Scholl, Jessica MD; Durfee, Sara M. MD; Russell, Michelle A. MD, MPH; Heard, Asha J. MD; Iyer, Chitra MD; Alammari, Roa MD; Coletta, Jaclyn MD; Craigo, Sabrina D. MD; Fuchs, Karin M. MD; D'Alton, Mary MD; House, Michael MD; Jennings, Russell W. MD; Ecker, Jeffrey MD; Panda, Britta MD; Tanner, Cassandre BA; Wolfberg, Adam MD; Benson, Carol B. MD
A first-trimester nuchal cystic hygroma is a developmental abnormality of the lymphatic system, characterized by the presence of edema and fluid-filled spaces at sites of lymphatic–venous connection within the posterior neck and back of a fetus.1–6 Since the widespread implementation of first-trimester aneuploidy screening programs with ultrasound measurement of nuchal translucency thickness, the diagnosis of first-trimester cystic hygroma is estimated to occur in 1 out of every 285 fetuses and has been associated with abnormal outcomes. These outcomes have included abnormal karyotype, genetic syndromes, congenital anomalies, perinatal death, and developmental delay.7 The reported rates of abnormal outcome vary and have been estimated from several smaller studies, which have included 22 to 134 fetuses with first-trimester cystic hygroma.3,7–12 From these studies, the rates of abnormal karyotype ranged from 29% to 60%.3,7–13 The rates of congenital anomalies in those with normal karyotype ranged from 25% to 53%.7–11 In the absence of karyotype or congenital anomalies, the rates of perinatal death have ranged from 3.3% to 11.8%,7,9,10 and rates of developmental disorders have been reported up to 5.9%.7–9,12
Although increased nuchal translucency in the setting of a cystic hygroma is likely associated with worse outcomes, there is a need to better-define this relationship in the first trimester. In a study by Molina et al,14 nuchal translucency thickness was shown to be the best independent predictor of abnormal karyotype in 386 fetuses with cystic hygroma, nuchal edema, or increased nuchal translucency. Additionally, among fetuses without cystic hygroma, Kagan et al15 reported increased rates of karyotype abnormality with increasing nuchal translucency thickness. However, in fetuses with first-trimester cystic hygroma, the relationship between nuchal translucency thickness and abnormal karyotype, major congenital anomaly, and perinatal loss has not been well-described. Our objective was to estimate the association of nuchal cystic hygroma with abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcomes, and to estimate the relationship between these outcomes and nuchal translucency thickness in a large cohort of first-trimester fetuses.
MATERIALS AND METHODS
We performed a retrospective cohort study of fetuses with first-trimester nuchal cystic hygroma seen in five academic medical centers during the period of January 7, 2000, through June 19, 2010. The study centers were Tufts Medical Center, Brigham and Women's Hospital, Massachusetts General Hospital, Columbia University Medical Center, and Dartmouth- Hitchcock Medical Center. All of the centers provide ultrasonography, genetic counseling, and prenatal diagnosis services, as well as delivery, neonatal, neonatal intensive, and specialty pediatric care to pregnant women and neonates either receiving all care or being seen as referrals to the center. In all of the centers, nuchal translucency measurements were performed according to previously described guidelines as part of an aneuploidy screening program. Briefly, with the fetus in the midsagittal plane and fetal neck in a neutral position, calipers were placed on the inner borders of the nuchal space, perpendicular to the long axis of the fetal body to obtain measurements.16 Institutional review board approval was obtained at each center.
Inclusion criteria were all fetuses with ultrasound-diagnosed nuchal cystic hygroma in the first trimester, identified from prenatal diagnosis and ultrasound databases at each center. A common definition of nuchal cystic hygroma was used by our centers after 2005: an enlarged hypoechoic space at the back of the fetal neck extending along the length of the fetal back, and in which septations are clearly visible.7 Before 2005, a standardized definition of cystic hygroma did not exist, and the diagnosis was made according to the discretion of experienced ultrasonographers and physicians across the five study centers.
Maternal data including age, race or ethnicity, and parity were extracted from hospital records and prenatal diagnosis databases. Pregnancy data including estimated date of delivery, singleton or multiple gestation, fetal crown-rump length at nuchal translucency measurement, nuchal translucency thickness and documented presence of septations, karyotype, and fetal morphology were extracted from hospital records, ultrasound reports, radiology databases, pathology reports, and prenatal diagnosis databases. At Brigham and Women's Hospital, a board-certified radiologist with credentials for nuchal translucency measurements reviewed the ultrasound images at that center to obtain measurements if they were not previously performed. Obstetric and delivery data including termination, spontaneous abortion, stillbirth, delivery, gestational age at delivery, and neonatal death were extracted from hospital records. Pediatric data including medical issues and developmental assessments were obtained from reviewing hospital records at each center. For neonates lacking follow-up in any of the five study centers, records from a regional pediatric referral center, Children's Hospital Boston, were searched using the delivery date or estimated date of delivery and the last names of the mother and the father. All data were extracted in 2010 using a standardized collection instrument and entered into a standardized spreadsheet. At each center, 20 fetuses were randomly chosen for double entry into the spreadsheet to assess the accuracy of data collection. All data reentry was conducted by someone other than the original person, and no discrepancies were found.
The outcome variables were abnormal karyotype, major congenital anomaly, perinatal loss, and a composite of abnormal outcome. An abnormal karyotype was defined as a karyotype other than 46, XX or 46, XY by metaphase analysis of cultured cells obtained from chorionic villus sampling, amniocentesis, or tissue biopsy. Major congenital anomaly, identified by ultrasonography, autopsy, or postnatal examination, was defined as a structural malformation that would be life-threatening, result in long-term disability, or negatively affect neonatal or pediatric outcomes.17 Ultrasound findings of mild ventriculomegaly, choroid plexus cyst, thickened nuchal skin fold, echogenic intracardiac focus, short long bones, echogenic bowel, echogenic kidney, renal pelviectasis, lymphectasia, ascites, pleural effusion, pericardial effusion, and skin edema were not included in the definition of major congenital anomaly. Perinatal loss was defined as previable loss before 24 weeks of gestation, stillbirth after 24 weeks of gestation, or neonatal death before hospital discharge. Pediatric neurodevelopment was defined as normal if the records had documentation of normal development, undocumented if the records did not have clear documentation of development, and delayed if the pediatric records had documentation of developmental delay. Abnormal outcome was defined as a composite outcome of abnormal karyotype, major congenital anomaly, perinatal loss, or developmental delay.
To explain the variability in the outcomes, several factors considered plausibly related were evaluated. Explanatory covariables related to the mother included maternal age, which was categorized in 5-year increments, race or ethnicity, and parity, which was dichotomized. Singleton or multiple gestation was considered as an explanatory variable associated with the pregnancy. Related to pregnancy outcome, gestational age at delivery as a continuous variable was considered as an explanatory covariable. Explanatory covariables related to the fetus included documentation of septations in the cystic hygroma and crown-rump length at the nuchal translucency measurement ultrasound scan as a continuous variable. To examine the lack of unified definition of cystic hygroma, fetuses were identified by their estimated dates of delivery, characterized as before 2005 or 2005 and after, and considered as a dichotomous variable. The study center was included as an explanatory covariable.
Descriptive statistics were calculated, including frequencies, means, standard deviations, medians, ranges, and interquartile ranges. Statistical tests of comparison included Pearson χ2, Student t test, Wilcoxon rank-sum test, Kruskal-Wallis, simple logistic regression, and multivariable logistic regression. STATA 11 was used for all data analyses. All tests were two-tailed and P<.05 was considered statistically significant.
A total of 944 fetuses with first-trimester cystic hygroma were seen in the five centers. Characteristics of the study cohort are presented in Table 1. In the univariable analyses, as shown in Table 2, multiple characteristics were associated with the primary outcomes, including maternal age, singleton or multiple gestation, nuchal thickness, crown-rump length, and study center.
Karyotype results were available for 729 fetuses, of which 329 (45.1%) were normal and 400 (54.9%, 95% confidence interval [CI] 51–58%) were abnormal (Fig. 1). The karyotype abnormalities were as follows: trisomy 21 in 156 (21.4%); monosomy X in 88 (12.1%); trisomy 18 in 83 (11.4%); trisomy 13 in 26 (3.6%); triploidy in 10 (1.4%); mosaicism in 10 (1.4%); and other chromosomal abnormalities in 27 (3.7%) fetuses. Other karyotype abnormalities included other trisomies, deletions, duplications, unbalanced translocations, inversions, and sex chromosome abnormalities. There were six genetic syndromes diagnosed in those with a normal karyotype, including Angelman syndrome, Noonan syndrome, skeletal dysplasia, cystic fibrosis, neurofibromatosis, and cerebromandibular syndrome.
Anatomic information was available for 450 fetuses, of which 150 (33.3%, 95% CI 29–38%) were found to have at least one major congenital anomaly. Of the 944 fetuses with cystic hygroma, 355 (37.6%) had both karyotype and anatomic data available. A major congenital anomaly was seen in 61 out of 212 (28.8%, 95% CI 23–35%) fetuses with a normal karyotype compared with 63 out of 143 (44.1%, 95% CI 36–52%) fetuses with an abnormal karyotype (P=.003, Fig. 1).
Among the 212 fetuses with a normal karyotype, cardiac anomalies were the most common form of major congenital anomaly, followed by urinary, central nervous system, and body wall anomalies. There were 32 (15.0%) fetuses with a cardiac anomaly and 19 (9.0%) had complex defects. Cardiac anomalies included eight fetuses with hypoplastic left heart syndrome, seven with ventriculoseptal defect, three with hypoplastic right heart syndrome, three with tetralogy of Fallot, and two with aortic coarctation. Other cardiac defects included atrial septal defect, tricuspid valve insufficiency, double-outlet right ventricle, atrioventricular canal defect, L-transposition great arteries, truncus arteriosus, left ventricular noncompaction syndrome, Ebstein anomaly, and twin reverse arterial perfusion sequence. There were 10 (4.7%) fetuses with a major congenital anomaly of the urinary system. These included five fetuses with hydronephrosis, three with bladder malformations, and two with hypoplastic or multicystic dyplastic kidney. Eight (4.2%) fetuses had a major congenital anomaly of the central nervous system, including five with Dandy Walker Malformation. There were seven (3.3%) fetuses with body wall anomalies, including gastroschisis, omphalocele, and limb body wall complex. Among the 61 fetuses with major congenital anomalies, five (8.2%) had diagnoses after birth, including one ventriculoseptal defect with aortic coarctation, one critical aortic coarctation, one esophageal atresia with tracheoesophageal fistula, one tracheoesophageal fistula, and one neck mass.
There were 742 fetuses with obstetric outcome data, of which 447 (60.2%, 95% CI 57–64%) underwent an elective termination of pregnancy. Of the electively terminated fetuses, 377 had a karyotype analysis performed: 93 (24.7%) had a normal karyotype whereas 284 (75.3%, 95% CI 71–79%) had an abnormal karyotype. Of those with abnormal karyotype, there were 110 fetuses with trisomy 21, the most common karyotype abnormality. Among the 40 electively terminated fetuses with normal karyotype, 15 (37.5%, 95% CI 22–53%) had no finding of a major congenital anomaly.
Of the 295 fetuses not electively terminated, perinatal loss occurred in 115 fetuses (38%, 95% CI 33–45%). Of those with obstetric outcome data, there were 106 (14%, 95% CI 12–17%) fetuses with pregnancy loss before 24 weeks, seven (1%, 95% CI 0.2–1.6%) with pregnancy loss after 24 weeks, and two (0.3%, 95% CI −0.1–0.6%) with a neonatal death. One of the neonatal deaths occurred in a neonate with trisomy 21, with ascites and a genitourinary anomaly, who delivered at 31 weeks of gestation. The other neonatal death occurred in a neonate with a normal karyotype with hydrops fetalis who was delivered at 30 weeks of gestation.
Of the 295 fetuses not electively terminated, there were 182 (61.7%, 95% CI 55–67%) live births. Among live births, the gestational age at delivery ranged from 23.8 to 41.7 weeks, with a median (interquartile range) of 38.8 weeks (26.8 to 41.5 weeks). There were 37 (20.3%, 95% CI 14–26%) live births occurring before 37 weeks of gestation. There were 180 infants discharged to home, of whom 10 (5.6%, 95% CI 2.2–8.9%) had trisomy 21 (Fig. 2).
Among the 180 infants discharged to home, there were 86 with normal karyotype and no congenital anomalies. Of the 86, there were 24 with definite pediatric follow-up data at one of the five centers, including seven (29%) developmentally normal, two (8%) developmentally abnormal, and 15 (62%) with undocumented development. In the two infants with developmental delay, the abnormality appeared isolated; one was described as having delayed fine motor skills and the other was defined as having speech delay.
There were 627 fetuses with complete data on the composite outcome, of which 543 (86.6%, 95% CI 84–89%) had an abnormal outcome. Nuchal translucency thickness measurements were available for 677 fetuses, ranging from 1.4 to 24.7 mm, with a median of 4.1 mm (interquartile range 1.7–16 mm). Of the 677 fetuses with nuchal translucency thickness measurements, 540 also had a karyotype analysis. The nuchal translucency thickness was significantly larger in 298 fetuses with an abnormal karyotype ranging from 1.4 to 24.7 mm, with a median of 6 mm (interquartile range 2–16 mm), compared with 242 fetuses with a normal karyotype that ranged from 1.6 to 14.4 mm, with a median of 4.1 mm (interquartile range 1.9–12 mm, P<.001). The median nuchal translucency was significantly different by karyotype (P<.001), as shown in Table 3.
We assessed the proportion of karyotype abnormalities by nuchal translucency thickness shown in Table 3. Nuchal translucency thickness was categorized into less than 3.5 mm, 3.5–4.9 mm, 5.0–8.0 mm, and more than 8.0 mm. There was a significant difference in the proportion of karyotype abnormalities by the nuchal translucency thickness category (P<.001). In all of the categories of nuchal translucency thickness, except those more than 8.0 mm, a normal karyotype was the most common finding, followed by trisomy 21, the most common abnormal karyotype. Monosomy X was the most common karyotype abnormality, occurring in 38 (40%, 95% CI 30–51%) of the 94 fetuses with nuchal translucency measurement more than 8 mm.
In the univariable and multivariable regression analyses assessing the relationship between nuchal translucency thickness and outcomes, increasing nuchal translucency thickness was associated with abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome. A karyotype abnormality occurred in 298 (55.3%, 95% CI 51–59%) of 539 fetuses with nuchal translucency thickness measurements and was significantly associated with nuchal translucency thickness (P<.001). Every 1-mm increase in nuchal translucency thickness increased the odds of an abnormal karyotype by 42% (odds ratio [OR] 1.42, 95% CI 1.30–1.56, P<.001). The fully adjusted model changed these findings only slightly. There were 509 fetuses with complete data for all variables in the multivariable logistic regression model. After adjusting for maternal age, race or ethnicity, multiple gestation, septations, dates before 2005, crown-rump length at nuchal translucency measurement, and study center, every 1-mm increase in nuchal translucency thickness increased the odds of an abnormal karyotype by 44% (adjusted OR 1.44, 95% CI 1.29–1.60, P<.001). In the fully adjusted model, maternal age was also associated with increased odds of abnormal karyotype. Compared with women younger than 25 years, women 35–40 years (adjusted OR 2.92, 95% CI 1.25–6.89, P=.014) and women older than 40 years (adjusted OR 20.5, 95% CI 6.99–60.25, P<.001) had significantly increased odds of abnormal karyotype. None of the other covariables was significantly associated with abnormal karyotype.
A major congenital anomaly was seen in 90 out of 322 (28%, 95% CI 23–33%) fetuses with nuchal translucency measurements and was significantly associated with nuchal translucency thickness (P<.001). Every 1-mm increase in nuchal translucency thickness increased the odds of a major congenital anomaly by 13% (OR 1.13, 95% CI 1.04–1.24, P=.006). The fully adjusted model changed these findings. There were 291 fetuses with complete data for all variables in the multivariable logistic regression model. After adjusting for maternal age, race or ethnicity, multiple gestation, septations, dates before 2005, crown-rump length at cystic hygroma diagnosis, karyotype, and study center, every 1-mm increase in nuchal translucency thickness increased the odds of a major congenital anomaly by 26% (adjusted OR 1.26, 95% CI 1.08–1.47, P=.003). None of the other covariables was significantly associated with major congenital anomaly.
Perinatal loss occurred in 67 (32.2%) out of 208 fetuses with nuchal translucency measurements not electively terminated and was significantly associated with nuchal translucency thickness (P<.001). Every 1-mm increase in nuchal translucency thickness increased the odds of a perinatal loss by 67% (OR 1.67, 95% CI 1.40–1.98, P<.001). The fully adjusted model changed these findings. There were 149 fetuses with complete data for all variables in the multivariable logistic regression model. After adjusting for maternal age, race or ethnicity, multiple gestation, septations, dates before 2005, crown-rump length at nuchal translucency measurement, study center, and karyotype, every 1-mm increase in nuchal translucency thickness increased the odds of a perinatal loss by 47% (adjusted OR 1.47, 95% CI 1.07–2.02, P=.019). In the fully adjusted model compared with karyotypes 46, XX and 46, XY, abnormal karyotype was associated with significantly increased odds of perinatal loss (adjusted OR 33.27, 95% CI 8.96–123.59, P<.001). Other covariables associated with perinatal loss included multiple gestation and crown-rump length at the nuchal translucency measurement. In the fully adjusted model, singleton gestation compared with multiple gestation was associated with a 77% lower odds of perinatal loss (adjusted OR 0.23, 95% CI 0.05–0.99, P=.049). In the fully adjusted model, every 1-mm increase in crown-rump length at the nuchal translucency measurement ultrasound scan was associated with a 5% lower odds of perinatal loss (adjusted OR 0.95, 95% CI 0.91–0.99, P=.03).
A composite abnormal outcome that included abnormal karyotype, major congenital anomaly, perinatal loss, or developmental delay occurred in 379 (85.6%, 95% CI 82–89%) out of 443 fetuses with nuchal translucency measurements and was significantly associated with nuchal translucency thickness (P<.001). Every 1-mm increase in nuchal translucency thickness increased the odds of an abnormal outcome by 88% (OR 1.88, 95% CI 1.54–2.29, P<.001). The fully adjusted model changed these findings. There were 308 fetuses with complete data for all variables in the multivariable logistic regression model. After adjusting for maternal age, race or ethnicity, multiple gestation, septations, dates before 2005, crown-rump length at nuchal translucency measurement, karyotype, study center, and gestational age at delivery, every 1-mm increase in nuchal translucency thickness increased the odds of an abnormal outcome by 77% (adjusted OR 1.77, 95% CI 1.15- 2.74, P=.01). In the fully adjusted model, every 1-week increase in gestational age at delivery was associated with a 51% lower odds of an abnormal outcome (adjusted OR 0.49, 95% CI 0.33–0.74, P=.001). Table 4 summarizes the relationship between nuchal translucency thickness and abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome from the univariable and multivariable logistic regression analyses. The fully adjusted predicted probabilities of abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome by nuchal translucency thickness are illustrated in Figure 3.
This study represents a large cohort of fetuses with first-trimester nuchal cystic hygroma and their abnormal outcomes, as well as the first description of the relationship between nuchal translucency thickness and these outcomes. We evaluated the rates of abnormal karyotype, major congenital anomaly, perinatal loss, and composite abnormal outcome, because we considered this information most useful to parents engaging in prenatal counseling and decision-making in the setting of a first-trimester ultrasound scan.
Recent publications have endorsed the need for subsequent evaluation after the detection of an increased nuchal translucency or cystic hygroma irrespective of normal karyotype.18,19 Our findings support the recommendations that fetuses with cystic hygroma of all sizes require rigorous evaluation, because the rates of cardiac, urinary, central nervous system, and body wall anomalies are all increased. We also recognize that not all major congenital anomalies are excluded by prenatal ultrasonography. Despite having prenatal evaluation in an academic medical center, there was a 2.4% rate of major congenital anomaly detected after birth among fetuses with normal karyotype, including aortic coarctation and trachoesphageal fistula.
Our findings now presented demonstrate a strong association of increasing nuchal translucency thickness with increasing rates of abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome among fetuses with cystic hygroma, as depicted in Figure 3. Importantly, these associations remained significant after adjustment for maternal age, race or ethnicity, multiple gestation, septations, dates before 2005, crown-rump length, and study center. We concur that among fetuses with first-trimester cystic hygroma diagnosed, karyotype analysis, detailed anatomic assessment, and fetal echocardiogram not only are essential components of subsequent evaluation but also become increasingly crucial with increasing thickness of the cystic hygroma. There are a number of limitations to our study. First, this is a retrospective cohort study with the inherent chance of bias and confounding found with this study design. We attempted to account for measured confounders by using multiple logistic regression analysis but unmeasured confounders likely remain. Second, a standardized definition of first-trimester cystic hygroma did not exist until 2005 and the ultrasound images were not reviewed to confirm the diagnosis. Inclusion was based on a diagnosis made by multiple ultrasonographers and physicians across the five medical centers spanning 10 years. We evaluated whether fetuses were seen before or after 2005 and accounted for this as a covariable in our multiple regression models. We found no association with dates before 2005 and abnormal karyotype, major congenital anomaly, perinatal loss, or composite abnormal outcome. To account for the variation between centers and similarities within centers, we included study center as a covariable in our multiple logistic regression models. To account for the presence or absence of documented septations, we also included septations as a covariable in our multiple logistic regression models. Third, all five centers were academic medical centers with large referral populations, making the results potentially less generalizable to cases seen in smaller nonacademic hospitals. Fourth, the available obstetric and pediatric outcome data were limited because a large proportion of our cohort presented as referrals and these patients most likely resumed prenatal care and delivered at their local institutions. Finally, the 10-year study period allows for changes in the accuracy of prenatal testing, possibly influencing the detection of karyotype abnormalities or congenital anomalies. Karyotyping was performed by banding, which detects abnormalities in chromosome number and large rearrangements, and deletions or duplications. The possibility remains that despite a normal karyotype on banding analysis there could have been microdeletions, duplications, or rearrangements because microarray data were not collected.
Although there are limitations to this study, there are also several strengths that enhance the existing body of literature. First, this is a large cohort study of fetuses with first-trimester cystic hygroma. Notably, the FASTER trial by Malone et al7 screened more than 38,000 women; however, it collected only 134 fetuses with first-trimester cystic hygroma. Although our study included data from overlapping study centers, there were no overlapping cases with those reported as part of the FASTER trial. Second, this study examines the relationship between nuchal translucency thickness and important abnormal outcomes in fetuses with cystic hygroma. Our sample size enabled construction of a multivariate model, accounting for potential confounders. Third, in searching for obstetric and pediatric outcomes, we had the ability to access both hospital records at each center, as well as records at a regional pediatric referral center. We assume that most infants with severe anomalies would be cared for at one of the participating medical centers. Their absence from this large registry therefore suggests that they most likely lacked major anomalies.
In conclusion, our study confirms that the detection of a first-trimester nuchal cystic hygroma is associated with high rates of karyotype abnormality, major congenital anomaly, perinatal loss, and abnormal outcome. Additionally, as the thickness of the nuchal translucency increases, the odds of abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome increase.
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