Paracetamol (acetaminophen or N-acetyl-p-aminophenol) is considered a safe analgesic and antipyretic nonsteroidal antiinflammatory drug commonly used during pediatric ages and during pregnancy. We report on a term neonate with closed ductus arteriosus, severe cardiomyopathy, right ventricular dysfunction, and functional stenosis of pulmonary arteries at birth after maternal self-medication with paracetamol and consumption of polyphenol-rich foods in late pregnancy. This drug, especially when associated with other vasoconstrictors (such as polyphenols), interferes with prostaglandin metabolism, which seriously accentuates the intrauterine ductus arteriosus constriction and leads to pharmacologic adverse events. We suggest maternal educational programs to avoid risky self-medications and provide training for the best diets.
Paracetamol (acetaminophen or N-acetyl-p-aminophenol) (APAP) is considered a safe analgesic and antipyretic nonsteroidal antiinflammatory drug (NSAID) commonly used during pediatric ages and pregnancy.1
APAP use during the first trimester of pregnancy has been associated with rare reports of congenital cataracts, cryptorchidism, renal failure, or limb-reduction effects.1 Recent studies hypothesize that concomitant hyperthermia does not act as a bias effect but as the real potential teratogenic factor and that instead, antipyretic treatment by APAP may decrease the risk of certain malformations.2
Recently, the potentiality of APAP as an alternative to indomethacin or ibuprofen for the treatment of persistent ductus arteriosus (DA) in the preterm newborn has been investigated.3 The sensitivity to NSAIDs increases with gestational age, DA remodeling, and development of the vascular smooth muscle layer. Cases of premature ductal closure in utero in the third trimester have been reported.4
We report on a female neonate who was born in the springtime at 38 weeks’ gestation with a systolic heart murmur and the triad of closed DA (Fig 1), severe cardiomyopathy (Fig 2), and right ventricular dysfunction (Fig 3) at birth. She also presented functional stenosis of pulmonary arteries, twofold elevated serum aspartate aminotransferase (94 U/L) and troponin (peak value on day 5: 0.25 µg/L), and mild respiratory distress syndrome characterized by high oxygen demand, all of which ameliorated spontaneously after oxygen therapy and noninvasive ventilation for 6 days. The cardiomyopathy regressed after 2 months. We excluded Tetralogy of Fallot–like, metabolic, and infectious cardiomyopathies. In an anamnestic reevaluation, the pregnancy was declared uneventful and an echocardiographic screening at 22 weeks’ gestation was normal, but the mother revealed a self-medication with 3000 mg per day of APAP for pain relief during the 4 days before undergoing a cesarean delivery. No additional pain relief or other medication was taken immediately before or during the pregnancy. However, she referenced a Mediterranean diet for obesity that is rich in polyphenols (PPs), which maintained her stable body weight during the entire gestation. For her diet, she consumed mostly cereal biscuits with cocoa beans, red oranges, and orange juice, a lot of springtime vegetables, fava beans, capers, onions, Zingiber officinale, and aromatic herbs instead of salt.
Closed DA with a slightly prominent muscle layer (indicated by the arrow) is evidenced in the two-dimensional, parasternal short-axis view. In addition, a normal aortic valve (A) and pulmonary outflow (shown in blue) can be seen.
Closed DA with a slightly prominent muscle layer (indicated by the arrow) is evidenced in the two-dimensional, parasternal short-axis view. In addition, a normal aortic valve (A) and pulmonary outflow (shown in blue) can be seen.
Hypertrophic cardiomyopathy secondary to intrauterine DA closure (IVSd = 8.3 mm, z score = 7) is shown by M-mode in the parasternal long-axis view. EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; IVSd, end-diastolic interventricular septum thickness; IVSs, end-systolic interventricular septum thickness; LVIDd, end-diastolic left ventricular internal dimension; LVIDs, end-systolic left ventricular internal dimension; LVPWd, end-diastolic left ventricular posterior wall thickness; LVPWs, end-systolic left ventricular posterior wall thickness; RVIDd, end-diastolic right ventricular internal dimension.
Hypertrophic cardiomyopathy secondary to intrauterine DA closure (IVSd = 8.3 mm, z score = 7) is shown by M-mode in the parasternal long-axis view. EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; IVSd, end-diastolic interventricular septum thickness; IVSs, end-systolic interventricular septum thickness; LVIDd, end-diastolic left ventricular internal dimension; LVIDs, end-systolic left ventricular internal dimension; LVPWd, end-diastolic left ventricular posterior wall thickness; LVPWs, end-systolic left ventricular posterior wall thickness; RVIDd, end-diastolic right ventricular internal dimension.
Tricuspid regurgitation (PG = 26 mm Hg) is measured by using a continuous-wave Doppler in the apical 4-chamber view. PG, pressure gradient.
Tricuspid regurgitation (PG = 26 mm Hg) is measured by using a continuous-wave Doppler in the apical 4-chamber view. PG, pressure gradient.
The patency of DA in utero is regulated by a number of relaxing chemical and neurohumoral factors that are in equilibrium with constricting factors. If the latter are predominant, they may generate lumen alterations, which may cause fetal and neonatal complications such as heart failure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternal administration of indomethacin or other NSAIDs interferes with prostaglandin metabolism and causes these adverse events. In rats, APAP has mild but significant and persistent transplacental cardiovascular effects such as ductal constriction (9% when compared with unexposed fetuses), right ventricular mass increase (40%), and signs of congestive cardiac failure such as pericardial effusion (50%).5 In our case, we encountered the above mentioned pathologies but even not persistent pulmonary hypertension. Recently, it was postulated that the latter can be absent if the antiinflammatory action of a substance prevails over the vasoactive effect on the pulmonary vasculature during the complex establishment of secondary neonatal pulmonary hypertension.6 At least in this regard, it underlines the synergistic and predominant antiinflammatory effect of APAP with PP.
Nowadays, events of idiopathic DA constriction and/or closure are attributed to maternal consumption of PP-rich foods in the late stages of pregnancy. The biological activity of PP is related to antiinflammatory and antioxidant effects, which interfere with prostaglandin metabolism.7,–12 Chocolate and Mediterranean fruits and vegetables are rich in (epi)catechins, (epi)gallocatechins, (pro)anthocyanins, and other flavonoids, which are even more potent than indomethacin.8,9 In our case, the synergic effect of PP with APAP probably accentuated the DA constriction that led to the pharmacologic adverse event even if the etiology may not be clearly proven in retrospect. Progressive, augmented self-medications because of economic crisis as well as the return to ethnomedical methods or phytonutrients have been observed during the past years. Despite prevalent and beneficial effects in the common population, these attitudes are not always devoid of risk in the late stages of pregnancy. Furthermore, active principles are often hidden in composed analgesic therapies or functional foods. According to the ongoing Italian Prime Minister’s campaign against abuse of drugs during pregnancy, we suggest maternal educational programs to avoid risky self-medications and train for the best diets.
Dr Schierz conceptualized and designed the report and drafted the initial manuscript; Drs Giuffrè, Piro, and La Placa conducted the differential diagnoses and critically reviewed and revised the manuscript; Prof Dr Corsello designed the data collection, coordinated and supervised the clinical performance, and critically reviewed the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
14-Mar-2018
Lewis R. First
Editor
Pediatrics
Dear Prof. First:
I would like to ask you to consider the attached manuscript entitled “Dilated Cardiomyopathy Due to Premature Ductus Arteriosus Constriction” for publication in Pediatrics as a Letter to the Editor. The paper was coauthored by Jun Muneuchi and Yuki Iwaya.
This letter discusses a previous article on hypertrophic cardiomyopathy due to premature ductus arteriosus closure by Schierz et al. We also report a similar experience we had with a patient delivered at 36 weeks and 6 days via emergency Cesarean section due to abnormal cardiotocogram and a fetal echocardiography showing dilated left ventricle and right atrium, severe tricuspid regurgitation, hypertrophic right ventricle, and a cardiothoracic area ratio of 0.58. All of these findings were consistent with premature closure/constriction of the ductus arteriosus. Following delivery, the patient received respiratory support, diuretics, and inotropic agents. His lowest ejection fraction measurement was 27% and left ventricular end diastolic volume was 27.8 mm (Z-score 4.4). At 6 months of age, the patient had fully recovered with a complete resolution of his cardiomyopathy.
We think that this case is important for the readership of your journal because it suggests that the clinical manifestations of premature closure/constriction of the ductus arteriosus are dependent upon the timing and speed of constriction of the ductus.
This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. The parents of the study participant provided informed consent for publication. We have read and understood your journal’s policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare.
Thank you for your consideration. I look forward to hearing from you.
Respectfully yours,
Seigo Okada, M.D., Ph.D.
Department of Pediatrics
Japan Community Healthcare Organization, Kyushu Hospital
1-8-1, Kishinora, Yahatanishiku, Kitakyushu, Fukuoka, 806-8501, Japan.
Tel: 81-93-641-5111
Fax: 81-93-642-1868
E-mail: sokada0901@gmail.com
Dilated Cardiomyopathy Due to Premature Ductus Arteriosus Constriction
Seigo Okada1, M.D., Ph.D, Jun Muneuchi1, M.D., Ph.D, Yuki Iwaya1, M.D.
1Department of Pediatrics, Japan Community Healthcare Organization, Kyushu Hospital, 1-8-1, Kishinuora, Yahatanishiku, Kitakyushu, Fukuoka, 806-8501, Japan
Address correspondence and reprint requests to: Seigo Okada, M.D., Ph.D.
Department of Pediatrics, Japan Community Healthcare Organization, Kyushu Hospital, 1-8-1, Kishinora, Yahatanishiku, Kitakyushu, Fukuoka, 806-8501, Japan. Tel: 81-93-641-5111; Fax: 81-93-642-1868; E-mail: sokada0901@gmail.com
Short title: DCM due to PCDA
Word count: 499
Supplemental file count: 3
Financial disclosure statement:
The authors have no financial relationships relevant to this article to disclose.
Funding source:
None.
Conflict of interest:
The authors have no conflicts of interest relevant to this article to disclose.
Abbreviations:
LVEDD: left ventricular end diastolic diameter
LVEF: left ventricular ejection fraction
NSAIDs: non-steroidal anti-inflammatory drugs
PCDA: premature closure/constriction of the ductus arteriosus
Contributors’ Statement:
Seigo Okada: Dr. Okada led conceptualization and design of the analysis, analyzed and interpreted data, and drafted the initial manuscript.
Jun Muneuchi: Dr. Muneuchi supervised data collection, reviewed the manuscript critically, and approved the final manuscript as submitted.
Yuki Iwaya: Dr. Iwaya contributed to collection of the data, reviewed the manuscript critically, and approved the final manuscript as submitted.
Sirs,
We read with great interest the article in Pediatrics on hypertrophic cardiomyopathy due to premature ductus arteriosus closure by Schierz et al.1 This article demonstrated that premature closure and /or constriction of the ductus arteriosus (PCDA) could lead to right and left ventricular dysfunction. Recently, we encountered a term newborn with dilated cardiomyopathy due to PCDA.
A 27-year-old woman, gravida 1, was referred at 36 weeks of gestation due to fetal cardiomegaly. She had neither a personal nor familial history of congenital heart disease. She had taken no non-steroidal anti-inflammatory drugs (NSAIDs) or prostaglandin inhibitors during her pregnancy. A detailed fetal echocardiography showed a cardiothoracic area ratio of 0.58, a dilated left ventricle, and a hypertrophic right ventricle (Figure S1A). The right atrium was also dilated due to severe tricuspid regurgitation with a peak systolic velocity of 3.4 m/s. There was no structural cardiac anomaly. The pulmonary valve was patent and an antegrade flow in the pulmonary trunk was observed. However, the ductus arteriosus was narrowed and color Doppler flow mapping could not identify blood flow through the ductus (Figure S1B). These findings were consistent with PCDA. On follow-up, a cardiotocogram showed non-reassuring fetal status with a sinusoidal pattern. Subsequently, a 3,050-g male neonate was born by emergent Cesarean delivery at 36 weeks and 6 days. The Apgar score was 2 at 1 minute and the patient was intubated immediately due to severe dyspnea. Neonatal echocardiography revealed a left ventricular dilated cardiomyopathy concomitant with a hypertrophic right ventricle and moderate tricuspid regurgitation. The left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were 25.1 mm (Z-score 3.4) and 62%, respectively (Figure S2A and Video S1). The ductus arteriosus was almost closed. The patient required respiratory support and inotropic agent and diuretic administration. The left ventricular function was transiently worse the day after birth. The LVEDD and LVEF were 27.8 mm (Z-score 4.4) and 27%, respectively (Figure S2B and Video S1). However, both ventricular functions gradually improved day by day. The patient was extubated on the 14th day after birth and discharged on the 47th day. Echocardiography at the time of discharge showed a persistent mild left ventricular dilatation. At 6 months of age, the cardiomyopathy had fully resolved (Figure S2C and Video S1). The possibility of metabolic and infectious cardiomyopathies were excluded by metabolic screening and viral isolation.
Mechanical constriction of the ductus arteriosus can cause an increase in fetal pulmonary blood flow, which leads to hypertrophy of the pulmonary artery smooth muscle and an increase in right ventricular afterload.2,3 Previous animal models demonstrated that PCDA could affect both the right and left ventricles.3 In fetal circulation, PCDA can increase blood flow through the foramen ovale and increase pulmonary blood flow after an increase in left ventricular preload.3 When the ductus constricts rapidly, a rapid increase in left ventricular preload may lead to left ventricular dilated cardiomyopathy. This case suggested that clinical manifestations of PCDA depend on the timing and speed of constriction of the ductus.
References
1. Schierz IAM, Giuffrè M, Piro E, La Placa S, Corsello G. A case of cardiomyopathy due to premature ductus arteriosus closure: The flip side of paracetamol. Pediatrics. 2018;141. pii: e20163850.
2. Enzensberger C, Wienhard J, Weichert J, et al. Idiopathic constriction of the fetal ductus arteriosus: three cases and review of the literature. J Ultrasound Med. 2012;31:1285-1291.
3. Momma K, Takao A. Right ventricular concentric hypertrophy and left ventricular dilatation by ductal constriction in fetal rats. Circ Res. 1989;64:1137-1146.
Figure legends
Figure S1.
Fetal echocardiographic findings during the initial visit. (A) A four-chamber view at 36 weeks and 5 days shows a dilated right atrium and left ventricle, and a hypertrophic right ventricle. The cardiothoracic ratio at that time was 0.58. (B) The narrowed ductus arteriosus (arrow heads). LA: left atrium; LV: left ventricle; PA, pulmonary artery; RA: right atrium; RV: right ventricle.
Figure S2.
Sequential echocardiographic findings after birth. Figures show 4-chamber view (upper part) and M-mode measurement of the left ventricle (lower part). (A) At birth. LVEDD and LVEF are 25.1 mm (Z-score 3.4) and 62%, respectively. (B) On the day after birth. LVEDD and LVEF are 27.8 mm (Z-score 4.4) and 27%, respectively. (C) At 6 months of age. LVEDD and LVEF are 26.8 mm (Z-score 1.3) and 75%, respectively. LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction.