Changing Clinical Presentations and Survival Pattern in Trisomy 18

Pediatr Neonatol 2009;50(4):147−151

O R IGINAL ART IC L E

Changing Clinical Presentations and Survival Pattern in Trisomy 18 Chien-Chou Hsiao1,2*, Lon-Yen Tsao1, Hsiao-Neng Chen1, Han-Yao Chiu1, Weng-Cheng Chang2 1

Department of Pediatrics, Children’s Hospital, Changhua Christian Hospital, Taiwan Institute of Medical Research, College of Health Sciences, Chang Jung Christian University, Taiwan

2

Received: Aug 20, 2006 Revised: Dec 15, 2008 Accepted: Dec 28, 2008 KEY WORDS: clinical presentation; counseling; Edwards syndrome; survival; trisomy 18

Background: The clinical presentations and survival patterns of infants with trisomy 18 have changed with increasing utilization of prenatal ultrasound and amniocentesis, and improvements in neonatal intensive care. Methods: We obtained data on duration of survival, male to female ratio, and clinical details for patients with trisomy 18, and calculated the prevalence rate. Results: We studied 31 consecutive trisomy 18 infants. The estimated prevalence was 1/4,144. Eleven (35%) were premature infants, and 20 (65%) were full term. Mean birth weight was 1,896 g. Median life expectancy was 12 days; 11 days for males and 14 days for females (p = 0.87). The short-term survival rates of 1 week, 4 weeks, and 6 months were 58%, 32%, and 10%, respectively. The long-term survival rates of 1 year, 2 years, and 3 years were 6%, 6%, and 3%, respectively. Families signed do-not-resuscitate consent forms for five male (50%) and 19 female infants (90%) (p = 0.043). Conclusion: All trisomy 18 infants in this study were preterm or full-term deliveries. Mean birth weight was lower than previously reported, and a high percentage of families signed do-not-resuscitate consent forms. Females did not survive longer than males, due to more females not being resuscitated. Most infants died in the first few weeks of life, but 3−6% of infants lived for ≥ 1 year. The possibility of longterm survival should be considered when counseling parents regarding trisomy 18.

1. Introduction Trisomy 18, also known as Edwards syndrome, is the second most common trisomy after trisomy 21, with an incidence of approximately 1 per 3,000−8,000 births.1−3 Continuing improvements in the quality of prenatal ultrasound and increased utilization of amniocentesis have made second- and thirdtrimester diagnosis of trisomy 18 more common.

Counseling of parents on prognosis for this condition is critical in order for families and physicians to be able to make informed decisions regarding delivery management and newborn care. Parents are invariably distressed when confronted with a neonate with the characteristic clinical features of trisomy 18,1,4 and objective advice about average survival time and the possible range of life spans are essential components of medical care and counseling.

*Corresponding author. Department of Pediatrics, Children’s Hospital, Changhua Christian Hospital, 135 Nan-Siau Street, Changhua City, 500 Taiwan. E-mail: [email protected] ©2009 Taiwan Pediatric Association

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Survival patterns and clinical details of these infants have been published previously,5−8 but due to the improvements in neonatal intensive care, earlier diagnosis and changes in medical management, the clinical presentations and survival patterns have recently changed. We studied these important aspects of trisomy 18 based on the experience of a medical center in mid-Taiwan.

2. Materials and Methods This study included index cases of infants with trisomy 18 diagnosed by cytogenetic studies in Changhua Christian Hospital from January 1991 to December 2006. The diagnosis of trisomy 18 was based on prenatal genetic analysis following amniocentesis (3 cases) or postnatal chromosome studies (28 cases). The three amniocenteses were performed during the 26th, 27th, and 30th weeks of gestation, and therapeutic abortions were not performed because of delayed diagnosis. Two sources of information were used for this total population study: Workbooks and laboratory registers from the cytogenetic laboratory were examined, and hospital case records and medical charts were reviewed. We identified 31 infants over the 16-year period. The prevalence rate in live newborns was calculated. Survival estimates were obtained, using information on age at death, male-to-female ratio, and other relevant clinical details. The survival of male and female infants was compared using the log-rank test. The percentages of families signing do-not-resuscitate consent forms for male and female infants were compared using the χ2 test. p values < 0.05 were considered to be significant.

3. Results Thirty-one cases were identified from 1991 to 2006; 13 of them were born at Changhua Christian Hospital and 18 were referred from obstetric clinics. Out of a total of 53,874 live births, the estimated prevalence of trisomy 18 in our hospital was 1 per 4,144. Females were predominant; there were 10 males (32%) and 21 females (68%). The median gestation period was 37 weeks (range 26−41 weeks). Eleven cases (35%) were premature and 20 (65%) were full term. The mean birth weight was 1,896 g (range 1,028−2,760 g). Sixteen cases (52%) were born by vaginal delivery, and 15 (48%) by Cesarean section. The median life expectancy for all live-born infants with trisomy 18 was 12 days (range 1 day−3 years). The median ages at death in males and females were 11 and 14 days, respectively, but this difference was not significant (p = 0.87). The short-term survival rates of 1 week, 1 month, and 6 months were 58%, 32%, and 10%, respectively. The long-term survival rates of 1 year, 2 years, and 3 years were 6%, 6%, and 3%, respectively. The survival curve from this study is compared with those from Weber’s report in 1967,5 Young et al in 1986,9 Root and Carey in 1994,2 and Lin et al in 2006 in Table 1 and Figure, derived from Root and Carey.2 The incidences of the clinical features are listed in Table 2. The most common clinical feature was intrauterine growth retardation (90%). None of our infants underwent surgery during the neonatal period. All of the 31 cases demonstrated complete trisomy 18, and no mosaic form was found. The sibling’s recurrence rate was zero in this study. Twenty-four families (77%) signed do-not-resuscitate consent forms after trisomy 18 was diagnosed; five were for male infants (50%) and 19 for female infants (90%) (p = 0.043).

Table 1 Survival of live-born with trisomy 18 Age/ % surviving Birth 1d 1 wk 2 wk 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 1 yr 2 yr 3 yr

New York Weber, 1967 n = 192

Utah Root, 1994 n = 64

Leicester Young et al, 1986 n = 21

Taipei Lin et al, 2006 n = 39

Changhua Hsiao et al, 2007 n = 31

100 98 89 81 72 51.8 38 30 23 13 8 5 3

100 86 45 41 34 22 20 14 9 9 5 5 5

100 67 32

100 95 46 27 16 11 5 5 3 3 3 3 3

100 90 58 45 32 14

18

0

10 6 6 3

Clinical features and survival pattern in trisomy 18

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100

New York Utah Leicester Taipei Changhua

90

Percent surviving

80 70 60 50 40 30 20 10

yr 3

yr 2

yr 1

o 6

m

o m

o 5

m

o 4

3

m

o 2

m

o m 1

w k 2

w k 1

d 1

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Figure Comparison of survival studies.

Table 2 Common clinical features in trisomy 18: total 31 cases

Intrauterine growth retardation Congenital heart disease Low-set, malformed ear Small oral opening Micrognathia Characteristic overlapping hand Prominent occiput Rocker bottom feet Hypotonia or hypertonia Microcephaly Prematurity Short sternum Small nipples Hypoplastic or absent thumb Syndactyly of toes or fingers Small pelvis Thrombocytopenia Short palpebral fissure Short hallux Narrow palatal arch Corneal opacification Choanal atresia Ulnar or radial deviation of hands Single umbilical artery Inguinal or umbilical hernia

4. Discussion The rates of trisomy 18 reported in the literature range from 1:3,000−1:8,000 livebirths.1,3,10 We estimated the prevalence at birth in our hospital to be about 1:4,144, which is in agreement with other recent reports.2,6,7 This may be an over-estimate, because of selection bias. Compared with Weber’s

Cases

Frequency (%)

28 24 22 19 18 18 17 16 16 16 11 10 9 9 8 8 8 7 6 6 5 4 4 3 3

90 77 71 61 58 58 55 52 52 52 35 32 29 29 26 26 26 22 22 22 16 13 13 10 10

data,5 our results showed a shorter survival time. However, it is not surprising that recent studies should show shorter survival times, since in the 1960s, trisomy 18 was typically not diagnosed until infants were 2 months old. More recent studies using population-based data from Denmark,7 Australia,6 England,9 and Utah2 concluded that survival in infants with trisomy 18 was poorer than

150 previously reported, either due to previous underdiagnosis,11 or to changes in medical management. Even though trisomy 18 infants have multiple structural abnormalities, as listed in Table 2, none of our infants underwent surgery during the neonatal period, compared with 13% reported in one textbook1 and 42% in a Japanese study.12 This is because more cases were diagnosed early, and because of the high percentage (77%) of families who signed donot-resuscitate consent forms in our study. Weber first reported that female trisomy 18 infants lived longer than males,5 an observation that has been confirmed by later studies.2,8,9 In our study, however, there was no significant difference in survival between males and females. Many factors have the potential to affect survival rates, including gestational age; all of our infants were preterm or full-term deliveries. Differences in resuscitation efforts and life-support measures are also important factors; because boys are more favored than girls in traditional Chinese families, more female than male infants’ families signed do-not-resuscitate consent forms after trisomy 18 was diagnosed. This seems to be the major factor affecting the duration of survival, and accounts for the fact that females did not live longer than males. Other prognostic factors reported by Tanigawa et al13 revealed that prenatal ultrasonographic findings associated with survival of < 1 month included severe polyhydramnios, absence of fluid in the stomach and severe cardiac anomaly, which are also important factors to consider when counseling parents. The changes in gestational age and mean body weights of trisomy 18 infants were another important finding of this study. According to Jones,1 one third of trisomy 18 cases were premature and one third were post-term, while 35% of trisomy 18 infants in the current study were premature and 65% were term babies. There were no post-term infants. This discrepancy is probably due to advancements in prenatal care and ultrasound assessment; when poor weight gain is detected before term, obstetricians urge the mother to deliver early, thus changing the infant’s natural course. These factors can account for the differences in gestational timing and smaller for date (mean birth weight 1,896 g) infants in our study, compared with those previously reported in the literature (2,340 g).1 Although the survival of trisomy 18 infants was poorer than previously reported, and the fact that it is often assumed that trisomy 18 is a universally lethal condition, with all affected neonates dying within days of birth,14,15 a small but significant percentage of infants can survive the first 6 months to a year of life. Trisomy 18 is thus not universally lethal.2,6 Infants receiving intensive treatment including Cesarean section, intubation with ventilator

C.C. Hsiao et al support, and surgical operations after birth, had median survival times as long as 152 days,12 and the survival rates at ages 1 week, 1 month, and 1 year were 88%, 83%, and 25%, respectively. We recommend that counseling of parents of affected fetuses or neonates should include information on the fact that, although the majority of infants with trisomy 18 die, some do survive. About 42% of newborns with trisomy 18 die in the first week of life, and 90% have died by 6 months of age. About 3−6% of trisomy 18 infants in Taiwan are alive at 1 year of age. This information is important to providers who care for patients with these conditions and their families. However, these data are based on results from live-born infants, and should therefore be used cautiously for prenatal counseling, bearing in mind that a significant proportion of these pregnancies are expected to be lost before birth.16,17

5. Conclusions All the trisomy 18 infants in this study were preterm or full-term deliveries. The mean birth weight was 1,896 g, which was lower than previously reported, and a high percentage of families signed do-not-resuscitate consent forms after trisomy 18 was diagnosed. Females did not survive longer than males, because more females were not being resuscitated. Most infants with trisomy 18 died in the first few weeks of life, but 3−6% of infants lived for ≥ 1 year. Early diagnosis, and changes in medical management and family’s attitudes seem to be the major factors affecting the duration of survival. The possibility of long-term survival should be considered when counseling parents regarding trisomy 18.

Acknowledgments We would like to acknowledge the assistance of Mei-Yuan Chen, who helped with the collection of the index cases and performed critical evaluation of the medical charts.

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