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ORIGINAL RESEARCH |
From the 1Fetal Treatment Center, Division of Pediatric Surgery and the Department of 2Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California.
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ABSTRACT |
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METHODS: We examined our institutional database from August 1995 to August 2005, examining 679 cases of congenital diaphragmatic hernia, identifying all fetuses and newborns with congenital diaphragmatic hernia and spinal anomalies. Patients who had both congenital diaphragmatic hernia and spinal anomalies were identified by prenatal ultrasound reports, postnatal radiographs, operative notes, and pathology reports.
RESULTS: Seven patients were identified in the fetal or neonatal period with concomitant diagnoses of congenital diaphragmatic hernia and spinal anomalies. All patients had normal karyotype analysis. Six of these patients had both defects diagnosed using prenatal ultrasonography. All patients died before hospital discharge.
CONCLUSION: Although the numbers are limited in our series, patients with congenital diaphragmatic hernia and spinal anomalies have a dismal prognosis. This finding has significant implications for prenatal counseling.
LEVEL OF EVIDENCE: III
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METHODS AND MATERIALS |
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RESULTS |
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A brief synopsis of the individual cases follows:
Case 1
A prima gravida patient referred at 25 weeks of gestation carrying a fetus diagnosed with left-sided CDH and liver up with unknown lung-to-head ratio. Ultrasound examination revealed hemivertebrae with segmental abnormality and focal kyphosis in mid-thoracic spine. Karyotype analysis revealed 46XY. The newborn was born at 36 weeks of gestation age via spontaneous vaginal delivery. Hemivertebrae of ribs 9 and 10 was noted. The newborn did poorly with conventional ventilation and nitric oxide therapy, underwent extracorporeal membrane oxygenation cannulation, but died on day of life 17 of pulmonary failure. A diaphragmatic hernia repair was not attempted and postmortem examination was not performed.
Case 2
A prenatal ultrasound examination of a 25-week gestational age fetus in a mother with an unknown birth history revealed left-sided CDH, liver up, lung-to-head ratio 1.0. Karyotype revealed 46XX. Ultrasound examination revealed multiple segmentation abnormalities with kyphosis and scoliosis (Fig. 1), and magnetic resonance imaging (MRI) confirmed cervical spine diastematomyelia seen as an area of duplication of the spinal cord with an intervening bony bar and dual thecal sacs in the cervicothoracic junction region. The newborn was born at 37 weeks of gestation by normal spontaneous vaginal delivery and survived only few hours after birth, dying from pulmonary failure despite resuscitative attempts. Post mortem revealed hypoplastic lungs.
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Case 3
A 31-year-old, prima gravida woman referred with a 16-week ultrasound revealing left CDH with liver up and lung-to-head ratio 1.0. Cervical spine segmental abnormality was noted on ultrasound examination (Fig. 2), and MRI confirmed hemivertebrae in cervicothoracic junction, along with butterfly vertebrae and partial vertebrae. Karyotype analysis revealed 46XY. The newborn was born at term (40 weeks of gestation) by normal spontaneous vaginal delivery with a shortened right humerus, the right arm in fixed contracture, and vertebral anomalies. Postnatal course included patch repair of the hernia defect on day of life 7 while on high-frequency ventilation. Hospital course included subsequent nitric oxide and extracorporeal membrane oxygenation therapy (days of life 13–25), along with chylothorax. The infant died on day of life 40.
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Case 4
A 25-year-old, prima gravida woman was referred at 25 weeks of gestation with a fetus that had a left-sided CDH with liver down and a lung-to-head ratio of 0.6. Ultrasound findings included cervicothoracic and lumbosacral junction spinal abnormalities, as well as a right pelvic kidney. During the initial referral, the patient was briefly hospitalized for preterm contractions and cervical change, and amniocentesis was performed revealing a 46XX chromosomal pattern. Preterm labor was avoided with intravenous nifedipine and bed rest, and the patient was discharged to home. The infant was born without obstetric complications at term (40 weeks of gestation) via normal spontaneous vaginal delivery at another institution but died soon after birth of pulmonary insufficiency.
Case 5
A 31-year-old, prima gravida woman referred at 25 weeks of gestation with ultrasonography documenting bilateral CDH and lung-to-head ratio 0.7. Ultrasound examination and MRI revealed kyphosis of spine but no segmentation abnormality. No abnormalities were detected on karyotype analysis. At 37 weeks of gestation, fetal monitoring demonstrated decreased fetal movement and late decelerations. An emergent cesarean delivery was performed, but resuscitation of the newborn in the delivery room was unsuccessful. Postmortem examination confirmed the imaging findings and pulmonary insufficiency.
Case 6
A 22-year-old, gravida 2, para 0 patient was first admitted to the hospital at 32 weeks of gestation with a left-sided CDH with liver up. Other noted anomalies on ultrasound examination included 2-vessel cord and misaligned spine with lower thoracic abnormality suspicious for segmentation abnormality. Amniocentesis revealed a 46XX karyotype. Maternal steroids (2 doses of betamethasone 12 mg) were given to the mother in anticipation of preterm delivery. Delivery occurred at 36 weeks of gestation due to fetal distress, and the newborn showed features consistent with Fryns syndrome (cleft lip and palate, nail hypoplasia). The newborn died soon after birth, and the family did not consent to an autopsy.
Case 7
A 39-year-old, gravida, 5 para 1 woman was evaluated for left CDH with lung-to-head ratio 0.9 and normal fetal echocardiogram. Amniocentesis revealed normal 46XX karyotype. There were no other anomalies identified. The newborn was delivered at term via spontaneous vaginal delivery and underwent patch repair of diaphragm. A cyst removed at 1 month of life was initially thought to be a foregut duplication cyst but MRI later delineated a tenting of the ventral spinal cord at C-3, and a cleft through the mid C-2 vertebral body and rotary scoliosis to the left centered at C-3, at the origin of a neurenteric cyst. The infant remained hospitalized and ultimately died at 6 months of age secondary to pulmonary insufficiency and recurrent sepsis, confirmed by postmortem examination.
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DISCUSSION |
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Concomitant diagnosis of CDH with any other anomaly has been shown to be a poor prognostic indicator. Bollman et al8 showed that only 2 of 28 newborns diagnosed with CDH and any non-thoracic anomaly survived (7%). Witters et al9 reported only 1 of 15 patients diagnosed prenatally with CDH and either chromosomal or anatomic anomalies survived. The presence of associated cardiac anomalies has been shown to be nearly uniformly fatal.6,10,11 Obstetric ultrasonography allows detection of CDH before birth in most cases, often during the early second trimester. The prenatal diagnosis of CDH, in particular before 25 weeks of gestational, is associated with a significantly higher rate of other life-threatening anomalies than in CDH cases diagnosed postnatally.5 Magnetic resonance imaging can be useful to evaluate the diaphragmatic defect and associated anomalies, particularly as spinal malformations can be difficult to assess by prenatal ultrasound evaluation.12
Spinal anomalies have been sporadically reported with CDH, including thoracoschisis13 and spondylothoracic dysostosis.14 Congenital diaphragmatic hernia has been linked to numerous syndromes that include spinal abnormalities. Vertebral anomalies are described in patients with Fryns syndrome, an autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, craniofacial anomalies, distal limb hypoplasia, and malformations of the cardiovascular, gastrointestinal, genitourinary, and central nervous systems. Fryns syndrome has traditionally been described as a clinical entity, but recent array comparative genomic hybridization has revealed submicroscopic chromosomal deletions in patients with this syndrome that had previously been undetectable with traditional karyotype analysis.15 Many patients with CDH and spinal anomalies may in fact have undetected submicroscopic chromosomal deletions that would be evident using array comparative genomic hybridization. In our series, array analysis was not available during the time course of this study.
Larger case series of CDH have generally described musculoskeletal or central nervous system anomalies in up to 10–15% of cases, although reports of spinal defects are more rare.4,5,6,16,17 Martinez-Frias et al18 found that CDH was associated with significantly increased incidence of vertebral defects because such defects were present in 3.2% of CDH patients and in only 0.73% of those with other anomalies, leading to the conclusion that CDH may be a risk factor for spinal anomalies. Spina bifida was present in 1.8% newborns with CDH but only 0.5% newborns with other anomalies. When patients with known syndromes were analyzed, vertebral and rib defects were present in 25% of cases with CDH and in only 2.38% without CDH.
The etiology of concurrent CDH and spinal anomalies is unknown. As suggested by Migliazza et al,19 the origin of both the CDH and spinal defects may result from developmental disturbance involving axial and para-axial mesoderm. Early disturbance of muscle precursors from somites results in the diaphragmatic defect and embryonal mesenchymal regional disturbance results in vertebral anomalies similar to those seen in esophageal, duodenal, or anorectal atresias. There may therefore be an embryological disturbance corresponding chronologically to the moment of somatic segmentation resulting in synchronous deficiencies in the diaphragmatic pleuroperitoneal folds and vertebral segmental sclerotomes, suggesting that fetuses with spinal deformities in addition to CDH have a more extensive derangement of this somatic region.
All fetuses in the current series died soon after birth. As with cardiac anomalies, spinal anomalies may signal a more severe form of the defect, serving as a marker for a more lethal condition. In our series, the lung-to-head ratio was less than or equal to 1.0 in all cases in which these measurements are available, a signal that these patients had a severe form of disease and an indication of poor prognostic outcome. Prenatal intervention studies in CDH patients require that diagnostic and prognostic information be accurate to assess outcomes.
In evaluating fetuses with CDH, certain associated anomalies must be excluded, as they impact overall prognosis. While fetuses with isolated CDH have survival rates of better than 50%, spinal abnormalities associated with CDH, both syndromic and nonsyndromic, portend a poor prognosis. The uniformly fatal outcome in our series of patients has significant implications for prenatal counseling.
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Footnotes |
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doi:10.1097/01.AOG.0000254174.25795.d6
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REFERENCES |
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18. Martinez-Frias ML, Prieto L, Urioste M, Bermejo E. Clinical/epidemiological analysis of congenital anomalies associated with diaphragmatic hernia. Am J Med Genet 1996;62:71–6.[Medline]
19. Migliazza L, Xia H, Diez-Pardo JA, Tovar JA. Skeletal malformations associated with congenital diaphragmatic hernia: experimental and human studies. J Pediatr Surg 1999;34:1624–9.[Medline]
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