Neonatal management of trisomy 18: clinical details of 24 patients receiving intensive treatment

American Journal of Medical Genetics Part A 140A:937 – 944 (2006) Clinical Details of 24 Patients Receiving Intensive Treatment Tomoki Kosho,1* Tomohiko Nakamura,2 Hiroshi Kawame,3 Atsushi Baba,4 Masanori Tamura,5 and Yoshimitsu Fukushima1 1Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan 2Department of Neonatology, Nagano Children’s Hospital, Azumino, Nagano, Japan 3Division of Medical Genetics, Nagano Children’s Hospital, Azumino, Nagano, Japan 4Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan 5Department of Pediatrics, Saitama Medical Center, Kawagoe, Japan Received 4 May 2005; Accepted 23 October 2005 Management of neonates with trisomy 18 is controversial, with left diaphragmatic eventration and hypoplasia accom- supposedly due to the prognosis and the lack of precise panied by lung hypoplasia, even with maximal ventilation.
clinical information concerning efficacy of treatment. To The common underlying factors associated with death were delineate the natural history of trisomy 18 managed under congenital heart defects and heart failure (96%), followed by intensive treatment, we reviewed detailed clinical data of pulmonary hypertension (78%). The common final modes of 24 patients with full trisomy 18 admitted to the neonatal death were sudden cardiac or cardiopulmonary arrest (26%) intensive care unit of Nagano Children’s Hospital, providing and possible progressive pulmonary hypertension-related intensive treatment to those with trisomy 18, from 1994 to events (26%). These data of improved survival, through 2003. Cesarean, resuscitation by intubation, and surgical neonatal intensive treatment, are helpful for clinicians to operations were performed on 16 (67%), 15 (63%), and 10 offer the best information on treatment options to families of (42%) of the patients, respectively. Mechanical ventilation patients with trisomy 18. ß 2006 Wiley-Liss, Inc.
was required by 21 (88%), and 6 (29%) of them wereextubated. Survival rate at age 1 week, 1 month, and 1 yearwas 88%, 83%, and 25%, respectively. Median survival time Key words: trisomy 18; neonate; intensive treatment; nat- was 152.5 days. Respiration was not stabilized in two patients How to cite this article: Kosho T, Nakamura T, Kawame H, Baba A, Tamura M, Fukushima Y. 2006.
Neonatal management of trisomy 18: Clinical details of 24 patients receiving intensive treatment.
Am J Med Genet Part A 140A:937–944.
seem be associated with early death [Embleton et al.,1996; Rasmussen et al., 2003].
Trisomy 18, first described by Edwards et al. [1960], Management of neonates with trisomy 18 is is the second most common autosomal trisomy controversial. Withdrawal of intensive treatment in liveborn infants. Patients with trisomy 18 have such as cesarean, resuscitation, respiratory support, prenatal-onset severe growth retardation, character- and surgical procedures has been recommended istic craniofacial features, various visceral and because of the lethality and severe mental retardation skeletal malformations, and significant psychomotor [David and Glew, 1980; Schneider et al., 1981; Carter mental retardation [Carey, 2001]. Several population- et al., 1985; Rochelson et al., 1986; Goldstein and based studies showed a remarkably reduced life- Nielsen, 1988; Bos et al., 1992; Embleton et al., 1996].
span, with survival rates at age 1 year from 0 to 10%and with median survival time from 3 to 14.5 days[Carter et al., 1985; Young et al., 1986; Goldstein andNielsen, 1988; Root and Carey, 1994; Embleton et al.,1996; Naguib et al., 1999; Nembhard et al., 2001; Grant sponsor: Ministry of Education, Culture, Sports, Science, and Brewer et al., 2002; Rasmussen et al., 2003]. The major causes of death were reported to be apnea and *Correspondence to: Tomoki Kosho, M.D., Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto withdrawal of treatment [Embleton et al., 1996], and 390-8621, Japan. E-mail: [email protected] the presence of a congenital heart defect did not American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a It has also been argued that management should be parents refused surgical correction of esophageal individualized and intensive treatment should be atresia; but accepted mechanical ventilation, intra- considered in patients who could be expected longer venous hyperalimentation, administration of anti- survival and better quality of life through such treatment [Van Dyke and Allen, 1990; Carey, 2001; Eleven patients were transferred to regional Derbent et al., 2001]. This controversy is related to hospitals; after the diagnosis was confirmed by lack of precise clinical data on survival and causes karyotyping, their treatment courses were deter- of death, evaluated in the aspect of efficacy of mined and, no extensive procedures such as major surgery were for the time being required, and the Nagano Children’s Hospital, established in 1993 as parents consented to transfer. In every regional a tertiary prefectural hospital for sick children, has hospital, general pediatricians with training in received neonates who were born in Nagano neonatology continued the treatment according to prefecture and required intensive care due to prematurity, asphyxia, and congenital malformation.
Neonatologists of this hospital have often helped toresuscitate, stabilize, and transfer sick babies at other regional hospitals and obstetric clinics. Since 2000, We collected clinical data about prenatal findings, when the obstetric department was established in delivery, complications, treatment, survival, and this hospital, pregnant women whose fetuses were causes of death from medical records in Nagano found to have severe abnormalities by ultrasono- Children’s Hospital and regional hospitals where graphy have also been referred for further evalua- patients were given medical care before or after tion, genetic counseling, and delivery. In the neonatal intensive care unit of this hospital, patients From careful observation of each patient under with trisomy 18 have been managed under the intensive treatment, we found that the patients’ principle of providing intensive treatment, based on conditions deteriorated gradually due to complex careful discussion with the parents. The manage- underlying factors such as heart failure and pulmon- ment consists of resuscitation including intratracheal ary hypertension resulting from congenital heart intubation, appropriate respiratory support, estab- defects. They frequently died suddenly from cardi- lishment of enteral nutrition including corrective and opulmonary arrest and possible pulmonary hyper- palliative surgery for gastrointestinal malformation, tension-related events. Therefore, causes of death and pharmacological treatment for congenital heart were classified into underlying factors associated defects. To delineate the natural history of trisomy with death and final modes of death.
18, and specifically survival and causes of deathunder this principle of intensive management, wereviewed detailed clinical data on patients with trisomy 18 admitted to this hospital from 1994 to2003.
Data on prenatal findings and delivery are sum- marized in Table I. Fetal ultrasonographic abnorm-alities were detected during all pregnancies except for Patient 5, whose mother had received no obstetric Twenty-six patients with karyotypically confirmed examinations. However, no patient was diagnosed trisomy 18 were admitted to the neonatal intensive karyotypically including Patients 1, 16, and 19, who care unit of Nagano Children’s Hospital from April were suspected to have trisomy 18 clinically. Twelve 1994 to March 2003. We excluded two patients with patients were delivered in regional hospitals, seven 47,XX, þ18/46,XX mosaicism, and evaluated the in obstetric clinics (Patients 4, 8, 15, 16, 22, 23, and other 24 patients with full trisomy 18 (9 boys, 15 girls) 24), four in this hospital (Patients 1, 2 17, and 19), and (Tables I and II). Twenty peripheral blood lympho- one at home (Patient 5). Sixteen patients were born cytes were routinely analyzed for G-banded karyo- by cesarean (67%), which was elective in four typing. All the parents were informed of natural (Patients 4, 16, 21, and 24) and emergent in 12. The history of trisomy 18 based on the medical literature, common indications for cesarean were fetal distress and were presented the above-mentioned principle in ten and intrauterine growth retardation in six.
of management as an approach to care in this Fifteen patients needed resuscitation by intubation hospital. The parents could choose to accept or (63%). All but Patients 4, 5, 8, 15, and 22 were refuse this principle. If they refused, accepted part of resuscitated and stabilized by neonatologists of the treatment was continued in the hospital or in Nagano Children’s Hospital or general pediatricians other regional hospitals. After careful discussion, all in regional hospitals. Mean gestational age was parents except parents of Patient 9 consented. These 37 weeks and 5 days (range, 31 weeks and 4 days American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a to 42 weeks and 0 day), with three patients delivered Seven of eight patients with esophageal atresia and after 41 weeks. Mean birth weight was 1,708 g (range, tracheoesophageal fistula had gastrostomy safely 1,017–2,135 g). Mean Apgar score was 4.0 (range, 1– and only Patient 14 needed reoperation due to in- 8) at 1 minute and 6.0 (range, 1–10) at 5 min.
sufficient suture. Five of the eight patients underwentsurgical correction of esophageal atresia (anastomo- Structural Defects and Medical Complications sis of esophagus and resection of tracheoesophagealfistula); whereas the others did not because of Data on structural defects and medical complica- uncontrollable respiratory failure in Patient 2, fulminant infection in Patient 4, and parental refusal All patients had congenital heart defects and the in Patient 9. Postoperative course of corrective defects were classified into two groups according to surgery was complicated in Patient 6 with mediasti- the hemodynamic state: those that reduced pulmon- nitis resulting in death, and in Patient 24 with ary blood flow in Patients 3 and 24 with pulmonary reopening of the tracheoesophageal fistula necessi- atresia, and Patients 12 and 18 with tetralogy of Fallot; tating resection. Ileostomy was performed on Patient and those that increased pulmonary blood flow in 22 with gastric obstruction supposedly due to pyloric the others. Twenty-three patients had heart failure stenosis, who thereafter showed bowel dysfunction (96%). Patient 12, who did not have heart failure in because of inappropriate positioning of the stoma.
the neonatal period, manifested heart failure there- Colostomy and surgical repair of omphalocele were after resulting from progressive pulmonary artery successful. Tracheostomy was also accomplished stenosis. Patient 22, who had heart failure in the safely in Patients 21 and 24, and the latter patient neonatal period, did not manifest heart failure could be discharged to home. Enteral duodenal tube thereafter because of spontaneous closure of ven- was effectively placed in three patients with gastro- tricular septal defect. Only Patient 23, who had a esophageal reflux. No patient received cardiac spontaneously closed small patent ductus arteriosus and is still alive, has never manifested heart failure.
Mechanical ventilation, including intermittent The tendency of prolonged pulmonary hypertension mandatory ventilation, high frequency oscillation, was observed in most of the patients, including and nasal continuous positive airway pressure, was six patients who developed persistent pulmonary performed on 21 patients (88%). High frequency oscillation was applied successfully to Patients 13 Among non-cardiac structural defects, C-type eso- and 14 with severe respiratory distress syndrome in phageal atresia with tracheoesophageal fistula was the neonatal period, and both were extubated there- the most common (33%). Patient 22 was suspected to after. But it could not achieve respiratory stabilization have pyloric stenosis retrospectively, in considera- in Patients 1 and 2 even with the maximal setting.
tion of complicated episodes of gastroesophageal Pulmonary surfactant was administered to eight reflux and difficulty in inserting a feeding tube via patients for respiratory distress syndrome (Patients gastrostomy into the duodenum. Respiratory failure 6, 13, 14, 18, 20, and 24) and/or for pneumonia or of various etiologies and severity occurred in atelectasis (Patients 6, 14, 21, and 22) with partial or 21 patients (88%). Patients 1 and 2 had left diaphrag- complete effectiveness, while it was ineffective matic eventration and hypoplasia accompanied by for lung hypoplasia in Patient 2. Patients 8, 22, and lung hypoplasia. Additionally, Patient 1 had tracheal 24 with severe apnea needed intermittent mandatory atresia with tracheoesophageal fistula and Patient 2 ventilation; and Patient 3 with moderate apnea had esophageal atresia with tracheoesophageal received nasal continuous positive airway pressure.
fistula. Five patients had seizures: subtle-type Six patients were extubated (29%), and the median (mouth movement) in Patient 6, tonic-type in Patient duration of mechanical ventilation in them was 21, tonic-clonic-type in Patient 8, and myoclonic- type in Patient 14, according to the classification Cardiovascular drugs were used in 22 patients (92%). Diuretics (furosemide with or without spir- Thrombocytopenia with platelet counts under onolactone) and dopamine with or without dobuta- 15 Â 104/ml had been noted in 20 patients. Radial mine pressors were commonly used for heart failure.
aplasia (Patients 1, 2, and 15), cleft lip and palate Prostaglandin E1 was administered to four patients (Patients 2 and 16), ocular abnormalities (Patients 10 with PDA-dependent congenital heart defects. It was and 13), umbilical cord cysts (Patients 4 and 18), discontinued after long-term use in Patient 13 (Day choanal atresia (Patient 17), and syndactyly (Patient 88) and Patient 24 (Day 33). In both patients, the 18) were also observed. Patient 19 exhibited ductus had narrowed in the first few weeks of life in accordance with tapering of dosage. Nitroglycerinwas given to three patients with severe persistent pulmonary hypertension of the newborn, and they Data on treatment are summarized in Table II. Ten could survive this critical period except Patient 2 patients (42%) underwent a total of 21 operations.
with uncontrollable respiratory failure. Beta-blocker, American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a used in Patient 12 who exhibited progressive pul- The most frequent final mode of death was sudden monary artery stenosis associated with tetralogy of cardiac or cardiopulmonary arrest (six patients, Fallot with frequent anoxic spells, had only tempor- 26%). All of the patients who died finally of sudden cardiac or cardiopulmonary arrest had congenital All patients received parenteral therapy. Five heart defects and heart failure, and five had patients with esophageal atresia had intravenous pulmonary hypertension as underlying factors asso- hyperalimentation due to poor enteral feeding.
ciated with death. Intensive resuscitation was not Platelet transfusion was given to three patients with effective in this condition. Observed triggers were disseminated intravascular coagulation resulting crying and procedures that could cause stress: from severe infections. Exchange transfusion was after crying (Patient 5), while changing a diaper applied to Patient 4 with fulminant infection and (Patient 8), after crying and suctioning (Patient 13), Patient 24 with severe hyperbilirubinemia. For the and after cleansing the body (Patient 18). Possible control of seizures, Patients 4 and 6 had single use of progressive pulmonary hypertension-related events phenobarbital, Patients 8 and 14 regular use of including pulmonary hemorrhage and pulmonary phenobarbital, and Patient 21 regular use of pheno- hypertensive crisis occurred in six patients (26%).
barbital and valproic acid. Aminophylline had a Untreatable respiratory failure from birth was noted partial effect on apnea in Patient 11.
in Patients 1 and 2 with left diaphragmatic eventra-tion and hypoplasia accompanied by lung hypopla-sia. Patients 11 and 20 had progressive respiratory failure associated with pulmonary congestion.
Patient 22 died of acute renal failure due to Prognosis is summarized in Table II. Five patients were discharged to home (21%); three of themneeded home oxygen therapy due to hypoxiaassociated with pulmonary hypertension or respira- tory failure. Median hospital stay among the five We have presented detailed clinical information on patients was 137 days (range, 30–947 days). Survival 24 patients with trisomy 18, managed under the rates at age 1 day, 1 week, 1 month, and 1 year were principle of providing neonatal intensive treatment.
96%, 88%, 83%, and 25%, respectively. Median Although the treatment was did not include cardiac survival time for both sexes was 152.5 days, (range, surgery, the results suggested improved survival 0–1,786 days). It was longer for girls (210 days) than compared with previous population-based studies.
Selection bias could be present in this institution- Several patients showed sucking movements, based data. Although many neonates, born in gazed up parents and caregivers, and moved their Nagano prefecture, who required intensive care limbs. Patient 23 accomplished head control, rolling and surgery have been transferred to Nagano over, smiling, and babbling at the time of this study.
Children’s Hospital; there might have been patients Patient 24 could play with a toy and be fed with a with trisomy 18 that were treated in regional hospitals throughout their lives, and those that diedundiagnosed without karyotyping. In this prefecture,there has been no surveillance system for birth defects or registry for death. Moreover, mosaicism Causes of death are summarized in Table II. The including normal cell line could contribute to longer most frequent underlying factors associated with survival in some patients, because we did not death were congenital heart defects and heart failure perform further karyotyping such as analysis of (22 patients, 96%), followed by pulmonary hyperten- many peripheral blood lymphocytes or analysis of sion (18 patients, 78%), and respiratory failure cells from other tissues in patients with longer (14 patients, 61%). Pulmonary hypertension was survival. However, the most accurate estimate in live noted in Patients 3 and 24 who had congenital heart births with only minimal influence by prenatal defects with reduced pulmonary blood flow. Pro- screening indicated a figure in live births of about 1 gressive pulmonary artery stenosis resulting in heart in 6,000 [Root and Carey, 1994]. Considering that failure was noted in Patients 12 and 18 with tetralogy approximately 20,000 babies are born annually in of Fallot. Patient 9 had malnutrition due to micro- Nagano prefecture, the total number of live births ileum. Patient 21 showed severe liver dysfunction with trisomy 18 during this time period could be after aspiration pneumonia, on the background of estimated as 33. The fact that almost all patients in this increasing dose of valproic acid. Patient 22 had renal study had fetal ultrasonographic abnormalities could insufficiency due to recurrent urinary tract infection bias survival negatively. Finally, if resuscitation by and malnutrition associated with malpositioned intubation in 15 patients or corrective surgery for ileostomy. Most patients had complex underlying esophageal atresia in Patients 21 and 22 had not been performed; the median survival time would have American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a been much shorter, probably within a week; and the case reports described five patients who underwent survival rate at age 1 year would have been much seven cardiac surgeries [Van Dyke and Allen, 1990; smaller, probably 4% (only Patient 23 could have Baty et al., 1994; Teraguchi et al., 1997; Derbent et al., survived long). Thus, the patients in this study did 2001]. Research by the Support Organization for not seem to compose at least a positively biased Trisomy 18, 13 and Related Disorders (SOFT) population with respect to survival, but a substantial Registry group found that eight of twelve patients portion of babies born with trisomy 18 in this pre- who underwent cardiac surgery (seven intracardiac repairs and five palliative) survived to be discharged There has been little documentation of the precise [Carey, 2001]. A recent multicenter registry-based reason for death in infants with trisomy 18 [Carey, report by Graham et al. [2004] showed that 21 of 2001]. In a population-based study by Embleton et al.
24 patients who underwent cardiac surgery includ- [1996], the major causes of death were cited as apnea ing intracardiac repair survived to be discharged.
and withdrawal of treatment. Another population- Detailed clinical review of each patient who under- based study by Rasmussen et al. [2003] showed that went cardiac surgery will be needed to evaluate the presence of a congenital heart defect did not seem to affect survival. A support group-based study High rates of mechanical ventilation and unfavor- by Baty et al. [1994] showed the major cause of death able pulmonary outcome seemed to be related to as cardiopulmonary arrest. The review by Carey, factors such as birth asphyxias, lung hypoplasia, [2001] mentioned that central apnea, or its presence respiratory distress syndrome, infections, pulmonary with a combination of other factors, was the primary hypertension, congestion due to heart failure, pathogenesis of the increased infant mortality.
mechanical lung injury, and apnea. However, two However, in a detailed pathological study by patients with severe respiratory failure in the early Kinoshita et al. [1989], the major causes of death neonatal period due to respiratory distress syndrome were heart failure and pulmonary hemorrhage were successfully extubated, suggesting that initial resulting from congenital heart defects. Both a large severity of respiratory status might not be a definitive ultrasonographic study by Musewe et al. [1990] and predictor of poor prognosis. We observed that, left an autopsy-based study by Van Praagh et al. [1989], diaphragmatic eventration accompanied by lung concerning heart defects of trisomy 18, suggested hypoplasia was consistently seen as a predictor of that patients might exhibit unusually early develop- lethality even with maximized interventions.
ment of pulmonary vascular obstructive diseases Perinatal management of trisomy 18 has been resulting in early progression of pulmonary hyper- discussed as an ethical issue. Chervenak and Mc tension leading to death. In our observation under Cullough [1990] categorized trisomy 18 as a condition intensive treatment, the major underlying factors in which a choice between aggressive management associated with death were heart failure and pul- and non-aggressive management should be made, monary hypertension resulting from congenital heart due to probable lethality or absent cognitive devel- defects, frequently accompanied by respiratory fail- opmental capacity if the patient survived. In Japan, ure. The major final modes of death were sudden there has been no established principle in caring cardiac or cardiopulmonary arrest and possible critically sick neonates like trisomy 18. Nishida et al., progressive pulmonary hypertension-related events.
[1987] introduced a classification in medical decision The result that most of the events of sudden cardiac making of caring them [Nishida and Sakamoto, 1992].
or cardiopulmonary arrest were observed in the In this classification, trisomy 18 was categorized into patients with pulmonary hypertension and were a condition in which no additional treatments were triggered by crying or stressful procedures suggested considered but ongoing life-supporting procedures that these events might also be related to progressive or routine care (temperature control, enteral nutri- tion, skin care, and love) was not withdrawn.
Although present data suggested that medical Although this principle has had a certain impact on treatment, such as cardiovascular drugs and respira- the society of neonatology in Japan, patients with tory support, might be effective for cardiopulmonary trisomy 18 have actually been managed under a lesions in the aspect of survival, we are unable to principle of each hospital, including intensive treat- evaluate the effectiveness of cardiac surgery. We ment for longer survival and better quality of life like experienced, during this time period, only one Nagano Children’s Hospital. This situation might palliative surgery (ligation of patent ductus arterio- have been supported by a secure national health sus) to a mosaic patient with heart failure due to insurance covering all costs of treatment to every sick ventricular septal defect, atrial septal defect, and child, general respect for life, and the families’ strong patent ductus arteriosus, in addition to myelome- wishes to prolong the patients’ lives, just as ningocele and pyloric stenosis, which were also Sakakihara et al. [2000] suggested in the study on corrected surgically. The ligation surgery improved physicians’ attitude toward long-term ventilator heart failure and enabled the patient to be discharged support in patients with Werdnig–Hoffmann disease and prolonged survival (553 days). To date, several American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a In conclusion, the patients with trisomy 18 Embleton ND, Wyllie JP, Wright MJ, Burn J, Hunter S. 1996.
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