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First-Trimester Septated Cystic Hygroma: Prevalence, Natural History, and Pediatric Outcome

Malone, Fergal D. MD; Ball, Robert H. MD; Nyberg, David A. MD; Comstock, Christine H. MD; Saade, George R. MD; Berkowitz, Richard L. MD; Gross, Susan J. MD; Dugoff, Lorraine MD; Craigo, Sabrina D. MD; Timor-Tritsch, Ilan E. MD; Carr, Stephen R. MD; Wolfe, Honor M. MD; Dukes, Kimberly PhD; Canick, Jacob A. PhD; Bianchi, Diana W. MD; D’Alton, Mary E. MD

doi: 10.1097/01.AOG.0000173318.54978.1f
Original Research

Objective: To estimate prevalence, natural history, and outcome of septated cystic hygroma in the first trimester in the general obstetric population, and to differentiate this finding from simple increased nuchal translucency.

Methods: Patients at 10.3–13.6 weeks of gestation underwent nuchal translucency sonography as part of a multicenter clinical trial. Septated cystic hygroma cases were offered chorionic villi sampling for karyotype, and targeted fetal anatomical and cardiac evaluations. Survivors were followed up for fetal and long-term pediatric outcome (median 25 months, range 12–50 months). Cases of septated cystic hygroma were also compared with cases of simple increased nuchal translucency.

Results: There were 134 cases of cystic hygroma (2 lost to follow-up) among 38,167 screened patients (1 in 285). Chromosomal abnormalities were diagnosed in 67 (51%), including 25 trisomy-21, 19 Turner syndrome, 13 trisomy-18, and 10 others. Major structural fetal malformations (primarily cardiac and skeletal) were diagnosed in 22 of the remaining 65 cases (34%). There were 5 cases (8%) of fetal death and 15 cases of elective pregnancy termination without evidence of abnormality. One of 23 (4%) normal survivors was diagnosed with cerebral palsy and developmental delay. Overall, survival with normal pediatric outcome was confirmed in 17% of cases (22 of 132). Compared with simple increased nuchal translucency, cystic hygroma has 5-fold, 12-fold, and 6-fold increased risk of aneuploidy, cardiac malformation, and perinatal death, respectively.

Conclusion: First-trimester cystic hygroma was a frequent finding in a general obstetric screening program. It has the strongest prenatal association with aneuploidy described to date, with significantly worse outcome compared with simple increased nuchal translucency. Most pregnancies with normal evaluation at the completion of the second trimester resulted in a healthy infant with a normal pediatric outcome.

Level of Evidence: II-2

First-trimester cystic hygroma has the strongest prenatal association with aneuploidy described to date, with significantly worse outcome compared with simple increased nuchal translucency.

From the Columbia University College of Physicians and Surgeons, New York, New York; University of Utah and Intermountain HealthCare, Salt Lake City, Utah; Swedish Medical Center, Seattle, Washington; William Beaumont Hospital, Royal Oak, Michigan; University of Texas Medical Branch, Galveston, Texas; Mount Sinai School of Medicine, New York, New York; Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York; University of Colorado Health Sciences Center, Denver, Colorado; Tufts University School of Medicine, Boston, Massachusetts; New York University School of Medicine, New York, New York; Brown University School of Medicine, Providence, Rhode Island; University of North Carolina Medical Center, Chapel Hill, North Carolina; and DM-STAT, Boston, Massachusetts.

* For a list of other members of the FASTER Trial Research Consortium, see the Appendix.

Funded by the National Institutes of Health, National Institute of Child Health and Human Development, grants RO1 HD 38652 and M01 RR 00054.

Corresponding author: Fergal Malone, MD, Royal College of Surgeons in Ireland, Department of Obstetrics and Gynecology, The Rotunda Hospital Parnell Square, Dublin 1, Ireland; e-mail:

Fetal cystic hygroma is a congenital malformation in which distended fluid-filled spaces develop, typically in the region of the fetal neck. Two distinct categories of fetal cystic hygroma have been described: those diagnosed in later pregnancy, which tend to be isolated lymphangiomas, and those diagnosed in early pregnancy, which are commonly associated with other malformations.1–4 Retrospective case series describing the prenatal diagnosis of this condition suggest that those diagnosed early in pregnancy are associated with a poor prognosis.2,3–5 When cystic hygroma appears septated, the prognosis is considered even worse than the nonseptated form.5–7 However, the counseling of patients based on these data is limited because these data are derived mostly from series of selectively referred cases, have used unclear or inconsistent definitions of cystic hygroma, and have limited or no pediatric outcome information.

Since the widespread introduction of first-trimester sonographic screening for fetal aneuploidy using nuchal translucency measurement, the prenatal diagnosis of cystic hygroma is becoming more frequent. Confusion currently exists as to how to differentiate between increased nuchal translucency and cystic hygroma, and as to whether there is any prognostic difference between these findings. There is therefore a growing need for detailed outcome information regarding cystic hygroma to enable accurate patient counseling and to support emerging first-trimester population screening programs.

The First and Second Trimester Evaluation of Risk (FASTER) trial was a prospective multicenter study designed to compare a range of serum and sonographic screening methods for fetal aneuploidy at different gestational ages (Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First and Second Trimester Evaluation of Risk for Fetal Aneuploidy [FASTER]: principal results of the NICHD Multicenter Down Syndrome Screening Study. Submitted for publication, 2005). The objectives of this study were to use the FASTER trial to estimate the prevalence of septated cystic hygroma in the first trimester of pregnancy in the general population, to estimate the association between this finding and fetal malformations, to evaluate the natural history of cystic hygroma, to describe the pediatric outcome for survivors with this condition, and to evaluate whether there was a prognostic significance to differentiating between hygroma and simple increased nuchal translucency.

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This study was performed at 15 centers in the United States. Institutional review board approval was obtained, and participants gave written informed consent. Eligibility criteria and screening protocol for the FASTER trial have been described previously (Malone et al, 2005). Inclusion criteria were unselected patients from the general population aged 16 years or older, with a singleton live pregnancy from 10 3/7 to 13 6/7 weeks of gestation. Exclusion criteria included the presence of a multiple gestation, or the diagnosis of fetal anencephaly at the time of nuchal translucency sonography. Nuchal translucency sonography was provided to all patients. When septated cystic hygroma was diagnosed, serum samples were not obtained for Down syndrome risk assessment and the patient was informed immediately of this finding. A standardized definition of septated cystic hygroma was used by all sonographers, namely an enlarged hypoechoic space at the back of the fetal neck, extending along the length of the fetal back, and in which septations were clearly visible (Fig. 1). Patients were advised of an association with fetal aneuploidy, and were offered fetal karyotyping by chorionic villi sampling. For ongoing pregnancies, targeted sonographic evaluation of fetal anatomy was performed at 18 to 22 weeks of gestation, together with fetal echocardiography. All ongoing pregnancies were followed up for pregnancy and pediatric outcome. Additionally, parents of surviving infants were contacted at least 1 year after completion of the trial to evaluate later pediatric development. This follow-up protocol included direct communication by central trial personnel, including review by a pediatric geneticist, with the surviving child’s pediatrician, to objectively confirm outcome and development.



Descriptive statistics were generated for all study variables including means, standard deviations, medians, and interquartile ranges for continuous variables, and relative frequencies for categorical variables. Statistical comparisons were made using χ2 for categorical variables and analysis of variance for continuous variables. A P value of less than .05 was considered statistically significant.

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A total of 38,167 patients were enrolled at 15 study centers from October 1999 until December 2002 for nuchal translucency sonography. A total of 134 cases of septated cystic hygroma were diagnosed in this population, for a prevalence of 1 in 285 first-trimester pregnancies. Demographic characteristics of septated cystic hygroma patients and the general screened population are shown in Table 1. Patients with septated cystic hygroma were significantly older and were significantly more likely to be of Asian ethnic background, compared with the general screened population. Fifteen of 134 cases (11.2%) were diagnosed in the 10th week of gestation, 49 (36.6%) in the 11th week, 49 (36.6%) in the 12th week, and 21 (15.6%) in the 13th week.

Table 1

Table 1

Pregnancy and pediatric outcome was obtained in 37,002 cases (97%) of the population of 38,167 patients that underwent nuchal translucency evaluation, including 132 of 134 cases of septated cystic hygroma, (2 cases lost to follow-up). Evaluation for presence of fetal or pediatric aneuploidy was performed by karyotype analysis in 114 cases (86%), and by newborn physical evaluation or autopsy in the remaining 18 cases (14%). Chromosomal abnormality was diagnosed in 67 of 132 cases (51%) of cystic hygroma, the details of which are summarized in Table 2. Down syndrome was the most common aneuploidy diagnosed, but Turner syndrome and trisomy 18 were also seen frequently. Table 2 also summarizes the structural malformations diagnosed among the remaining 65 cases in which chromosomal abnormality was not found. Major structural fetal malformations, primarily cardiac and skeletal, were diagnosed in one third of these remaining cases (22 of 65, 33.8%). Overall, two thirds (89 of 132, 67.4%) of all cases of septated cystic hygroma were diagnosed with either chromosomal or major structural fetal abnormalities.

Table 2

Table 2

Table 3 describes pregnancy and pediatric outcome of the 132 cases of septated cystic hygroma in which follow-up was obtained. Elective pregnancy termination was chosen by 79 patients (60%), and spontaneous fetal demise occurred in a further 20 patients (15%). Five of these 20 spontaneous fetal demises occurred in chromosomally normal pregnancies, one each in the 11th, 12th, and 13th weeks of gestation, and 2 in the 14th week.

Table 3

Table 3

There were a total of 33 live births in this cohort of 132 cases of cystic hygroma. Chromosomal or structural malformations had been diagnosed prenatally in 10 of these, and in 1 of these 10 cases (with hydrops) a neonatal demise occurred in the 4th week of life. Pediatric outcome was pursued in the remaining 23 liveborn cases in which no obvious chromosomal or structural abnormality had been diagnosed prenatally. Pediatric outcome evaluation beyond 12 months of age was obtained in 21 of these 23 cases, with outcome being limited to evaluations at 2 and 9 months of life in the remaining 2 cases. Median long-term follow-up extended to 25 months of age (range 12–50 months). The only additional pediatric abnormality diagnosed in this cohort of 23 apparently normal pediatric survivors was 1 case of spastic diplegia and developmental delay. This infant had a normal-term vaginal delivery, with normal Apgar scores and cord blood gases. No clear etiology for cerebral palsy has been documented in this case, and no genetic syndrome or other abnormality has been diagnosed.

Median measurements for nuchal translucency were established at each of the 15 clinical sites, and nuchal translucency measurements were expressed as multiples of these center-specific medians (MoM values). Mean nuchal translucency measurement in cases of cystic hygroma was 6.5 mm (standard deviation 4.1, range 2.0–23.0 mm), or 6.9 MoM (standard deviation 2.9, range 2.8–17.7 MoM). Table 4 summarizes mean nuchal translucency measurements in each category of pregnancy outcome. Mean nuchal translucency measurements were significantly larger among Turner syndrome cases compared with euploid cases and compared with other aneuploid cases (P < .01). In the 23 cases of septated cystic hygroma without malformation that were followed up expectantly, cystic hygroma resolved in 18 cases (78%), at a mean gestational age of 18.2 weeks (standard deviation 3.7, range 15–30 weeks).

Table 4

Table 4

To evaluate whether septated cystic hygroma represents a distinct clinical entity from simple increased nuchal translucency, the 132 cystic hygroma cases were compared with the 140 cases of simple increased nuchal translucency with measurements greater than or equal to 3.0 MoM diagnosed in the general screened population from the FASTER trial. These results are described in Table 5 and confirm a significantly worse prognostic outcome for cystic hygroma cases compared with fetuses with simple increased nuchal translucency.

Table 5

Table 5

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First-trimester screening for fetal aneuploidy using nuchal translucency sonography is an increasingly popular component of routine antenatal care and is a powerful tool for prenatal identification of fetal Down syndrome.8 In the recently completed FASTER trial, 86% of all Down syndrome cases (5% false-positive rate) were diagnosed using first-trimester screening in a general U.S. population of over 38,000 patients (Malone et al, 2005). As screening programs using such first-trimester markers become more widespread, the diagnosis of septated cystic hygroma will become increasingly frequent. Although it is possible to measure the nuchal translucency space in such fetuses, and incorporate this measurement into a Down syndrome risk algorithm together with serum analytes, the FASTER trial has now confirmed that this finding can stand alone as the strongest association with fetal aneuploidy known to date. Fully 50% of all fetuses with this sonographic finding will have a chromosomal abnormality and only 17% will result in a healthy newborn.

Given the power of this unique marker, there is no reason to delay patient counseling to obtain serum analyte measurements and use risk-calculation software programs before offering patients the option of definitive diagnosis with chorionic villi sampling. Additionally, individualized Down syndrome risk calculations based on nuchal translucency sonography require strict quality-control programs in the form of special training and ongoing surveillance to confirm accuracy of technique. In contrast to nuchal translucency sonography for Down syndrome risk assessment, the first-trimester diagnosis of cystic hygroma is relatively straightforward and does not require specialized quality-assurance systems to be established before it can be used as a marker for patient counseling. The mean nuchal translucency measurement in these cases was almost 7-fold greater than the median nuchal translucency in the general population, making it a relatively easy marker for clinicians in general practice to identify. For these reasons, we believe that the sonographic diagnosis of cystic hygroma in the first trimester of pregnancy could be quickly implemented in the general population, without need for serum analytes, ongoing quality-assurance systems, or individualized Down syndrome risk calculations. Provided the sonographic features as described in the FASTER protocol are present (enlarged nuchal translucency space extending along the length of the fetus, and with septations clearly visible, as shown in Fig. 1) it is reasonable to immediately counsel patients regarding their extremely high risks of adverse outcome.

The prevalence of 1 in 285 first-trimester pregnancies from a general obstetric population is considerably more common than noted in earlier studies.9 Additionally, prior studies of cystic hygroma have been difficult to apply to general clinical practice as the diagnosis was quite variable. Some refer to cystic hygroma in later gestation, which likely represents a lymphangioma that is not associated with either aneuploidy or other fetal malformations, and can be expected to yield a good prognosis after surgical correction.2,3 Other studies have focused on first-trimester cystic hygroma but have not differentiated between septated and nonseptated forms.10 The latter group likely reflects simple increased nuchal translucency that, though associated with fetal aneuploidy, may not be nearly as strong a marker as the septated cystic hygroma. We believe that fetuses with enlarged nuchal translucency in which septations are absent should not be referred to as cystic hygromas and should remain part of a formal aneuploidy screening program, in which the size of the nuchal translucency space is combined with serum analyte values to yield an individualized Down syndrome risk assessment. It is possible that use of higher-frequency transvaginal transducers may yield different appearances of tissue in the nuchal region, and overlap may exist between cases of simple increased nuchal translucency and cystic hygroma. Nevertheless, even if recognized as an extreme form of increased nuchal translucency, it is now indisputable that first trimester septated cystic hygroma is associated with a much worse prognosis. The comparative data presented in Table 5 clearly support these conclusions, with cystic hygroma cases having significantly increased risks of fetal aneuploidy (odds ratio 5.2), cardiac malformation (odds ratio 12.4), and death (odds ratio 6.0), compared with cases of simple increased nuchal translucency.

Prior studies of nuchal translucency sonography have suggested that this form of screening is a useful tool for detecting a range of structural fetal malformations, including cardiac anomalies.11,12 However, prior population studies of nuchal translucency sonography have combined cases of septated cystic hygroma with simple nuchal translucency. Given the large number of structural fetal malformations that cluster in the subgroup of fetuses with septated cystic hygroma, it is possible that first-trimester sonographic screening, when restricted to simple nuchal translucency, may not be nearly as powerful a marker for fetal abnormalities as previously suggested. It is important to realize that the outcome results documented here should only be used to counsel patients with cases of septated cystic hygroma that fulfill the diagnostic criteria as outlined in the FASTER trial. Additionally, in our study many structural abnormalities clustered in the cardiac subgroup, including cases of hydrops. It is important to realize that the causes of hydrops are multifactorial and, when evaluating such cystic hygroma cases with hydrops, consideration should be given to other noncardiac etiologies.

Given that our findings are derived from a general obstetric population, these results can be used for widespread patient counseling. It is not surprising that patients with cystic hygroma were significantly older than the general screened population in FASTER, because both cystic hygroma and advancing maternal age are risk factors for fetal trisomy. We cannot explain why a significantly increased prevalence of Asian ethnic background was noted in the cystic hygroma population compared with the general screened population. Significant ethnic variation has not previously been identified with nuchal translucency measurements, and we know of no biological reason as to why Asian ethnic background should be specifically associated with cystic hygroma. It is possible that this finding is a chance occurrence, especially given that only 13 pregnancies with cystic hygroma were of Asian mothers.

Another major limitation of prior studies of cystic hygroma, and indeed increased nuchal translucency in general, has been the underascertainment of abnormal cases and the lack of long-term pediatric outcome data. In the FASTER trial outcome information was obtained in 97% of the overall population and in 132 of the 134 cases (99%) of cystic hygroma, with pediatric outcome being available to a median of 25 months and a range of up to 50 months. For those cases in which the pregnancy is managed expectantly, natural history information is now available. The majority (78%) of expectantly managed cases demonstrated spontaneous resolution of the cystic hygroma, between 15 and 30 weeks of gestation. A limitation of our study is that in 15 cases elective pregnancy termination was chosen by parents before completion of full prenatal evaluation. However, in 11 of these 15 cases, chromosomal evaluation was obtained and confirmed normal fetal karyotype. It is possible that other structural malformations were present in these 11 cases, and it is also possible that the remaining four cases may have had karyotypic abnormalities. If these 15 pregnancies continued, and if all 15 resulted in normal survivors, than the rate of normal outcome with cystic hygroma might be as high as 28% (37/132).

When faced with the diagnosis of septated cystic hygroma in the first trimester, we recommend three separate counseling sessions with prospective parents, based on a standardized diagnostic algorithm. Initial counseling should occur immediately after sonographic diagnosis, and an overall risk of fetal aneuploidy of 1 in 2 should be quoted. After confirmation of a normal fetal karyotype by chorionic villi sampling, a second counseling session should be provided. At that time, prospective parents should be given a residual risk of 1 in 2 of a major structural fetal abnormality or spontaneous fetal death. After completion of detailed fetal anatomic sonography and echocardiography by 16–20 weeks of gestation, patients with normal findings can then be quoted a 95% chance of a normal pediatric outcome. While prior studies have suggested an association between fetal cystic hygroma and Noonan syndrome, we failed to confirm this, with no case of Noonan syndrome diagnosed in this population.13 However, it is important to note that Noonan syndrome can be a challenging diagnosis to make and it is possible that one or more of this cohort of 23 surviving children may represent an undiagnosed case, or may indeed have other undiagnosed genetic conditions. Given the reported association of cystic hygroma with Noonan syndrome,13 it may be reasonable to recommend physical examination of survivors by a pediatric geneticist. Additionally, a 95% chance of normal pediatric outcome after a detailed prenatal evaluation should be quoted cautiously to parents as it is possible that the true figure may be lower if there were missed genetic conditions or if follow-up was longer than the median of 25 months in this study.

In conclusion, the FASTER trial data demonstrate that first-trimester sonographic diagnosis of septated cystic hygroma has a very strong association with both fetal aneuploidy and major structural abnormalities, with significantly worse prognosis than simple increased nuchal translucency. We recommend here a structured diagnostic and counseling algorithm that should be useful for parents and clinicians when faced with this increasingly common prenatal finding. If the results of the recommended diagnostic algorithm are normal, prospective parents may be reassured about the apparently normal long-term pediatric outcome demonstrated in this study.

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The members of the FASTER Trial Research Consortium include K. Welch, MS, R. Denchy, MS (Columbia University, New York, NY); F. Porter, MD, M. Belfort, MD, B. Oshiro, MD, L. Cannon, BS, K. Nelson, BSN, C. Loucks, RNC, A. Yoshimura (University of Utah, and IHC Perinatal Centers, Salt Lake City, Provo, and Ogden, UT); D. Luthy, MD, S. Coe, MS (Swedish Medical Center, Seattle, WA); J. Esler, BS, D. Schmidt, MS (William Beaumont Medical Center, Royal Oak, MI); G. Hankins, MD, R. Bukowski, MD, J. Lee, MS, (UTMB Galveston, TX); K. Eddleman, MD, Y. Kharbutli, MS (Mount Sinai Medical Center, New York, NY); I. Merkatz, MD, S. Carter, MS (Montefiore Medical Center, Bronx, NY); J. Hobbins, MD, L. Schultz, RN (University of Colorado Health Science Center, Denver, CO); M. Paidas, MD, J. Borsuk, MS (NYU Medical Center, New York, NY); B. Isquith, MS, B. Berlin, MS (Tufts University, Boston, MA); G. Lambert-Messerlian, PhD, C. Duquette, RDMS (Brown University, Providence, RI); R. Baughman, MS (University of North Carolina, Chapel Hill, NC); and T. Tripp, MA, D. Emig, MPH, L. Sullivan, PhD (DM-STAT Inc, Medford, MA).

© 2005 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.