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- Neonatal and paediatric intensive care
- Neonatal health
- Pediatrics
- Musculoskeletal syndromes
- Neonatal intensive care
Description
The case is of a female infant born late preterm via elective lower segment caesarian section (ELSCS) due to intrauterine growth restriction (IUGR), at 36 + 3 weeks. The mother was 25 years, gravida 2 para 0+1, with no significant medical history. She had an antenatal follow-up in a private clinic and was referred to the Feto Maternal Medicine Unit (FMU) at our institution at 23 + 6 weeks due to an abnormal scan of a small date fetus with skeletal problems. Repeat ultrasound showed a bilaterally absent fibula, also known as fibular hemimelia. The mother was referred to the genetic clinic for counselling, and explained that possible causes include chromosomal anomalies or single gene causes, especially since the parents are consanguineous direct cousins. She denied known similar conditions in the family. No scans were found for her first spontaneously aborted pregnancy. Subsequent monthly scans at FMU showed similar growth and bony findings along with talipes equinovarus. She was planned for delivery at 37 weeks of gestation. She was admitted for delivery and received 2 doses of betamethasone as planned by the obstetric team at the gestational age of 36 weeks + 2 days as per the institutional protocol for fetal lung maturity. On the day of delivery at 36 + 3 weeks, the FMU scan showed severe IUGR. She underwent an uneventful ELSCS with a smooth perinatal course.
The infant was born non-vigorous. She required continuous positive airway pressure (CPAP), and then she developed a good respiratory drive. Apgar scores were 9 and 10 at 1 and 5 min, respectively. On examination, she had a low birth weight of 1509 g (below the fifth percentile) and a low length of 42 cm (below the fifth percentile) with a low head circumference of 30 cm (below the fifth centile), bilaterally absent fibula, talipes equniovarus, two toes in each foot (figure 1) and mildly receded chin. She was admitted to the neonatal intensive care unit (NICU) with symmetrical IUGR, respiratory distress syndrome (RDS) and congenital limb deficiencies in the form of fibular aplasia and oligosyndactyly for investigation.
A photo for both lower limbs showing absent fibula of both legs with bowing of tibia, absent distorted small bones of both feet, talipes equniovarus and two toes in each foot.
She was weaned from CPAP to nasal cannula after 10 hours of life, and subsequently to room air 12 hours later. Routine labs were reassuring apart from initial hypoglycaemia of 1.4 mmol/L that was corrected with feeding. Newborn screening tests and chromosomal microarray were unremarkable. The parents declined further genomic testing.1 Toxoplasmosis, rubella, cytomegalovirus (CMV), herpes simplex and HIV screening was only remarkable for CMV and rubella immunoglobulin G positive results, which likely indicates transplacental passage of maternal immunity. A skeletal survey was done and confirmed absent fibula of both legs with bowing of the tibia and absent distorted small bones of both feet. It also showed a mildly retracted mandible (figure 2). It was unremarkable for additional deformities. Screening ultrasound of the head and abdomen were unremarkable. Physical and occupational therapy specialists have been involved since birth. They indicated restricted lower limb movements that may slightly improve with physiotherapy, but normal upper limb activity and good mature sucking abilities.
Skeletal survey showing mildly retracted mandible, absent fibula of both legs with bowing of tibia and absent distorted small bones of both feet.
On the third day of life, the infant developed persistent desaturation that was refractory to a nasal cannula with a flow of 4 L/min and a fraction of inspired oxygen (FiO2) of 30–35%. Capillary blood gas (CBG) was remarkable for low partial pressure of oxygen of 38 mm Hg and chest X-ray showed mild RDS changes with prominent pulmonary vasculature (figure 3). She was shifted to nasal CPAP of 5 cm H2O which improved oxygen saturation with FiO2 of 25%. Late-onset sepsis workup was done and it came back negative. The cardiology team assessed the patient and indicated a normal cardiac examination. Echocardiography revealed findings indicative of severe persistent pulmonary hypertension of the newborn (PPHN) in addition to dilated coronary sinus with left superior vena cava (figure 4, online supplemental video 1 and 2). Accordingly, FiO2 was increased to 40% to improve pulmonary blood flow.
Supplementary video
Supplementary video
Chest X-ray showing prominent pulmonary vasculature and features of mild respiratory distress syndrome.
Echocardiography showing features of severe persistent pulmonary hypertension of the newborn (PPHN). Echocardiogram, (a) apical four-chamber view with dilated right atrium and right ventricle denotes pulmonary hypertension, (b) Doppler showing right ventricular systolic pressure of 80 mm Hg-indicates severe PPHN, (c) parasternal short axis view of the patent arterial duct with a right to left shunt (R>L), (d) apical four-chamber view showing atrial septal defect with R>L shunt-both indicates severe PPHN.
She developed tachypnoea after 2 days which required a gradual increase of CPAP to 7 cm H2O. Follow-up echocardiography in 1 week showed similar findings. The cardiology team recommended starting nitric oxide for pulmonary hypertension and consulting the pulmonology team to rule out lung-related causes. The pulmonology team indicated that there is no clinical or radiological evidence of underlying lung pathology. Differential diagnoses include PPHN due to IUGR, PPHN with RDS and congenital heart disease as comorbidity, genetic PPHN or idiopathic PPHN. Inhaled nitric oxide (iNO) was initiated with a dose of 10 ppm with a satisfactory response. Two days later, on the 10th day of life, the infant was desaturating to 80s% but CBG was acceptable. She was shifted to nasal intermittent positive pressure ventilation 22/7 cm H2O, with fluctuating oxygen saturation. Follow-up chest X-ray showed diffuse patchy pulmonary infiltrates. iNO dose was increased to 20 ppm with no improvement. Accordingly, she was sedated, intubated and connected to the pressure control mode of conventional mechanical ventilation (CMV) that was escalated later to high-frequency oscillatory ventilation due to persistent desaturation and hypercapnia with respiratory acidosis that required high settings of conventional mechanical ventilation.
Her condition was not getting better and systemic blood pressure started to drop requiring inotropic support with dopamine and epinephrine infusions. Therapeutic interventions were maximised to include additional pulmonary vasodilators including milrinone and sildenafil as well as hydrocortisone with suboptimal response. A septic workup was done and the infant was started on prophylactic antibiotics, amikacin and teicoplanin. Inflammatory markers initially came reassuring with negative culture. Two days later inflammatory markers increased with white blood cells of 46×103 /uL and C reactive protein of 28.8 mg/L along with stress hyperglycaemia of 35.2 mmol/L. Amikacin was shifted to a meningitic dose of meropenem as infection was highly suspected in this scenario. Haemoglobin dropped from 15 to 10.1 g/L and she was transfused with 1 unit of packed red blood cells. Acidosis got worse with both respiratory and metabolic components that were refractory to adjustment of mechanical ventilation and sodium bicarbonate boluses, respectively. Accordingly, the options of extracorporeal membrane oxygenation (ECMO) and cardiac catheterisation were discussed among the team and with the family and the infant’s status was deemed incompatible with ECMO criteria due to low birth weight, presence of congenital anomaly as well as the critical situation of the baby. The family was constantly updated about the guarded situation and the high risk of mortality.
On the 13th day of life, a chest X-ray showed lung hyperinflation. Mean airway pressure was weaned gradually and the infant was shifted back to the pressure control mode of conventional mechanical ventilation. Initially, she showed some improvement in heart rate and oxygen saturation. Shortly after, she started to develop bradycardia with systemic hypotension and worsening acidosis, which were refractory to resuscitative measures, including manual respirations with T-piece PPV and chest compressions along with increasing milirinone and epinephrine infusions with vasopressin infusion and providing normal saline, epinephrine and sodium bicarbonate boluses. Eventually, she was declared dead after a total of 20 min of cardiopulmonary resuscitation. The family declined an autopsy.
In summary, this is a case of a late preterm female infant, who was electively delivered due to symmetric IUGR, with suspected genetic disease due to bilateral lower limb skeletal anomalies. In the NICU, she was found to have severe PPHN, when she started to develop oxygen requirements. She started to deteriorate at 7 days of life to die by the end of her second week with respiratory failure that was refractory to high settings of mechanical ventilation and PPHN vasodilator and anti-inflammatory therapy and with a shock that was refractory to aggressive inotropic support.
PPHN, a form of failed circulatory adaptation at birth, is one of the main causes of neonatal morbidity and mortality. It is relatively common in term or near-term infants but is being increasingly recognised in preterm infants with worse outcomes.2 It leads to a wide range of haemodynamic changes due to sustained elevation of pulmonary vascular resistance, precipitating limitation of pulmonary blood flow via right to left shunting of blood across patent channels of fetal circulation, namely foramen ovale and ductus arteriosus, which impairs blood oxygenation and results in hypoxaemia.3 In addition, it leads to systemic hypotension via several mechanisms that include systemic vasodilation due to hypoxia, sedation or use of vasodilator PPHN medications, intravascular oligaemia due to inflammatory capillary leak, impedance of venous return due to high airway pressure requirement and impaired left ventricular filling due to left-warded deviation of interventricular septum.4
The majority of PPHN cases are secondary to lung parenchymal diseases, lung hypoplasia or abnormal transition of pulmonary vasculature at birth due to perinatal stress, syndromic causes including trisomy 21, RDS or associated congenital heart disease. However, 10–20% of PPHN cases are idiopathic in which patients have abnormally remodelled pulmonary vasculature with normal lung parenchyma. The principles of PPHN management include optimal oxygenation, lung recruitment, limitation of respiratory and metabolic acidosis, blood pressure stabilisation, sedation, limitation of inflammation and use of pulmonary vasodilator therapy. iNO is the only approved pulmonary vasodilator for PPHN.5 However, nearly 40% of infants are iNO resistant and may benefit from other vasodilators like sildenafil, prostaglandins, milrinone and bosentan. Failure of vasodilators besides supportive therapy would lead to consideration of ECMO, when not contraindicated.3 5 However, ongoing advances in understanding novel pathways of PPHN, and the subsequent emergence of new targeted therapies, such as antioxidants (superoxide dismutase), soluble guanylate cyclase activators and rho-kinase inhibitors, would decrease the need for ECMO and improve the outcome in terms of survival or long-term neurodevelopmental abilities.3
Intrauterine growth restriction (IUGR) is an increasingly recognised problem that affects 7– 15% of pregnancies worldwide. Abbas et al highlighted the increased chance of PPHN in IUGR infants.6 In addition, congenital limb deficiencies are common birth defects occurring in 1 in 2000 neonates.7 In an attempt to explain the constellation of clinical features in our case, we looked at several studies that discuss similar potential risk factors or syndromic features that may be associated with PPHN, especially with the highlighted severe resistant picture. This is particularly important because a similar picture of skeletal dysplasia has been repeatedly reported in the literature under the descriptive term of (FATCO) syndrome which entitles: fibular aplasia, tibial campomelia, oligosyndactyly and talar aplasia. FATCO syndrome is a rare syndrome with unclear cause or genetic basis, that is more common in males but has been reported in females. In contrast to our case, affected children have no other comorbidities.6–10 The association between isolated skeletal anomalies and the development of PPHN is infrequently reported. Skeletal deformities that have been reported with PPHN are, in most, chest deformities that can lead to PPHN via pulmonary hypoplasia.9–11 In addition, Galambos et al highlighted rare variants of the T-box transcription factor 4 gene that are associated with PPHN along with other congenital anomalies including foot anomalies.12 Another genetic alteration that can be associated with both conditions is a mutated bone morphogenetic protein receptor type 2 (BMPR2) gene. BMPR2 gene encodes one of the transforming growth factor-β superfamily receptors, that perform diverse roles during embryonic development, vasculogenesis and osteogenesis.13
Learning points
Planning of healthcare improves the readiness of family and healthcare teams to deal with anticipated health problems. This applies to close antenatal follow-up and genetic counselling, where appropriate, in case of fetuses who are found to be small-for-date or to have congenital anomalies and applies to the constant involvement of family in care decisions in the neonatal intensive care unit, including decisions on whether to resuscitate in case of cardiac arrest and the validity of advanced resuscitative options like extracorporeal membrane oxygenation.
Persistent pulmonary hypertension of the newborn (PPHN) is a complex multidimensional condition, that is frequently associated with comorbidities, which calls for a multidisciplinary management plan that includes intensivists, cardiologists, pulmonologists, geneticists and other subspecialties as indicated, in addition to clinical pharmacists and allied healthcare practitioners like respiratory therapists, physical and occupational therapists and dietitians, with proper communication between all team members.
PPHN is an interesting area of research that has been yielding promising results, in terms of the newly discovered mechanisms and potential targeted therapies, and in terms of likely risk factors and clinical associations that can aid in early diagnosis and intervention.
Ethics statements
Patient consent for publication
Footnotes
Contributors MAAB was the guarantor, the principal investigator, and the lead clinician in charge of the clinical care of the patient, initiated the idea of submission, was responsible for obtaining informed consent from the parents, performed the literature review, collected the patient’s medical data, collected and edited the images, supervised the preparation of the manuscript, revised the manuscript and was responsible for the overall integrity of the content of the manuscript. KM was the trainee resident involved in patient care, performed the literature review, collected the patient’s medical data, collected and edited the photos, and drafted and revised the manuscript. EEE critically revised the manuscript for intellectual clinical inputs. MRR is the paediatric cardiologist involved in patient care, collecting the patient’s medical data, collecting and editing the images and videos, and revising the manuscript. All the authors read the paper and revised and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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