Abstract
BACKGROUND:
There is no consensus on managing pregnancy when the fetus is diagnosed with idiopathic premature constriction or closure of the ductus arteriosus (PCDA). Knowing whether the ductus reopens is valuable information for managing idiopathic PCDA. We conducted a case-series study to investigate the natural perinatal course of idiopathic PCDA and examined factors associated with ductal reopening.
METHODS:
We retrospectively collected information about the perinatal course and echocardiographic findings at our institution, which, on principle, does not determine delivery timing based on fetal echocardiographic results. We also examined perinatal factors related to the reopening of the ductus arteriosus.
RESULTS:
Thirteen cases of idiopathic PCDA were included in the analysis. The ductus reopened in 38% of cases. Among cases diagnosed in < 37 weeks of gestation, 71% reopened, which was confirmed seven days after diagnosis (interquartile range 4–7). Diagnosis earlier in gestation was associated with ductal reopening (p = 0.006). Two cases (15%) developed persistent pulmonary hypertension. No fetal hydrops or death occurred.
CONCLUSIONS:
The ductus is likely to reopen when prenatally diagnosed before 37 weeks gestation. There were no complications due to our pregnancy management policy. In idiopathic PCDA, especially if the prenatal diagnosis is made before 37 weeks of gestational age, continuing the pregnancy with careful monitoring of the fetus’s well-being is recommended.
Keywords
Abbreviations
premature constriction or closure of the ductus arteriosus non-steroidal anti-inflammatory drugs neonatal intensive care unit
Introduction
Idiopathic premature constriction or closure of the ductus arteriosus (PCDA) is a rare condition in which the ductus arteriosus constricts or closes during fetal development, resulting in right ventricular dysfunction without any other cause, such as non-steroidal anti-inflammatory drugs (NSAIDs). Echocardiographic findings in PCDA include turbulent or undetectable ductus arteriosus flow, hypertrophy of the right ventricular wall, an enlarged right ventricular cavity, and tricuspid regurgitation [1].
It is well known that in NSAID-induced PCDA, drug discontinuation results in the reopening of the ductus arteriosus, and reopening in idiopathic cases is also a possibility [2]. The prognosis of patients with ductal reopening is favorable [3]; therefore, identifying the population prone to reopening is helpful for decision-making and parental counseling.
The current consensus on pregnancy management for PCDA is close monitoring of fetal status, including biophysical profile scores and fetal ultrasonographic findings [4–6]. In previous reports, a deterioration in right ventricular function was a reason for terminating the pregnancy. However, right ventricular function assessment was not standardized, and there was a lack of objective findings to support the management strategy. [4–6]. Currently, therefore, termination of pregnancy is performed based on ambiguous criteria, making it unclear whether a premature birth or cesarean section was necessary.
The purpose of this study was to describe the perinatal course and echocardiographic findings of idiopathic PCDA cases seen in our institution, where termination of pregnancy is not determined by fetal echocardiography findings. Additionally, we investigated factors associated with ductal reopening to suggest approaches for managing pregnancy.
Material and methods
Ethical approval
This research, involving human participants, complied with all relevant national regulations and institutional policies, was conducted in accordance with the tenets of the Declaration of Helsinki, and was approved by the authors’ institutional review board (No. 2011-4).
Study participants and design
The study participants were newborns and their mothers, with a prenatal diagnosis of PCDA from births between January 2000 and December 2020 at Kanagawa Children’s Medical Center, a tertiary perinatal care center. Information about the mother’s clinical course (timing of diagnosis, whether the ductus reopened or not, and the timing of reopening), echocardiographic findings of the fetus (ductal flow velocity, pulsatility index), and infant’s clinical course were collected from medical records.
Mothers who had taken drugs that can cause PCDA, such as NSAIDs and paracetamol, were excluded from the study [7–9]; mothers on other drugs that have no clear association with PCDA were not excluded. Also, cases with comorbidities that could affect respiration or circulation were excluded.
Two fetal cardiologists performed the echocardiographic examinations. Echocardiography was performed via the transabdominal route, using 2–5 Hz or 4–8 Hz transducers. Fetal echocardiography was performed by standard procedures using 2D, M-mode, pulsed Doppler, and color Doppler modes. The diagnosis of PCDA was made as follows: Constriction was defined by (1) turbulent flow in the ductus and (2) a pulsatility index < 1.9 [10], and closure was observed when no flow was detected in the ductus by color Doppler echocardiography. Following diagnosis, each patient underwent fetal monitoring and follow-up echocardiography. The follow-up plan was determined by an obstetrician. The ductus was defined as having reopened upon confirmation that the patient no longer met the above diagnostic criteria.
In our center, on principle, the diagnosis of PCDA itself or right ventricular dysfunction on fetal echocardiography (such as cardiac enlargement or severe tricuspid regurgitation) was not considered an indication for termination of pregnancy unless there were signs of fetal hydrops. Delivery timing was determined by the usual processes (biophysical profile score, fetal heart rate monitoring, maternal condition, and comorbidities). At birth, a neonatologist examined the patient, and treatment was administered according to the condition.
Statistical analysis
Continuous variables were expressed as medians (interquartile range, IQR), and nominal variables were expressed as counts and frequencies.
Associations between perinatal factors and ductal reopening and postnatal symptoms were analyzed by the Mann–Whitney U test and Fisher’s exact test. A P-value<0.05 was regarded as statistically significant. IBM SPSS Statistics for Windows, Version 25.0. (Armonk, NY, USA) and Microsoft Excel 2019 (Redmond, WA, USA) were used to perform the statistical analyses.
Results
Baseline characteristics
During the study period, 17 cases of idiopathic PCDA were diagnosed; none of the pregnant women used ductal constrictive agents, such as NSAIDs or paracetamol. Four cases with comorbidities that can cause respiratory or cardiac failure after birth (twin-to-twin transfusion syndrome, sacrococcygeal teratoma, congenital diaphragmatic hernia, and total abnormal pulmonary venous drainage, respectively) were excluded from the analysis. Thus, 13 patients were included in the analysis. The characteristics of the patients are summarized in Table 1.
Baseline characteristics of the study patients
Baseline characteristics of the study patients
Values are expressed as median (interquartile range) or n (%).
The echocardiographic findings and prenatal course of each patient are summarized in Table 2. At the time of diagnosis, the median ductal systolic flow velocity was 2.4 (2.1–2.5) m/s, the diastolic flow velocity was 0.9 (0.7–1.3) m/s, and the pulsatility index was 0.7 (0.7–1.1). These values were not obtained in cases of complete closure of the ductus arteriosus. The overall rate of ductal reopening during pregnancy was 38%. In 5 (71%) of the 7 patients diagnosed in < 37 weeks of gestation, the ductus reopened, with changes observed 7 (4–7) days after diagnosis. Only one fetus, diagnosed at 40 weeks and 6 days of gestation, was delivered by emergency cesarean section based on the PCDA diagnosis (case 13). In other cases, pregnancy was not terminated based on fetal echocardiographic findings of PCDA.
Perinatal outcomes and fetal echocardiographic results
Perinatal outcomes and fetal echocardiographic results
GW, Gestational weeks; PI, Pulsatility index; NA, Not available; NR, Not reopened (Ductal reopening was not confirmed); OT, Oxygen therapy; MV, Mechanical Ventilation. Ductal flow velocity and PI are the values at diagnosis. Apgar score is expressed as 1 minute/5 minute. Duration of closure/constriction indicates the time from diagnosis to reopening or birth, whichever is shorter.
Associations between ductal reopening during pregnancy and perinatal factors are shown in Table 3. Diagnosis earlier in gestation (p = 0.006) was associated with ductal reopening during pregnancy. Ductal diastolic flow velocity at diagnosis was lower among reopened cases but statistically insignificant (p = 0.06).
Association of prenatal factors with ductal re-opening
Values are expressed as median (interquartile range) or n (%).
The postnatal courses are summarized in Table 2. Of the 13 cases, 7 (54%) were asymptomatic, and 4 (31%) had mild cyanosis. The remaining two cases (15%) developed severe cyanosis and were diagnosed with persistent pulmonary hypertension of the newborn (cases 10 and 12).
Case 10 was referred to our hospital at 38 weeks of gestation for evaluating cardiomegaly and tricuspid regurgitation and was diagnosed with PCDA. Fetal monitoring revealed a non-reassuring fetal status, and a female infant was delivered by emergency cesarean section. The Apgar score was 4 (1 min)/6 (5 min). Due to severe cyanosis, she was intubated and admitted to the neonatal intensive care unit (NICU). Echocardiography showed closure of the ductus arteriosus and severe tricuspid regurgitation (maximal flow velocity 4.0 m/s). The patient was mechanically ventilated, and nitric oxide inhalation and epoprostenol were administered to treat pulmonary hypertension. The patient was weaned from the ventilator on the 9th day after birth, and oxygen administration was discontinued on the 12th day.
Case 12 was referred to our hospital at 40 weeks of gestation for suspected congenital heart disease and was diagnosed with PCDA. She was immediately admitted to the hospital, and a male infant was vaginally delivered one day later. The Apgar score was 7 (1 min)/8 (5 min). Due to severe cyanosis, the patient was intubated and admitted to the NICU. Echocardiography showed closure of the ductus arteriosus and severe tricuspid regurgitation (maximal flow velocity 2.9 m/s). He was mechanically ventilated, with nitric oxide inhalation, sildenafil, prostaglandin, and bosentan administration for treating pulmonary hypertension. Ventilation was discontinued on the 12th day after birth. Oxygen supplementation was discontinued on the 20th day after birth. Both patients were discharged without any sequelae.
Cyanosis was more common in complete ductal closure than in constriction (83% vs. 14%, p = 0.03). Oxygen therapy was administered to 9 patients (69%) for 5 (4-13) days. Oxygen was also administered prophylactically to patients who did not present with cyanosis. There were no fetal deaths, fetal hydrops, or neonatal deaths. The interval from diagnosis to birth and the duration of ductal constriction or closure in symptomatic and asymptomatic cases was 2 (IQR: 0-6) vs. 13 (IQR: 5-24) days, (p = 0.14), and 7 (4–7) vs. 2 (0–2) days, (p = 0.14), respectively. None of the patients born more than one day after diagnosis developed severe cyanosis.
Discussion
This study reports a case series of idiopathic PCDA in an institution that, on principle, does not determine delivery timing based on fetal echocardiographic findings. Most patients prenatally diagnosed before 37 weeks of gestation experienced reopening of the ductus within a few weeks of diagnosis. Earlier diagnosis was associated with ductal reopening. There were no fetal or neonatal deaths, but two patients (15%) developed persistent pulmonary hypertension and required intensive care.
In our study, the ductus reopened in 38% of all cases. This frequency was the same as in previous studies [2, 3], which suggests that the patient backgrounds were comparable. We also found that ductal reopening was associated with younger gestational age at diagnosis. Whether causality exists between early diagnosis and reopening is unclear because patients diagnosed at 37 weeks gestation or more are often born without confirmed reopening of the ductus. However, our results suggest that cases prenatally diagnosed before 37 weeks have an increased likelihood of ductal reopening. Also, diastolic flow velocity in the ductus tended to be lower in cases whose ductus reopened. It is known that the narrower the ductus, the higher the diastolic flow velocity [11]. Therefore, the results of this study are reasonable, as the lower the diastolic flow velocity, the higher the likelihood of ductal reopening.
In our patients, two (15%) developed persistent pulmonary hypertension, but no cases developed fetal hydrops. This frequency was comparable to previously reported case series [2, 3]. Both cases with persistent pulmonary hypertension were born within a day of referral, so the fetal management policy (no decision on the timing of delivery based on fetal echocardiography) did not cause the adverse outcome. In addition, those with a shorter period between diagnosis and delivery tended to be more symptomatic. These results support the strategy of observing pregnancy, without termination, following PCDA diagnosis.
Previous reports in the literature have shown that deteriorating right ventricular function on fetal echocardiography resulted in preterm births or cesarean sections, with concerns about fetal hydrops and fetal death [4–6]. However, the assessment of right ventricular function was inconsistent. It is unclear whether preterm births or cesarean section was necessary in these cases. It needs to be understood that preterm birth, even late preterm birth, can cause neurodevelopmental sequelae [12, 13].
There were several limitations to this study. First, the data were limited because of the small sample size and the retrospective nature of the study. However, we mitigated this by describing in detail the clinical picture. Second, we were unable to calculate cutoff values, sensitivity/specificity, or adjust for confounding factors related to ductal reopening in the analysis, which was unavoidable due to the small sample size. Third, we defined idiopathic PCDA as non-drug-induced. Although there have been reports on the possibility of developing PCDA due to specific diets, causality has not been sufficiently proven [14, 15]. Also, the definition of idiopathic PCDA is inconsistent in previous reports [2, 5]. Therefore, we considered our definition to be acceptable.
In conclusion, in idiopathic PCDA, not using fetal echocardiography findings to determine delivery timing did not adversely affect prognosis. Our management strategy might prevent unnecessary preterm births and cesarean sections. The ductus can reopen following diagnosis, especially when prenatally diagnosed before 37 weeks of gestation. In the prenatal management of idiopathic PCDA, continuing the pregnancy with careful monitoring of the fetal condition is recommended.
Disclosure statements
Financial disclosure statement
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Human research statement
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation (Ministry of Health, Labor and Welfare’s Ethical Guidelines for Life Science and Medical Research Involving Human Subjects) and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committees (Ethical committee of Kanagawa Children’s Medical Center).