Descriptive epidemiology of cystic hygroma: Hawaii, 1986 to 1999.

Objectives: Cystic hygroma is associated with chromosomal abnormalities and a low chance of survival. The purpose of this study was to examine the relationship between cystic hygroma and various clinical and demographic factors.

Methods: Cystic hygroma cases delivered in Hawaii from 1986 to 1999 were obtained from a population-based birth defects registry. The rate per 10,000 births was determined for various demographic and clinical factors.

Results: The total cystic hygroma rate was 5.13 per 10,000 births. Chromosomal abnormalities were identified for 39% of the cases. There were no secular trends in cystic hygroma rates. Rates increased with increasing maternal age (P = 0.031). Rates were highest among Far East Asians, followed by Filipinos and whites, and lowest for Pacific Islanders. Cystic hygroma rates were higher in metropolitan Honolulu than in the rest of Hawaii. Rates were higher for females than for males. Cystic hygroma rates did not vary significantly by plurality.

Conclusions: Cystic hygroma rates were not found to be associated with delivery year or plurality, but were associated with maternal age, race and ethnicity, residence at delivery, and sex.

Key Words: birth defects, cystic hygroma, pregnancy outcome, prenatal diagnosis 

**********

Cystic hygroma is a thin-walled cystic dilation of the lymphatic system, usually involving the neck. (1) The defect is believed to result from failure of the embryonic lymphatic sacs to connect with the venous system during development of the lymphatic system in the sixth week of gestation. (2)

Cystic hygroma is frequently detected prenatally by ultrasound or during the newborn period, although some cases occur after the first year of life. (1,3,4) The defect may spontaneously regress during pregnancy, leaving redundant neck skin at delivery. (5-8) As a result, estimates of cystic hygroma prevalence vary, depending on whether fetal deaths are included in the populations studied. Several population-based studies have reported the cystic hygroma prevalence to be 1 per 10,000 births, (4,9) whereas a hospital-based study that included live births, stillbirths, and elective terminations observed a prevalence of 30 per 10,000 births. (10) The cystic hygroma rate has increased over the last several decades, a phenomenon ascribed to increaseduse of prenatal ultrasound. (10)

Cystic hygroma is commonly associated with chromosomal abnormalities, most frequently Turner syndrome, but also trisomies 21, 18, and 13. (1,3,5-8,10-16) A large proportion of infants and fetuses with cystic hygroma also have other structural abnormalities. (10,17) The survival rate of live-birthed babies with cystic hygroma has been reported to be low. (9,14,18) Possibly as a consequence of its association with other birth defects and high mortality, a large percentage of fetuses with prenatally detected cystic hygroma are electively terminated. (3-5,8,11-13,17,18)

The purpose of the current investigation was to examine the relationship between various clinical and demographic factors and cystic hygroma, using data from a population-based birth defects registry in Hawaii. Review of the literature identified few population-based studies involving cystic hygroma. (3,4,9)

Materials and Methods

Cases were obtained from the Hawaii Birth Defects Program (HBDP), a population-based birth defects surveillance program for the entire state of Hawaii. (19) The HBDP includes all infants and fetuses of any pregnancy outcome and any gestational age for which the mother's pregnancy ended within the state of Hawaii and the infant or fetus had one or more reportable birth defects. Trained HBDP staff collec information on all eligible cases by reviewing logs and medical records at all delivery and pediatric tertiary-care hospitals, facilities that perform elective terminations secondary to fetal anomalies, cytogenetic laboratories, genetic counseling facilities, and all but one of the major prenatal ultrasound facilities in the state. Through this multiple-source ascertainment system, it is believed that identification of infants and fetuses with detected birth defects is as complete as possible.

The current investigation included all infants and fetuses with a detected cystic hygroma delivered during the period from 1986 through 1999. Infants and fetuses in whom the diagnosis of cystic hygroma was not confirmed but was listed as "possible" or "probable" (n = 12) were excluded from the study. The prevalence of cystic hygroma was calculated, and the distribution by pregnancy outcome was determined. Pregnancy outcome was categorized as "live birth," "elective termination," "late fetal death" (gestational age 20 or more weeks), and "early fetal death" (gestational age less than 20 weeks or, if the gestational age was not known, that the pregnancy's result was reported as a spontaneous abortion, missed abortion, or miscarriage).

The proportion of cases with a known chromosomal abnormality based on cytogenetic analysis was determined, and the types of chromosomal abnormalities were described. The pregnancy outcome distribution was calculated for those cases with a known chromosomal abnormality as well as for those cases without a known chromosomal abnormality. (Pregnancy outcome distribution was determined for those cases without a known chromosomal abnormality instead of only for those cases where the karyotype was known to be normal because a portion of the cases may not have been karyotyped, since no chromosomal abnormality was suspected.) The percentage of cases with a prenatal diagnosis of any birth defects and a prenatal diagnosis of cystic hygroma were calculated, and the pregnancy outcome distribution of cases with and without a prenatal diagnosis of cystic hygroma was identified.

The cystic hygroma rates for all cases, and for those cases without a known chromosomal abnormality, were calculated for various clinical and demographic factors. The proportion of total cases with prenatal diagnosis of cystic hygroma was also determined for the various groups. For analysis of delivery year, no attempt was made to adjust the delivery year of elective terminations and fetal deaths to reflect the potential year of birth had the pregnancies gone to term. Maternal race or ethnicity was classified as either white, Far East Asian (Japanese, Chinese, or Korean), Pacific Islander (Hawaiian, Samoan, or Guamanian), or Filipino. Mothers of other or unknown race or ethnicity (n = 19) were excluded from the analyses of race and ethnicity. Residence at delivery was grouped by county and whether the residence was in metropolitan Honolulu (zip codes starting with 968) or the rest of Hawaii (zip codes starting with 967).

Denominators were obtained from the Hawaii Department of Health, Office of Health Status Monitoring, as derived from birth and fetal death certificates. In Hawaii, fetal death certificates may be filed on fetal deaths of all gestational ages. Denominators were not readily available for all variables from fetal death certificates; as a result, for some variables denominators were restricted to birth certificates. Ninety-five percent confidence intervals (CIs) were calculated using Poisson probability. Trends were analyzed with the [chi square] test for trend.

Results

There were 145 infants and fetuses diagnosed with cystic hygroma among 282,900 live births and fetal deaths delivered in Hawaii from 1986 through 1999. The cystic hygroma prevalence rate was 5.13 per 10,000 births (95% CI, 4.33-6.03). The distribution of all cases by pregnancy outcome is shown in Table 1. The cases were almost evenly distributed among live births, elective terminations, and fetal deaths. Five (10%) of the live births died within 1 year of delivery.

Cytogenetic analysis was reported for 80 (55%) of the cases. A chromosomal abnormality was identified in 57 of the cases, constituting 39% of all cases and 71% of those cases where a cytogenetic analysis was reported. Thirty-eight (67%) of the cases with chromosomal abnormalities were karyotype 45,X; the rest of the observed chromosomal abnormalities were 45,X/47,XXX (n = 1), trisomy 21 (n = 7), trisomy 18 (n = 5), trisomy 13 (n = 2), triploidy (n = 1), tetraploidy (n = 1), isochromosome 22 (n = 1), and addition chromosome 4 (n = 1). Table 1 contains the pregnancy outcome distribution of cases with and without a known chromosomal abnormality. The majority of cases with a known chromosomal abnormality resulted in elective terminations, whereas the majority of cases without a known chromosomal abnormality were live births.

Eighty-nine (61%) of the cases were prenatally diagnosed with a birth defect, of which 49 (55%) resulted in elective termination. Prenatal diagnosis of cystic hygroma was reported for 75 (52%) of the cases, of which 42 (56%) were electively terminated. Thus, for seven cases, the diagnosis of cystic hygroma was made after the elective termination due to other prenatally diagnosed birth defects. When the pregnancy outcome distribution by prenatal diagnosis of cystic hygroma was examined (Table 1), it was found that the majority of cases where cystic hygroma was prenatally diagnosed resulted in elective termination, whereas the majority of cases where cystic hygroma was not prenatally diagnosed resulted in live births.

Table 2 contains the rate of cystic hygroma and the proportion of cases that were prenatally diagnosed with cystic hygroma by various demographic and clinical factors. The total cystic hygroma rate was slightly higher in the second half of the study period, although the increase was not statistically significant. A similar pattern was observed for the proportion of cases that were prenatally detected with cystic hygroma (rate ratio, 1.22; 95% CI, 0.88-1.66).

The rate of cystic hygroma increased with increasing maternal age, and the trend was statistically significant (P = 0.031). The relationship between cystic hygroma rate and maternal age remained when cases with a known chromosomal abnormality were excluded (P = 0.010).

Far East Asians had the highest rate of cystic hygroma, significantly higher than whites. Pacific Islanders had the lowest cystic hygroma rate, although the difference between Pacific Islanders and whites was only statistically significant for all cases.

Cystic hygroma rates did not vary significantly by county of residence, but cystic hygroma was significantly more common in metropolitan Honolulu than in the rest of Hawaii. Females were more likely to have cystic hygroma than males, although the difference between the sexes was only statistically significant for total cases. Plurality did not affect cystic hygroma rates.

Discussion

This study examined the relationship between cystic hygroma and various demographic and clinical variables using data from a population-based birth defects registry. A review of the literature identified few other published studies of cystic hygroma using population-based data. Moreover, those studies that were found did not examine a number of the variables included in the current investigation. As a result, much of the information in this study is new. The evaluation of potential associations between cystic hygroma and various demographic factors is important because such associations may provide insight into the cause of cystic hygroma. For instance, differences in rates between racial or ethnic groups might suggest either genetic or environmental causes for a portion of cystic hygroma cases. These potential causative factors could then be studied in greater detail. Moreover, knowledge of those portions of the population with higher cystic hygroma rates could be used to improve early detection and treatment of fetuses with cystic hygroma; that is, if a particular maternal age group were demonstrated to have higher rates of cystic hygroma, health care providers might be more likely to search for cystic hygroma in the fetus when performing prenatal ultrasound on pregnant women in that age group.

There were several limitations to this study. The relatively small number of cases, particularly when distributed among various subgroups, limits the statistical significance of some analyses. Moreover, the investigation is restricted to those cases where the cystic hygroma was detected. Any instances where a cystic hygroma may have existed prenatally but was not identified by ultrasound and then spontaneously regressed before delivery would be missed. Moreover, because the literature did not contain population-based data for some of the factors included in the current investigation, comparisons with other studies to validate the results were not always feasible. Comparisons between this investigation and other studies were made where possible.

The cystic hygroma prevalence reported in this study (5.13 per 10,000 births) was higher than the approximately 1 per 10,000 births reported by several population-based studies. (4,9) There are several possible explanations for differences between the observed rates. The different rates may reflect differences in inclusion criteria. One study (9) was limited to isolated cervical cystic hygroma and did not appear to include early fetal deaths. Because a large proportion of cystic hygroma cases are prenatally diagnosed (3,4) and may spontaneously regress before delivery, (5-8) differences in prenatal detection of cystic hygroma could account for differences in prevalence. However, the prenatal detection rate observed in the present investigation (52%) was lower than the 75% reported by one of the other population-based studies. (4) Differences in the study populations could also account for the different rates. The previous studies occurred in Europe, whereas the current study occurred in Hawaii, a population with a large proportion of Asians and Pacific Islanders. Because racial and ethnic differences were observed in the present study, populations with different racial and ethnic compositions may have different cystic hygroma rates.

A high percentage of those cases that underwent cytogenetic analysis were found to have a chromosomal abnormality. The most common chromosomal abnormality observed was 45,X--although other chromosomal abnormalities that were observed included trisomies 21, 18, and 13. These findings are consistent with the literature. (1,3,5-8,10-16) Only 4% of those cases with a known chromosomal abnormality were live births, whereas over half of the cases without a known chromosomal abnormality were live births. If a fetus has a cystic hygroma detected on prenatal ultrasound, the family might be more likely to electively terminate the pregnancy if a chromosomal abnormality was also antenatally diagnosed, because of the increased morbidity and mortality associated with chromosomal abnormalities.

Among cases with a prenatal diagnosis of cystic hygroma 5% resulted in live birth, and over 60% of those cases where the cystic hygroma was not prenatally detected ended in live birth. The majority of prenatally diagnosed cases resulted in elective termination. This pregnancy outcome pattern was noted by a number of other studies reporting the outcome of prenatally diagnosed cases of cystic hygroma. (8,11-13,17,18) Because cystic hygroma is associated with other birth defects and high mortality, if a cystic hygroma is prenatally diagnosed, the family might tend to decide on elective termination.

When the relationship between cystic hygroma and selected demographic and clinical factors was examined, the patterns of cystic hygroma risk were frequently similar between all cases and cases without a known chromosomal abnormality. It could be argued that a portion of those cases without a known chromosomal abnormality actually had a chromosomal abnormality that was undiagnosed, and that these cases account for the observed relationship between cystic hygroma and the various demographic and clinical factors considered. Cytogenetic analysis was reported for 55% of the cases; it is unclear why cytogenetic analysis was not performed on the remaining 45%. It may be that the family refused cytogenetic analysis, cytogenetic analysis was not possible, or that cytogenetic analysis was attempted but failed. Or it could be that, aside from the cystic hygroma, the infant or fetus did not have other conditions that would make health care providers suspect the presence of a chromosomal abnormality, and therefore cytogenetic analysis was not considered necessary.

In addition, the patterns of cystic hygroma rates were often consistent with the prenatal diagnosis rates of cystic hygroma; that is, subgroups with higher cystic hygroma rates tended to have higher prenatal diagnosis rates. This suggests that prenatal diagnosis influences rates of detected cystic hygroma among subgroups.

The cystic hygroma rate did not change significantly between the first and second halves of the study period, nor were the proportion of cases prenatally diagnosed with cystic hygroma significantly different between the two time periods. A previous investigation has reported an increase in the cystic hygroma rate, and tentatively associated the trend with increased prenatal detection of cystic hygroma. (10) However, that study included the time period from 1973 to 1990. By the time of the current study period (1986-1999), the prenatal detection of cystic hygroma in Hawaii might have been well established, so that any secular changes in prenatal detection would not be significant. It is noteworthy that the rate of cystic hygroma without known chromosomal abnormalities was lower in the second half of the study period. The proportion of cases with a known chromosomal abnormality increased significantly, from 21 (29%) in the period from 1986 to 1992, up to 36 (50%) from 1993 to 1999 (rate ratio, 1.73; 95% CI, 1.22-2.41). This could possibly be attributed to an increased tendency during the latter part of the time period to perform cytogenetic analysis in instances where cystic hygroma was diagnosed.

Cystic hygroma risk increased with advancing maternal age. Because cystic hygroma is associated with chromosomal abnormalities and the risk of chromosomal abnormality increases with advancing maternal age, the relationship between cystic hygroma and maternal age could be expected. However, the association between cystic hygroma and maternal age remained even after cases with a known chromosomal abnormality were excluded. Moreover, the most common chromosomal abnormality associated with cystic hygroma is 45,X, and 45,X does not appear to be associated with maternal age. (20-22)

The association between cystic hygroma and maternal age could also be ascribed to older women having more prenatal diagnostic tests because of their increased risk of chromosomal abnormalities, and therefore more cases of cystic hygroma being incidentally diagnosed through these tests. However, the proportion of cases with prenatal detection of cystic hygroma actually decreased with increasing maternal age in this study.

Cystic hygroma risk varied by race and ethnicity, being highest for Far East Asians and lowest for Pacific Islanders. The racial and ethnic differences observed could be due to differences in maternal age distribution between the various groups. However, when differences in maternal age distribution were taken into account, the significant racial and ethnic differences among all cases remained, but disappeared for cases without a known chromosomal abnormality (data not shown). Because detected cystic hygroma rates tended to vary with prenatal diagnosis rates, the differences could also be attributed to differences in prenatal detection of cystic hygroma. In fact, Pacific Islanders had both the lowest total cystic hygroma rate and the lowest prenatal detection rate.

The cystic hygroma rate for females was over twice that found among males, a fact that can be attributed in part to the fact that the most common chromosomal abnormality associated with cystic hygroma is 45,X, an abnormality associated with females. When cases with known chromosomal abnormalities are excluded, the difference in cystic hygroma rates between the sexes was reduced.

Conclusion

This investigation, using population-based data, indicated that the majority of cases of cystic hygroma did not result in live birth, and that cystic hygroma risk varied by maternal age, maternal race or ethnicity, and infant/fetus sex. Pregnancy outcome and risk of detected cystic hygroma was associated at least in part with prenatal detection of the cystic hygroma and the presence of chromosomal abnormalities. Further population-based studies would be useful to validate the associations observed in this study. If such associations are confirmed, investigation into potential causative factors underlying such associations are warranted. Health care providers may use some of the associations observed in this study to determine which patients would be most likely to have cystic hygroma, and thereby improve detection of the condition.

For extreme illnesses, extreme remedies are most fitting.
--Hippocrates

Table 1. Pregnancy outcome distribution of cystic hygroma, Hawaii,
1986-1999

                                       Known chromosomal
                                         abnormalities
Pregnancy               Total          Yes           No
outcome                 (n = 145) (%)  (n = 57) (%)  (n = 88) (%)

Live births             48 (33)         2 (4)        46 (52)
Elective terminations   49 (34)        33 (58)       16 (18)
Late fetal deaths (a)   31 (21)        13 (23)       18 (20)
Early fetal deaths (b)  17 (12)         9 (16)        8 (9)

                        Prenatally diagnosed with cystic
                                 hygroma

Pregnancy               Yes           No
outcome                 (n = 75) (%)  (n = 70) (%)

Live births              4 (5)        44 (63)
Elective terminations   42 (56)        7 (10)
Late fetal deaths (a)   21 (28)       10 (14)
Early fetal deaths (b)   8 (11)        9 (13)

(a) Fetal deaths with gestational age [greater than or equal to]20 wk.
(b) Fetal deaths with gestational age < 20 wk or, if gestational age
unknown, reported as missed abortion, miscarriage, or spontaneous
abortion.

Table 2. Rate per 10,000 of cystic hygroma by selected demographic and
clinical factors, Hawaii, 1986-1999

                                                 Total cases
                                                              Rate
                                Denominator (b)  Cases  Rate  ratio

Delivery year
  1986-1992                          146,968       73   4.97   --
  1993-1999                          135,932       72   5.30   1.07
Maternal age (yr)
  [less than or equal to]19           26,687       10   3.75   0.72
  20-24                               69,033       34   4.93   0.95
  25-29                               74,813       39   5.21   --
  30-34                               59,698       35   5.86   1.13
  [greater than or equal to]35        33,539       26   7.75   1.49
Race/ethnicity
  White                               70,449       36   5.11   --
  Far East Asian                      48,089       39   8.11   1.59
  Pacific islander                    73,098       24   3.28   0.64
  Filipino                            48,285       27   5.59   1.09
Residence at delivery
  City and County of Honolulu        209,413      110   5.25   --
  Hawaii                              29,834        9   3.02   0.57
  Maui                                25,793       16   6.20   1.18
  Kauai                               12,763        5   3.92   0.75
  Metropolitan Honolulu               78,226       52   6.65   1.40
  Rest of Hawaii                     184,931       88   4.76   --
Sex
  Male                               135,645       45   3.32   --
  Female                             128,150       94   7.34   2.21
Plurality
  Singleton                          257,279      143   5.56   --
  Multiple birth                       5,321        2   3.76   0.68

                                Total cases
                                                Prenatal
                                95% CI       diagnosis (%) (c)

Delivery year
  1986-1992                     --               34 (47)
  1993-1999                     0.83-1.34        41 (57)
Maternal age (yr)
  [less than or equal to]19     0.35-1.32         7 (70)
  20-24                         0.65-1.32        20 (59)
  25-29                         --               19 (49)
  30-34                         0.78-1.56        17 (49)
  [greater than or equal to]35  0.97-2.18        11 (42)
Race/ethnicity
  White                         --               18 (50)
  Far East Asian                1.13-2.17        20 (51)
  Pacific islander              0.41-0.96         9 (38)
  Filipino                      0.72-1.59        13 (48)
Residence at delivery
  City and County of Honolulu   --               61 (55)
  Hawaii                        0.26-1.09         3 (33)
  Maui                          0.68-1.92         7 (44)
  Kauai                         0.24-1.74         2 (40)
  Metropolitan Honolulu         1.04-1.83        32 (62)
  Rest of Hawaii                --               41 (47)
Sex
  Male                          --               16 (36)
  Female                        1.79-2.71        54 (57)
Plurality
  Singleton                     --               74 (52)
  Multiple birth                0.08-2.44         1 (50)

                                Cases without chromosomal
                                      abnormalities (a)
                                             Rate
                                Cases  Rate  ratio  95% CI

Delivery year
  1986-1992                       52   3.54   --    --
  1993-1999                       36   2.65   0.75  0.52-1.04
Maternal age (yr)
  [less than or equal to]19        5   1.87   0.52  0.17-1.21
  20-24                           16   2.32   0.64  0.37-1.04
  25-29                           27   3.61   --    --
  30-34                           22   3.69   1.02  0.64-1.55
  [greater than or equal to]35    17   5.07   1.40  0.82-2.25
Race/ethnicity
  White                           22   3.12   --    --
  Far East Asian                  24   4.99   1.60  1.02-2.38
  Pacific islander                14   1.92   0.61  0.34-1.03
  Filipino                        20   4.14   1.33  0.81-2.05
Residence at delivery
  City and County of Honolulu     67   3.20   --    --
  Hawaii                           6   2.01   0.63  0.23-1.37
  Maui                            11   4.26   1.33  0.67-2.38
  Kauai                            3   2.35   0.74  0.15-2.15
  Metropolitan Honolulu           31   3.96   1.31  0.89-1.86
  Rest of Hawaii                  56   3.03   --    --
Sex
  Male                            36   2.65   --    --
  Female                          46   3.59   1.35  0.99-1.80
Plurality
  Singleton                       86   3.34   --    --
  Multiple birth                   2   3.76   1.12  0.13-4.06

(a) Cases without a known chromosomal abnormality, including those cases
where no karyotype was obtained.
(b) Denominator is live births for all variables except for delivery
year, where the denominator is live births and fetal deaths.
(c) Prenatal diagnosis of cystic hygroma.

Acknowledgments

The authors thank Dr. Laurence N. Kolonel for serving as the program principal investigator, A. Michelle Weaver and Amy M. Yamamoto for their data collection, the staff of the Office of Health Status Monitoring at the Hawaii Department of Health for providing denominators, and the 33 participating Hawaii health facilities who allowed us access to their patient data.

Accepted December 8, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0631

Please see Benjamin R. Bates' editorial on page 622 of this issue.

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RELATED ARTICLE: Key Points

* If a chromosomal abnormality had been identified, a case of cystic hygroma was likely to result in elective termination or fetal death.

* Cystic hygroma risk increased with maternal age.

* Cystic hygroma was more common among females.

Mathias B. Forrester, BS, and Ruth D. Merz, MS

From the Hawaii Birth Defects Program, Honolulu, HI.

This research was supported by a contract with the Hawaii State Department of Health, Children With Special Health Needs Branch, and grants from the Centers for Disease Control and Prevention, Ronald McDonald Children's Charities, March of Dimes Birth Defects Foundation, George F. Straub Trust, Queen Emma Foundation, Pacific Southwest Regional Genetics Network, and Kamehameha Schools/Bishop Estate.

Reprint requests to Ruth D. Merz, Administrator, Hawaii Birth Defects Program, 76 North King Street, #208, Honolulu, HI 96817-5157. Email: [e-mail]