DOI: 10.1002/ajmg.a.

62133

RESEARCH REVIEW

Surveillance guidelines for children with trisomy 13

Jeffrey W. Kepple1 | Kristen P. Fishler2 | Eric S. Peeples3

1
School of Medicine, Creighton University,
Omaha, Nebraska Abstract
2
Munroe-Meyer Institute for Genetics and Trisomy 13 is one of the three most common aneuploidy syndromes in live-born
Rehabilitation, University of Nebraska Medical
infants. It is associated with mortality rates as high as 90% within the first year of life,
Center, Omaha, Nebraska
3
Department of Pediatrics, University of in large part, due to the high prevalence of severe congenital abnormalities that
Nebraska Medical Center, Omaha, Nebraska increase mortality and morbidity. However, life-saving and life-prolonging medical

Correspondence
Eric S. Peeples, Division of Neonatology,
Children's Hospital and Medical Center, 8200
Dodge Street, Omaha, NE 68114-4113
Email: epeeples@childrensomaha.org
interventions are being performed at a higher rate for these infants, resulting in
increased rates of survival. Although cardiac complications have been well described
in infants with trisomy 13, these patients also experience other complications such as
respiratory, neurological, genitourinary, abdominal, otolaryngologic, and orthopedic
complications that can impact their quality of life. The goal of this review is to pre-
sent a comprehensive description of complications in children with trisomy 13 to aid
in the development of monitoring and treatment guidelines for the increasing number
of providers who will be caring for these patients throughout their lives. Where the
evidence is available, this review presents screening recommendations to allow for
more rapid detection and documentation of these complications.

KEYWORDS
management, Patau syndrome, screening

1 | I N T RO DU CT I O N However, the most recent 1-year survival may be as high as 19.8%,

Trisomy 13 (Patau syndrome) is a chromosomal abnormality associated
with high morbidity and mortality, resulting from a spectrum of severe
congenital anomalies. Trisomy 13 is the third most common aneuploidy
syndrome, preceded by trisomy 18 and trisomy 21 (Goel et al., 2019;
Irving et al., 2011; Springett et al., 2015). The 1-year mortality for trisomy
13 can be as high as 90% (Forrester & Merz, 1999; Meyer et al., 2016).
The prevalence of trisomy 13 has increased over the past decades, in
large part, due to an increasing prevalence of pregnancies in women who
are advanced maternal age (>35 years old) (Loane et al., 2013). The preva-
lence of fetal trisomy 13, however, is unknown due to variability in the
reporting of pregnancy termination and spontaneous fetal demise. Tri-
somy 13, with only a 3%–4% live birth rate (Cavadino & Morris, 2017)
and a prevalence of 1.9 in every 10,000 births, tends to have a more
severe phenotype than trisomy 18 or 21 and is considered the most lethal
of all viable trisomies (Springett et al., 2015).
In a small case series published in 1988, the mean survival of
infants with trisomy 13 was around 10 days (Moerman et al., 1988).
depending in part on the number of screening procedures and inter-
ventions provided (Goel et al., 2019; Nelson et al., 2016). A recent
trend in clinical management has resulted in an increase in surgical
and aggressive medical management for these infants (Goel
et al., 2019; Meyer et al., 2016; Neubauer & Boss, 2020; Rasmussen
et al., 2003). As a result, more patients with trisomy 13 are now sur-
viving into their first year of life.
Trisomy 13 is often suspected clinically either due to prenatal
findings on ultrasound or due to characteristic physical features
detected after birth (Figure 1). Early diagnosis is important, in part,
due to the need to screen for underlying life-threatening complica-
tions such as the presence of significant cardiovascular anomalies
(Peterson et al., 2017). Of all patients with trisomy 13, 38%–92% will
have some cardiac anomaly (Nishi et al., 2018; Pont et al., 2006;
Springett et al., 2015). The majority (18%–66%) of infants with tri-
somy 13 presenting with ventricular septal defects (VSDs) (Emer
et al., 2015; Kosiv et al., 2017; Nishi et al., 2018; Pont et al., 2006;
Springett et al., 2015). Other common cardiac anomalies include atrial

Am J Med Genet. 2021;185A:1631–1637. wileyonlinelibrary.com/journal/ajmga © 2021 Wiley Periodicals LLC 1631

1632
F I G U R E 1 Representative facial, scalp, hand, and feet features in children with trisomy 13, from newborn to 4 years of age. Images used with
permission of the Logan, Rivera, and Tingey families [Color figure can be viewed at wileyonlinelibrary.com]
septal defects (ASDs) and tetralogy of Fallot (Kosiv et al., 2017; Lin
et al., 2006; Nishi et al., 2018; Pont et al., 2006). Some less common
cardiac anomalies that may be present in trisomy 13 patients include
transposition of the great arteries (3%), coarctation of the aorta (2%–
3%), hypoplastic left heart (1%–3%), endocardial cushion defect (1%),
and pulmonary valve stenosis (1%) (Pont et al., 2006; Springett
et al., 2015; Taylor, 1968). Many patients with trisomy 13 and cardiac
abnormalities develop pulmonary overcirculation and pulmonary
hypertension, resulting in increased mortality (Maeda et al., 2011;
Peterson et al., 2017).
Recently, the management of these infants has more commonly
included cardiac repair options. VSD and ASD repairs are among the
most common surgical intervention performed, and their surgical
repair has been associated with increased overall survival (Maeda
et al., 2011). Due to the high prevalence of cardiac malformation, car-
diac evaluation with echocardiogram is recommended soon after birth
for any infant diagnosed with trisomy 13 (Wyllie et al., 1994).
The decision to offer surgical interventions to a population with a
relatively low-survival rate must always come with a thorough discus-
sion of the ethical implications. These conversations have historically
KEPPLE ET AL.
surrounded quality of life, hospital resource allocation, and parental
decision-making (Pallotto & Lantos, 2017). Although thorough and
thoughtful dialogs are vital to the appropriate care of these infants,
these ethical discussions are outside the scope of this current review.
For readers who are interested in the robust discussion on these
topics, we would refer them to several recent publications on the sub-
ject (Andrews et al., 2016; Haug et al., 2017; Neubauer & Boss, 2020;
Pallotto & Lantos, 2017).
Historically, due to low-survival rates, most families of infants
with trisomy 13 have been provided with palliative care options, with-
out discussion of surgical intervention. Therefore, the data regarding
the typical course for these infants who receive a full range of medical
interventions are still rather sparse. Regardless of one's views on the
ethical implications, surgeries are increasingly being performed in this
population, and as a result, more of these infants are being cared for
by a greater number of neonatologists, pediatricians, and pediatric
specialists. The goal of this article, therefore, is to present a compre-
hensive description of the complications that arise in trisomy 13 to
contribute to monitoring and treatment guidelines for providers who
care for these patients throughout their lives.
KEPPLE ET AL.
2 | METHODS
Articles were selected from the databases MEDLINE via EBSCO,
Scopus, and PubMed between 1967 and 2020 that had the terms “tri-
somy 13” “Patau Syndrome,” “complications,” “nonlethal,” “cardiac,”
“respiratory,” “neoplastic,” “neurologic,” “renal,” “gastrointestinal,”
“hepatic,” “otolaryngologic,” “musculoskeletal,” “development,” and
“survival” using Mesh terms and keywords. The results of the search
were analyzed by two authors (E.S.P. and J.W.K.) independently, and
those determined to be relevant based on review of the abstracts
then underwent full text review. In addition, the reference lists of
selected publications were analyzed to ensure that no other relevant
literature was missed in the initial searches.
3 | COMPLICATIONS OF TRISOMY 13
3.1 | Respiratory
Outside of cardiac complications, respiratory complications are one of
the primary causes of the high mortality for patients with trisomy
13 (Wyllie et al., 1994). Despite this, the overall rate of tracheostomy
is around 3%–5% for infants with trisomy 13 (Nelson et al., 2012).
Specifically, those infants with trisomy 13 undergoing cardiac surgery
are at high risk for tracheostomy or prolonged need for noninvasive
positive-pressure ventilation. As such, preoperative discussions should
include considerations for postoperative respiratory management
(Swanson et al., 2016), and an airway assessment should be consid-
ered in any infant with trisomy 13 undergoing cardiac surgery.
In addition to acute respiratory complications, there are other
prolonged respiratory concerns that may occur. For example, patients
with trisomy 13 are at higher risk for pneumonia requiring hospitaliza-
tion (Barnes & Carey, 2018). Also, these patients are at risk for post-
operative respiratory depression and thus require close monitoring for
procedural interventions. After corrective cardiac surgery, for
instance, infants with trisomy 13 required a median of 2 days of
mechanical ventilation (Kosiv et al., 2017). Due to the increased risk
for respiratory morbidity, palivizumab may be considered to prevent
respiratory syncytial virus infections in infants with neuromuscular
disorders including trisomy 13 (Barnes & Carey, 2018). Due in part to
these concerns, as well as the number of infants with these disorders
requiring home oxygen or tracheostomy, close outpatient follow-up
with a pulmonologist should be highly considered.
3.2 | Neurologic
Central nervous system (CNS) disorders are seen in more than 39% of
patients with trisomy 13 and include cerebral, holoprosencephaly/
arhinencephaly (28%–32%), microcephaly (7%–26%), neural tube
defects (1%–14%), Dandy–Walker malformation (10%), hydrocephalus
(3%–5%), ventriculomegaly (3%), and choroid plexus cysts (3%) (Emer
et al., 2015; Goetzinger et al., 2008; Pont et al., 2006; Springett
1633
et al., 2015; Tomlinson, 1978). Most commonly, CNS disorders in tri-
somy 13 affect midline structures, including alterations in proper CNS
development often associated with a deficiency in the prechordal
mesoderm (Pont et al., 2006; Springett et al., 2015).
Screening for structural neurological abnormalities prenatally can
prove difficult due to the limitations of prenatal ultrasonography. Fetal
detection rates for significant CNS structural anomalies range
between 58% and 68% in trisomy 13 even when performed by experi-
enced ultrasonographers (De Vigan et al., 2001; Grandjean
et al., 1998). A common finding in trisomy 13, holoprosencephaly, can
be detected after 12 weeks of gestation and is present in 60%–70%
of these patients (Papageorghiou et al., 2006; Sepulveda et al., 2014;
Witters et al., 2011). Due to the inability of prenatal screening to fully
detect all CNS anomalies, postnatal cranial ultrasound and/or mag-
netic resonance imaging should be performed for all infants with tri-
somy 13 to ensure detection of malformations that may alter ethical
decision-making.
In addition to structural anomalies, functional CNS deficits play a
significant role in the morbidity and mortality of this disorder. Per-
haps, one of the most important neurological complications impacting
survival in these patients is central apnea (Wyllie et al., 1994). Some
studies show that central apnea was the main cause of death for 87%
of patients less than 1 year of age with trisomy 13 (Wyllie
et al., 1994). As such, a sleep study should be considered in any infant
with trisomy 13 being discharged home without positive-pressure
ventilation or home apnea monitoring. Seizures have also been docu-
mented in 25%–50% of older patients with trisomy 13 (Carey, 2010)
and may be a cause of apnea in this population. Clinical presentation
is widely variable; however, photosensitivity is a common trigger
(Barnes & Carey, 2018). Population-based studies using standard elec-
troencephalography screening are needed to better define the risk
and timing of seizures in these populations.
Ocular and ophthalmic manifestations of trisomy 13 are now
more commonly diagnosed and managed, given the increasing life
span and the breadth of treatment being offered to these patients.
The most common congenital anomalies include anophthalmos/
microphthalmos (11%–54%), iris colobomas (33%), bilateral retinal
dysplasia, optic nerve hypoplasia, congenital cataracts (6%), and glau-
coma (1%) (Barnes & Carey, 2018; Ginsberg & Perrin, 1965; Moerman
et al., 1988; Springett et al., 2015; Taylor, 1968). Nystagmus is also
found in trisomy 13 and can have a neurological origin (Barnes &
Carey, 2018). Early ophthalmologic screening should be performed in
any infant with trisomy 13 by a pediatric ophthalmologist in order to
assess eye structure and function (Barnes & Carey, 2018).
Significant developmental disabilities are seen in trisomy 13, with
the greatest impairments seen in communication and motor develop-
ment (Baty et al., 1994a). Most patients with trisomy 13 are not able
to walk independently due to the motor delays as well as musculo-
skeletal abnormalities (Barnes & Carey, 2018). During the first
2–3 years of life, the difference in developmental quotient between
infants with trisomy 13 and infants with normal development greatly
increases. This increase, however, does not appear to be due to a loss
of developmental skills but rather an advancement in development
1634
that is much slower than the typical exponential increase during this
time frame (Baty et al., 1994b).
3.3 | Neoplastic and hematologic
Neoplastic complications have been occasionally reported in infants
with trisomy 13, though not at higher rates than the general popula-
tion. Although trisomy 18 is associated with increased risk for hepato-
blastoma and Wilms' tumor, both of these seem to occur at a similar
rate in trisomy 13 compared to the general population (Satgé
et al., 2017; Shah et al., 2014; Sweeney & Pelegano, 2000; Traub
et al., 2006; Zhou et al., 2013). Due to the low prevalence in studies
performed to date, screening for these tumors is not currently rec-
ommended in patients with trisomy 13. The relatively low rates of
reported neoplastic disease in trisomy 13, however, may primarily
reflect the fact that thorough epidemiological reports have been hin-
dered by high-early mortality rates. As survival increases, future
population-based studies will be required to better assess the true
rates of neoplastic disease in this population.
As opposed to neoplastic complications, infants with trisomy
13 commonly present after delivery with hematologic abnormalities.
The most common hematological abnormalities in the first week of life
are neutrophilia (83%) and thrombocytopenia (75%). Of the infants
with trisomy 13 and thrombocytopenia, 43% had moderate
(50,000–100,000/μl) and only 6% had severe (<50,000/μl) thrombo-
cytopenia, with 11% receiving at least one platelet transfusion
(Wiedmeier et al., 2008). Although likely clinically insignificant, trisomy
13 has also been associated with persistence of fetal hemoglobin
(Sankaran & Sapp, 2012) and nuclear projections of neutrophils
(Huehns et al., 1964; Kader et al., 2018). Because of the high rate of
hematologic abnormalities, a complete blood count with differential
should be obtained in infants with trisomy 13 after delivery, especially
in any infant requiring surgery.
3.4 | Genitourinary
Approximately 60% of patients with trisomy 13 present with kidney
and urinary malformations. Pyelectasis (56%) and cystic kidney dis-
ease (33%) are the most common pathological manifestations,
although congenital hydronephrosis (5%–23%), duplication of kidney
(7%–18%), obstructive genitourinary kidney defect (5%), renal dyspla-
sia (1%), and hypospadias/epispadias (1%) are also frequently seen
(Barakat & Butler, 1987; Egli & Stalder, 1973; Emer et al., 2015;
Moerman et al., 1988; Pont et al., 2006; Springett et al., 2015). Up to
33% of patients with trisomy 13 have ambiguous genitalia (Emer
et al., 2015; Niedrist et al., 2006).
Abdominal ultrasound should be performed shortly after birth to
detect any renal complications. Infants with concern on prenatal imag-
ing for hydronephrosis but with normal initial postnatal ultrasounds
should have a repeat renal ultrasound at 4–6 weeks of age. If either
imaging detects hydronephrosis or concern for anatomic
KEPPLE ET AL.
abnormalities, pediatric urology and/or nephrology should be consul-
ted and additional imaging such as a voiding cystourethrogram consid-
ered (Becker, 2009). Prophylactic antibiotics should be considered for
structural anomalies that place the infants at high risk for urinary tract
infections (Barnes & Carey, 2018; Peroos et al., 2012).
3.5 | Abdominal and feeding
Feeding complications are also quite frequent in trisomy 13. Nearly all
patients with trisomy 13 have difficulty with oral feeding and ulti-
mately require nasogastric or gastrostomy tube feeding (Barnes &
Carey, 2018; Baty et al., 1994a; Bruns & Campbell, 2014). It has been
suggested that some of these patients have difficulty feeding due to
structural differences, but abnormal muscle coordination and develop-
ment also play a role (Barnes & Carey, 2018; Carey, 2010). The impair-
ment of muscle coordination also places these patients at higher risk
for aspiration and can result in an increased rate of aspiration pneu-
monia (Barnes & Carey, 2018). Thus, video fluoroscopic swallowing
studies should be considered in any infant with trisomy 13 receiving a
significant portion of his or her nutrition orally to assess for frank or
silent aspiration. Growth should be measured according to trisomy
13 growth charts (Baty et al., 1994b).
A few studies have also demonstrated gastrointestinal complica-
tions in trisomy 13, including abdominal wall defects (1%–12%),
Meckel's diverticulum (11%), anorectal atresia and stenosis (1%–3%),
and diaphragmatic hernia (1%–3%) (Pont et al., 2006; Springett
et al., 2015; Taylor, 1968). In addition, 42% of trisomy 13 patients will
have jaundice (Taylor, 1968). In our experience, we have seen a high
rate of conjugated hyperbilirubinemia in infants with trisomy 13. The
incidence, natural course, and potential etiology of cholestasis in this
population, however, have not yet been fully evaluated in the
literature.
3.6 | Otolaryngologic
One of the most common types of procedures performed in infants
with trisomy 13 is otolaryngologic surgeries. Of all the surgeries in
both trisomy 13 and 18 patients, 17% are otolaryngologic, including
tympanostomy placement (25%), cleft lip repair (17%), tracheostomy
(16.5%), tonsillectomy/adenoidectomy (16%), and cleft palate repair
(13%) (Karimnejad & Costa, 2015). Although most surgeries are per-
formed early in life, consistent evaluation of otolaryngologic complica-
tions should be assessed over the life course. Orofacial clefts are
common in trisomy 13, and corrective surgery should be strongly con-
sidered in patients surviving the newborn period due to the potential
impact on feeding and development (Barnes & Carey, 2018;
Temple, 2007).
All infants with trisomy 13 should have standard newborn hearing
screens performed, as well as repeat hearing screening performed by
9 months of age or by 3 months if they had meningitis, encephalitis,
or were on extracorporeal life support (“Year 2019 Position
KEPPLE ET AL. 1635

Statement: Principles and Guidelines for Early Hearing Detection and TABLE 1 Screening recommendations in trisomy 13
Intervention Program,” 2019 (Journal of Early Hearing Detection and Time period Screening recommendation
Intervention, 2019)).
Prenatal Ultrasound (US) screening at 19 weeks of
gestation
Consider fetal echocardiogram if known
3.7 | Orthopedic trisomy diagnosis or abnormal ultrasound
After delivery Thorough physical exam for external
anomalies
Positional foot abnormalities and other lower limb deformities can pre-
Complete blood count with differential
sent in trisomy 13 and result in few patients being able to walk indepen-
Echocardiogram
dently during their lifetime (Pont et al., 2006). Occupational and physical Total abdominal ultrasound
therapy consultation should be initiated early in these infants, with Cranial US and/or magnetic resonance
follow-up determined based on each infant's specific therapy needs. imaging of the brain
Early screening by pediatric ophthalmologist
Airway assessment, with consideration for
sleep study
4 | C O N CL U S I O N 0–12 months of life Frequent feeding assessments
Audiology exam at 6–8 months
Due to the increased survival associated with increased availability of Dental screening
care for trisomy 13, significant postnatal complications may present in 1–2 years of life Annual ophthalmologic evaluation
patients with trisomy 13. The complex care needed to optimize out- Routine dental visits every 6 months

comes for patients with trisomy 13 requires multidisciplinary care that 2+ years of life Annual ophthalmologic evaluation
Annual orthopedic examinations and spinal
should attend to both the medical and psychosocial needs of the
X-ray
patient and family (Weaver et al., 2020). In addition to the medical Routine dental visits every 6 months
care described within this review (Table 1), attention should also be
10+ years of life Annual orthopedic examinations and spinal
paid to supporting the wellness of families, including referral to sup- X-ray including bone scan
port groups such as the Support Organization for Trisomy 18, 13, and Puberty Evaluate for seizures and behavioral changes
Related Disorders. A helpful parent guide to the care of these infants Monitor normal sex characteristic
can be found online and may be provided to families to aid in educat- development
For females, evaluate menstrual cycles (risk
ing them about their infant (Barnes & Carey, 2018). In addition,
for primary or secondary amenorrhea)
genetic counseling should be provided for all families of infants with
Nonspecific Refer to pediatric pulmonologist when
trisomy 13, with special consideration of parental karyotypes to
appropriate
assess for chromosomal translocation. Voiding cystourethrogram if initial abnormal
Despite an expanding understanding of the complex pathophysi- renal US
ologies of trisomy 13, many questions remain unanswered. For exam- Repeat renal US at 4–6 weeks of life if fetal
concern for renal abnormality but normal
ple, although the prevalence of documented seizures appears to be
early postnatal US
low in all trisomy 13 patients, the prevalence is significantly elevated Early referral to physical/occupational/
in older patients. There has been no comprehensive study examining speech therapy
the etiology and pathophysiology of seizures in this population. In Have high index of suspicion for urinary
tract infection
addition, management of these seizures has not been well docu-
mented and needs exploration. Similarly, hepatic function—specifically
cholestasis and direct hyperbilirubinemia—in these infants has not
been well documented in the literature. In our practice, we have important in measuring the prevalence of comorbidities with trisomy
observed a high rate of direct hyperbilirubinemia despite negative 13, which may influence screening guidelines. In addition, sites who
abdominal ultrasounds; an observation that likely deserves further offer surgical intervention should consider multisite collaboration
exploration. Finally, recent studies have shown that cardiac surgery and/or randomized controlled trials to measure clinical outcomes of
helps improve survival in trisomy 18 patients; however, the impacts surgical intervention for this population. Further research to under-
on infants with trisomy 13 and those of specific cardiac procedures stand how surgical intervention impacts the length and quality of life
for trisomy 18 have not yet been thoroughly explored. for patients with trisomy 13 may help direct ethical decision-making
A more complete understanding of these patients' pre- and from the patient, provider, and resource allocation perspectives for
postnatal complications are necessary, including how somatic mosai- this high-risk population.
cism may play a role in phenotypic severity and survival. The data
presented in this review are based on published cases and recom- ACKNOWLEDG MENTS
mendations to date. As intervention options evolve over time, col- We thank the families and their healthcare providers for engaging in
lection and publication of these data will become increasingly research and data banking to increase awareness and understanding
1636
of trisomy 13. Also, we would like to thank Dr Lois Starr for her sup-
port and guidance in the drafting of this article.
CONF LICT OF IN TE RE ST
The authors have no conflicts of interest to declare.
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How to cite this article: Kepple JW, Fishler KP, Peeples ES.
Surveillance guidelines for children with trisomy 13. Am J Med
Genet Part A. 2021;185A:1631–1637. https://doi.org/10.
1002/ajmg.a.62133