Why is trisomy 18 more common in girls

Presence of major malformations is common, and any organ and system can be affected. From Jones [ 52 ], Baty et al. The clinical pattern of trisomy 18 is quite well-defined, and it is rarely misdiagnosed [ 12 ]. There are some overlapping features with Pena-Shokeir syndrome type 1 or syndromes with fetal akinesia sequence because of polyhydramnios and joint contractures including overriding fingers , with distal arthrogryposis type 1 because of the similar finger positioning and with CHARGE syndrome because of the overlapping of major malformations.

The not well characterized and co-called condition known as pseudotrisomy 18 syndrome [ 53 ] probably belongs to the group of disorders with fetal akinesia sequence.

Perinatal and neonatal management of fetuses and newborn diagnosed with trisomy 18 is multifaceted issue for a variety of reasons: the complexity and, most of the time, the severity of the clinical presentation at birth; the need of parents and care providers to urgently make decisions in care of the baby; the inevitable ethical implications due to the well known high neonatal and infant mortality, and the significant developmental disability in the surviving children that characterize this unique together with trisomy 13 condition.

There is a high percentage of fetuses dying during labor An increased incidence of cesareans has been reported [ 4 , 54 ], even if in the previous obstetric literature avoidance of delivery by cesarean was recommended [ 55 , 56 ].

The first study about postnatal survival of children with trisomy 18 was published in Weber reported a mean survival of 70 days [ 57 ]. Most of the ensuing population studies showed a shorter survival, likely because, with prenatal and neonatal diagnosis, it is now possible to diagnose many cases, which would have died prior to detection in the past [ 3 ].

Most recent studies report a median survival of The major causes of death are sudden death due to central apnea, cardiac failure due to cardiac malforxmations and respiratory insufficiency due to hypoventilation, aspiration, upper airway obstruction or, likely, the combination of these and other factors [ 4 , 12 , 13 , 15 , 49 , 54 , 58 , 59 , 63 - 65 ].

The factors underlying the potential of survival are not known; the presence of heart defects does not seem to affect long-term survival [ 6 ]. However a recent trend toward consideration of performing cardiac surgery may alter that premise as surgery may play a role in preventing pulmonary hypertension, a point not investigated in determining the notion that heart defects do not affect survival [ 6 ]. A longer survival for females compared to males has been reported, as in the prenatal period [ 4 , 6 ].

Because of the elevated risk of mortality in the first month of life and the presence of significant developmental disability in the surviving children, historically there has been a consensus among care providers that trisomy 18 be considered a condition for which non intervention in the newborn was indicated [ 65 , 66 ]. Nevertheless, the most recent American Academy of Pediatrics neonatal resuscitation guidelines omit trisomy 18 from the list of examples of conditions for which resuscitation is not indicated [ 67 ].

A recent Japanese study documented the survival rate in a group of trisomy 18 newborn to which intensive care were offered: the median survival time To our knowledge this is the only study that addresses the question of infant survival if full intervention short of cardiac surgery is offered. In this study the authors also investigated the pathophysiology to death in patients who had intensive treatment; they distinguish between underlying factors associated with death and final modes of death.

The common underlying factors associated with death were congenital heart defects and heart failure, and pulmonary hypertension. On the other hand, the final modes of death were sudden cardiac or cardiopulmonary arrest and events related to progressive pulmonary hypertension [ 54 ].

From these observations, it becomes clear that apnea and withdrawal of treatment could be considered the major cause of death when a patient with trisomy 18 was managed with purely comfort care.

When a patient with trisomy 18 has intensive treatment, the common causes of death are altered, and survival does increase. The senior author had pointed out in an Editorial [ 69 ] in that there existed a dire need to have a dialogue regarding the ethical issues surrounding the management and care of infants and children with trisomy Such a dialogue seems to be occurring in recent years: the publication of the McGraw and Perlman paper [ 68 ] mentioned above and the Ethics Rounds, a Special Article in Pediatrics in [ 70 ], both discuss the key themes and controversies that needed current discussion.

The former paper indicated that the majority of neonatologists polled in the study would not resuscitate a newborn in the delivery room who had trisomy 18 and a heart defect. In the more recent Special Article two neonatologists and a parent discuss their views on the management of a baby with trisomy 18 and a heart defect surrounding the decision to have cardiac surgery [ 70 ]. These papers and the published responses to them in Pediatrics suggest that a dialogue is in fact now occurring.

Another recently published paper by Wilfond and Carey [ 71 ], a case-based discussion of the issues and themes involved in the management of trisomy 18 and related conditions , also illustrates this point of an emerging dialogue.

The reader is referred to these papers for further discussion of the relevant issues. We will discuss this issue in the Unresolved Questions section below as little data exist in the scientific literature on this topic. Prenatal growth retardation is one of the most frequent prenatal finding in trisomy 18 [ 30 , 35 - 39 ]; the mean birth weight is g at a mean gestational age of 37 weeks [ 4 , 54 ].

Head circumference also tends to be below the third centile [ 12 ]. Most of the children have feeding difficulties that often require tube feeding in the neonatal period or placement of gastrostomy in the older children at average age of 8 months [ 49 ]. Both sucking and swallowing problems can be present. Usually the skill of oral feeding if achieved is achieved in infancy, and not later [ 12 , 49 ].

If it is unclear if an infant can or cannot protect her airway, a swallow study can be performed to determine the safety of oral feedings. Gastroesophageal reflux is a significant medical problem because of both its high prevalence and its potential consequences, like irritability, recurrent pneumonia and aspiration [ 12 ].

Aspiration due to gastroesophageal reflux or during feeding is included among the causes of early death [ 4 , 12 , 13 , 49 , 54 , 58 , 59 , 61 - 63 ]. Gastrointestinal malformations, such as esophageal atresia with tracheo-esophageal fistula, occur with increased frequency but are not a common feature in trisomy 18; pyloric stenosis has been reported and should be considered in the older infant with vomiting [ 12 ]. Occasionally the newborn with trisomy 18 can have orofacial clefts that may contribute to feeding problems [ 12 ].

The majority of the malformations are unlikely to produce neonatal death; this is one of the reasons why the cardiac defect is usually regarded as not causing the early infant mortality. The role of cardiac malformations in causing early death is controversial.

Some studies reported that the presence of heart defect does not negatively affect the survival [ 6 ] and that the cardiac problems are not implicated in the deaths in most of patients [ 4 ].

Based on these data, cardiac surgery in the neonatal period is considered not likely to improve the survival of trisomy 18 children. However, in other studies heart failure and early development of pulmonary hypertension induced by heart defects were found to play a significant role in early death [ 69 , 74 - 76 ]. Traditionally, heart defects in trisomy 18 patients have been managed conservatively. Respiratory problems are one of the most common causes of death in trisomy 18 [ 4 , 12 , 49 , 54 , 58 , 59 , 61 , 62 ].

Pure respiratory problems, such as upper airway obstruction in some case due to a laryngomalacia or tracheobronchomalacia and central apnea, can act together with other problems of different origin, like early—onset pulmonary hypertension, feeding difficulties, recurrent aspirations and gastroesophageal reflux, leading to a severe respiratory symptoms [ 3 , 4 ].

Obstructive sleep apnea may be a more common finding in older infants [ 12 ] than realized. Occasionally, children with trisomy 18 can show anomalies such as a cataract or corneal opacities [ 81 , 82 ]. Short palpebral fissures, visual acuity abnormalities, and photophobia are common findings and underscore the need for ophthalmology assessment in older infants [ 12 ].

Photophobia is very common in children with trisomy 18 and requires sunglasses when going outside the home; it likely represents one reason why older infants experience unexplained irritability.

Structural ear anomalies, such as meatal atresia and microtia, are occasionally present. The features of external ear are characteristic: the ear is small with a small lobule, the helix is unfolded, simple and sometimes attached to the scalp cryptotia [ 12 ].

The ear canal is usually small making audiology screening sometimes challenging. A wide spectrum of middle and internal ear abnormalities has been described. Moderate to severe sensorineural hearing loss can also be present [ 12 ]. In addition, contractures of other joints can be present explaining why trisomy 18 is sometimes the basis for a neonate labeled artrogryposis. Scoliosis is common in older children; usually it is not related to vertebral structural abnormalities and may progress between 5 and 10 years of age [ 12 ].

Horseshoe kidney is common finding in trisomy 18 about two-thirds of patients. An increased frequency of urinary tract infections has been observed, perhaps due to structural defects [ 31 ].

Otherwise, renal failure is uncommon [ 12 ]. Trisomy 18 patients have an increased risk to develop some neoplasia, including Wilms tumor and hepatoblastoma [ 83 ].

At least 8 cases of Wilms tumor in trisomy 18 children have been reported in the medical literature [ 83 - 89 ]. Nephroblastomatosis, the presence of multiple embryonic rests of tissue within the kidney that may give rise to Wilms tumor, has been detected at autopsy in infants with trisomy 18 who did not die from a Wilms tumor [ 88 - 90 ].

Despite this biological origin, the average age of tumor development is 5 years, ranging from 12 months to 13 years, later than it occurs in general population, suggesting a different biological basis for the tumor in trisomy 18 children [ 12 ]. The prognosis is variable.

Seven cases of association between trisomy 18 and hepatoblastoma have been reported [ 91 - 97 ]. The age of diagnosis ranged from 4 months to 3 years. The prognosis was variable: surgical treatment was performed in three patients, two of them were alive without evidence of recurrence at 3 and 4 years of age [ 93 - 95 ], the other died from progression of the tumor [ 94 ].

Among the untreated patients, two died of cardiac failure in one of these hepatoblastoma was an incidental finding at the autopsy [ 92 - 96 ] and two from progression of the tumor [ 93 , 96 ].

Central apnea is one of the principal causes of early death [ 3 , 4 ]. A recent paper described an infant with trisomy 18 and apneic episodes representing complex partial seizures successfully treated with zonisamide [ 98 ]. In older children with trisomy 18 significant developmental delay is always present ranging from a marked to profound degree of psychomotor and intellectual disability.

There is not a regression, but a stable status with slow gaining of some skills. In the most cases expressive language and independently walk are not achieved, but some older children can use a walker [ 99 ]. There is also one report of a 4-year-old child with full trisomy 18 who could walk independently [ ]. While developmental age in older children is months overall, most have some skills of older children, including sleeping independently, self-feeding, imitating, using a sign board, following simple command, and understanding cause and effect [ 99 ].

All children acquire abilities such as recognizing their family and smiling appropriately [ 99 ]. Recognizing the significant delays, Baty et al.

A young lady with full trisomy 18 in early childhood and in adolescence; she lived to 19 years of age and achieved multiple milestones, including sitting and walking in a walker. This girl, now 16 years of age and very healthy, had a ventricular septal defect repair as an infant; she is shown here at various ages enjoying a favorite pastime and feeding herself.

She is walking with assistance but can climb stairs on her own. After the discharge from the hospital, follow-up visits for health supervision should be regular and often in the first weeks and months of life; referral to the appropriate pediatric subspecialists can occur. In the long-survival children, the frequency of health supervision visits may decrease as they advance, depending on the specific needs of each child.

Generally, children with trisomy 18 should receive the same routine care, e. In regards to administering immunizations, the weight and overall status of an infant, in particular the presence of a seizure disorder, should be taken into consideration.

Decisions surrounding the treatment of specific problems should be decided upon with the parents and medical team according to the degree of the involvement and what is in the best interest of the child [ 49 ]. These are modeled after other recent guidelines for the routine care of children with rare diseases.

Guidelines for routine evaluation in children with trisomy 18 at time of diagnosis and during follow up. Growth parameters weight, length and head circumference should be checked during each evaluation, more frequently in the first weeks and months of life, and plotted on the specific growth charts [ 49 ]. Assessment of the sucking or swallowing problems with a radiographic swallow study can be useful if needed to consider the ability of the child to protect the airway; use of feeding tube in neonatal period or placement of gastrostomy can be considered to assure appropriate and safe feeding.

Referral to a feeding or dysphagia team is an option. Gastroesophageal reflux should be considered as a potential factor in feeding problems. If needed, standard medical therapy may be started. If medical treatment is not successful, surgery can be considered [ 12 ].

At the time of diagnosis or in the newborn period cardiac evaluation including echocardiogram should be performed. Since s few reports of cardiac surgery in this population has been published [ 49 , 58 ], but recently four studies on larger series of patients appeared in the medical literature [ 76 - 79 ].

In one study from Japan the median postoperative survival reported was days, and the median survival for this group of patients was days [ 76 ]. In the same study, the most frequent cause of death was infections; otherwise heart failure was the cause of death in only one patient, suggesting that cardiac surgery is effective in preventing congenital heart defect-related death [ 76 ].

Therefore, the authors concluded that intensive care, including optional cardiac surgery, in selected patients with trisomy 18 is ethically acceptable [ 79 ]. In a recent investigation Yamagishi et al.

The author qualifies the recommendation in stating that the risk of surgery in patients with trisomy 18 is higher than in patients without trisomy 18 or in patients with trisomy 21, and acknowledges that it is still unknown whether the cardiac surgery improves the long-term prognosis of trisomy 18 children.

Recently Maeda et al. Operated patients survived longer than those who did not have surgery. The severity of cardiac defect and the indications for pharmacological or surgical treatment differ among patients with trisomy Therefore, individual evaluation considering the overall health state of the infant is needed to determine optimal treatment [ 78 ].

These above stated approaches and views that lead to the option of cardiac surgery are controversial as reflected in the paper cited above by Janvier et al. In this latter article the authors summarize much of the previous literature on the ethical and legal aspects of care and recommend a palliative care model in the care of infants with trisomy 18 and trisomy We will discuss this theme more below in the section on Unresolved Questions.

Evaluation by a pulmonologist can be performed if respiratory problems become important, especially in the infant where it is difficult to sort out the various factors that might be playing a role, i.

Evaluations do not differ from those in other children with similar symptoms. Sleep study can be useful to detect the severity of sleep apnea problems. Decisions about home monitoring and oxygen therapy should be made with parents on an individual basis [ 12 ].

As in all decision-making in the care of infants with trisomy 18, parents and physicians make these choices when the intervention is in the best interest of the child. Administration of palivizumab for the prevention of RSV lower respiratory tract disease should be considered in infants with trisomy 18 even those without congenital heart defects. Ophthalmologic evaluation is recommended to detect common structural abnormalities and, in older children, visual acuity defects [ 12 ].

When needed, treatment of eye defects is the same as in other children. In older infants with photophobia sunglasses are usually helpful. Audiological evaluation is recommended in all infants; if sensorineural hearing loss is detected, the use of hearing aids can be offered and attempted [ 12 ]. In children older than 2 years, clinical evaluation of the spine should be performed at each health supervision visit, followed by spine X-ray and specialist evaluation if scoliosis is clinically suspected.

Sometimes, in older children, surgery for severe scoliosis should be considered because of consequent restrictive lung disease. The decision about treatment of clubfoot in infants with cast or surgery is complex, because only a small percentage of children with trisomy 18 can walk assisted or independently. Abdominal ultrasound screening is recommended in children with trisomy If renal abnormalities are detected, follow up for urinary infection and renal failure by periodic blood and urine analysis should be performed.

The treatment of urinary infections does not differ from that in any other child. The high incidence of intra-abdominal tumors, particularly Wilms tumor and hepatoblastoma, in trisomy 18 children justifies the recommendation of abdominal sonographic screening in these patients. There is no established timing for the screening, but it may be started after 6 months of life with a screening every 6 months and continued into adolescence because one of the cases of Wilms tumor reported developed in a year-old female [ 12 , 87 ].

Neurological evaluation is recommended in all trisomy 18 patients. Usually they need physical therapy for tone muscle abnormalities. Management of epilepsy is similar to that in other children; seizures are generally well controlled by standard pharmacological therapy.

At each health supervision visits assessment of developmental progression through standard developmental evaluation is mandatory, and early referral to intervention programs and physical therapy is recommended. The key ingredient in carrying out effective health supervision in the care of infants and children with trisomy 18 is a committed primary care practitioner. As pointed out by Carey [ 48 ] a clinician who is willing to oversee the care and provide ongoing support to the family should not be hesitant to take on the challenge of shepherding the management of a child with this disorder despite its relative rareness and providing the Medical Home for the children.

Additionally referral to a palliative care team can aid in the needed ongoing support and be a good resource for the family and clinician.

As mentioned above the most clearly unresolved issue is the controversy surrounding the option of aggressive respiratory or surgical treatment of infants with trisomy In this concluding section we will try to provide some perspective on this highly complex topic. Because of the high neonatal and infant mortality and because of the issue usually described as the quality of life in children with the syndrome, many practitioners in the US and Europe have argued for a noninterventionist approach with accompanying comfort care sometimes called custodial and currently with the guidance of a palliative care team [ ].

This view was articulated by Bos et al and Paris et al. The Ethics Rounds paper by Janvier et al. These themes include the following: the best interest of the child standard, parent autonomy, allocation of resources, quality of life of children with trisomy 18, and the potential pain and suffering experienced if treatment occurs for the child. In the recent paper by Merritt et al.

These authors present a list of questions to consider in the setting of a prenatal and postnatal diagnosis of trisomy 18 and However, Merritt et al. In an Invited Comment Kosho [ ] reflected on the varied views in Japan on the care of infants with trisomy Unlike Down syndrome, which also is caused by an extra chromosome, the developmental issues caused by Trisomy 18 are associated with more medical complications that are more potentially life-threatening in the early months and years of life.

Again, baby boys will experience higher mortality rates in this neonatal period than baby girls, although those with higher birth weights do better across all categories. Some infants will be able to survive to be discharged from the hospital with home nursing support to assist with care by the parents.

And although 10 percent or more may survive to their first birthdays, there are children with Trisomy 18 that can enjoy many years of life with their families, reaching milestones and being involved with their community. Half are from the father and half are from the mother. But sometimes an error occurs when the 46 chromosomes are being divided in half. An egg or sperm cell may keep both copies of chromosome number 13 or 18, instead of just 1 copy. If this egg or sperm is fertilized, then the baby will have 3 copies of chromosome number 13 or If the baby has 3 copies of chromosome number 13, this is called trisomy If the baby has 3 copies of chromosome number 18, this is called trisomy The extra copy of chromosome number 13 or number 18 is present in every cell in the body.

Sometimes the extra number 13 or number 18 chromosome, or part of it, is attached to another chromosome in the egg or sperm. This is called a translocation. This is the only form of trisomy 13 or 18 that may be inherited from a parent. Some parents may have balanced translocation. This means the number 13 or 18 chromosome is attached to another chromosome. But it does not affect their own health. A rare form is called mosaic trisomy 13 or This is when an error in cell division happens after the egg is fertilized.

People with this syndrome have both normal cells and some cells with an extra chromosome number 13 or Structural problems of the brain, such as the front of the brain not divided normally holoprosencephaly. Part of the belly abdominal organs bulging through an opening near the umbilical cord omphalocele.

Most babies with trisomy 18 have problems that affect all parts of the body. Heart problems, feeding problems, and infections are what most often lead to death. Chromosome problems such as trisomy 13 or 18 can often be diagnosed before birth.

This is done by looking at cells in the amniotic fluid or from the placenta. This is a noninvasive prenatal screening. These tests are very accurate.

Fetal ultrasound during pregnancy can also show the possibility of trisomy 13 or