A case of intrauterine closure of the ductus arteriosus and non-immune hydrops

Introduction

Closure of the ductus arteriosus is a normal part of the transition from intrauterine to extrauterine environments in the newborn period. This closure is related to gestational age and is typically expected within the first days of life; intrauterine or delayed closure are both abnormalities with significant consequences in the neonatal period.

Abnormal intrauterine or preterm ductal closure can be associated with severe consequences including prenatal polyhydramnios and hydrops as well as postnatal pulmonary hypertension, ventricular hypertrophy and congestive heart failure.

There are several reports identifying cases of abnormal intrauterine ductal closure, however, as yet there is no longitudinal data commenting on the epidemiology of this specific phenomenon, all of the risk factors preceding this event or specific guidelines to assist in managing these patients. The majority of cases identified in a literature search are associated with maternal prenatal use of non-steroidal anti-inflammatory drugs (NSAIDs), but cases are not exclusive to this history. Another reported association may be with maternal consumption of polyphenol-rich foods, but again cases are not limited to this history.

Non-immune hydrops refers to abnormal fluid collection in two or more spaces in a fetal body that does not occur related to alloimmunization. It occurs for a variety of reasons but often is recognized as idiopathic; there is a known association between intrauterine ductal closure and non-immune hydrops as detailed in the 2007 review in the American Journal of Perinatology and additional publications.

Here, we report a case of spontaneous preterm ductal closure with non-immune hydrops unrelated to a maternal history of NSAID use with unknown dietary history.

Case presentation

This infant was admitted to the Neonatology Service after transfer from another facility on the 1^st day of life due to concerns including respiratory distress with hypoxemia, an abnormal abdominal X-ray with concern for mass or fluid collection and sepsis evaluation. The child was born at 40 weeks 0 days by estimated dating but appeared post-dates on examination. The child weighed 3130 g at delivery, and had APGAR scores of 7 and 8.

The child’s mother was gravida 6 with previous deliveries of two full-term and two preterm infants. The patient’s mother was late to prenatal care, presenting in the 3^rd trimester. The only prenatal ultrasound was performed at 37 weeks into pregnancy, and the results confirmed gestational age. There was no mention of fetal abnormality, oligo- or polyhydramnios. The patient’s mother denied NSAID use during pregnancy. Specific maternal dietary details from during pregnancy were not obtained though no specific restrictions were reported.

The child was born via cesarean section and required positive pressure ventilation via mask at delivery. Continuous positive air pressure (CPAP) was initiated after stabilization with positive end-expiratory pressure (PEEP) of 5 cm H₂O and fraction of inspired O₂ (FiO₂) of 30%. Decreased aeration bilaterally was noted on lung examination. No murmur or cardiac abnormalities were identified. The abdomen was taut and distended; palpation was non-revealing, but bowel sounds were present. Upon laboratory evaluation, mother and infant were found to be blood type O, Rh positive. The mother of patient was antibody negative and the infant’s Coombs test was similarly negative. Cord gas from delivery identified a pH of 7.19 and 9.0 base deficit. The infant was transitioned to CPAP with PEEP of 5 and FiO₂ of 90%. An abdominal X-ray was obtained at the outlying facility, worrisome for an abdominal mass and prominent cardiac silhouette. The need for CPAP and the abnormal imaging prompted transfer to our NICU on the 1^st day of life.

At this time, still on the 1^st day of life, the infant was transferred to our service. Our examination yielded similar findings including a post-term, comfortable appearing male infant, good air entry and intact breath sounds on CPAP as previously, a distended and firm abdomen, particularly on the right, abdominal wall and chest wall edema, slightly increased tone and decreased activity. At this time, the patient met criteria for non-immune hydrops and required continued management for respiratory distress and hypoxemia.

Additional labs and imaging were completed following admission to our institution. Sepsis workup was negative; empiric antibiotics were discontinued after 3 total days of therapy. A hepatic function panel noted significant elevations in liver function tests with an aspartate transaminase (AST) and alanine transaminase (ALT) of 885 and 485, respectively. A repeat abdominal X-ray demonstrated a more typical gas pattern but did not show an abdominal mass. An abdominal ultrasound again failed to demonstrate a mass, however, it did identify mild ascites, pericholecystic and periportal edema as well as small pleural effusions corroborating a diagnosis of hydrops. An echocardiogram (echo) done at approximately 11 h of life that showed a patent foramen ovale with bidirectional flow, mild-to-moderate dilation of the right atrium, small ventricular septal defect, trivial tricuspid insufficiency and septal flattening consistent with increased right ventricular pressure. No patent ductus arteriosus was detected.

This patient initially required CPAP which was gradually weaned to nasal cannula support by day 3 of life. Nasal cannula was continued until day 16 of life with subsequent transition to room air without the need for additional support. By the time of discharge, the patient was hemodynamically stable with a normal cardiovascular exam except for a grade I/VI systolic ejection murmur that warranted no specific follow-up per our pediatric cardiologists. Edema resolved with no further identification of an abnormality such as a mass. Liver function tests gradually improved with complete resolution to normal values within 2 weeks. The patient was ultimately discharged with recommendation of routine neonatal care only.

Discussion

This case presents a patient with non-immune hydrops identified on postnatal physical examination and imaging suspected to be related to intrauterine closure of the ductus arteriosus identified on postnatal echo. A link between intrauterine ductal closure and non-immune hydrops has significant pathophysiologic support and is known in the literature despite the rarity of these conditions. Additional commentary regarding this association is described below. Information on this case was identified through Elsevier’s SCOPUS and PubMed database searches.

The formation of non-immune hydrops following intrauterine ductal closure has a strong basis in fetal physiology. When open, the ductus shunts blood between the pulmonary artery, originating from the right ventricle, and the aorta. This allows blood to bypass the fetal lungs and continue through the circulatory system. However, if the ductus closes in utero, blood is no longer able to bypass the lungs. This leads to increased pulmonic arterial congestion and dilation as well as right atrial and right ventricular dilation [1]. This dilation may lead to diastolic dysfunction resulting in congestive heart failure [1]. In the fetus and immediate neonate, this diastolic dysfunction may result in the accumulation of fluid in tissues or non-immune hydrops as in our patient. Closure of the ductus is typically dependent upon gestational age though there are other identified factors that may result in premature closure, such as the association with maternal NSAID use.

A 2007 review published in the American Journal of Perinatology reviewed five cases of in-utero ductal closure recognized by fetal echocardiography similarly recognizing this association. These infants were identified with prenatal imaging due to hydrops, cardiomegaly and polyhydramnios [2]. Three of the five patients’ mothers had no identified drug or medication use during pregnancy [2]. Four out of the five patients followed had an uneventful postnatal course; one ultimately expired related to airway obstruction from a teratoma [2]. Based on these observations, the authors note that in-utero ductal closure should be suspected in patients with non-immune hydrops and right ventricular abnormalities [2].

Our patient’s mother did not report any NSAID medication use; much of the reviewed literature did report this association [3], [4], [5]. Maternal prenatal dietary history was not obtained, but there is a reported association of polyphenol rich foods, such as green tea, grape juice and chocolate, with intrauterine ductal closure [1].

The etiology of intrauterine closure is unknown in this case, however, had prenatal care and history been more extensive, there may have been other clues as to the etiology of the premature closure. In addition, this case analysis is limited as the diagnosis was retrospective; additional fetal evaluation ultrasonography and echocardiography may have been able confirm intrauterine closure of the ductus arteriosus and development of hydrops prior to our evaluation.

It is of note that premature closure of the ductus arteriosus is the most commonly identified cause of non-immune hydrops fetalis; as such, if hydrops is identified prenatally on ultrasonography, additional testing with fetal echocardiography should be performed [6]. With confirmation of ductal closure on these patients, serial echocardiography is required to manage these patients [6].

Additional surveillance is warranted to continue to evaluate the incidence of and relationship between intrauterine ductal closure and non-immune hydrops as well as the associated outcomes.