) 35 (4.2) 0.99 (0.70–1.38) 6 (3.4) 0.64 (0.26–1.56)
6th-94th (n = 69,340) 61,075 (91.2) Reference 4146 (90.6) 3366 (90.3) 753 (90.3) 162 (91.5)
≥95th (n = 3395) 2932 (4.4) 216 (4.7) 1.08 (0.95–1.23) 202 (5.4) 1.23 (1.08–1.42) 45 (5.4) 1.24 (0.92–1.67) 8 (4.5) 1.02 (0.50–2.07)
Smoking
No (n = 75,170) 66,151 (98.8) Reference 4517 (98.7) 3683 (98.8) 819 (98.2) 174 (98.3)
Yes (n = 919) 799 (1.2) 60 (1.3) 1.09 (0.86–1.40) 45 (1.2) 1.01 (0.76–1.35) 15 (1.8) 1.51 (0.91–2.50) 3 (1.7) 1.42 (0.46–4.45)
Diabetes mellitus
No (n = 75,540) 66,475 (99.3) Reference 4542 (99.2) 3696 (99.1) 827 (99.2) 176 (99.4)
Yes (n = 549) 475 (0.7) 35 (0.8) 1.07 (0.78–1.48) 32 (0.9) 1.20 (0.86–1.68) 7 (0.8) 1.18 (0.57–2.47) 1 (0.6) 0.78 (0.11–5.55)

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May 6, 2017 | Posted by in GYNECOLOGY | Comments Off on Risk of critical congenital heart defects by nuchal translucency norms

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