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

A Case of Cardiomyopathy Due to Premature Ductus Arteriosus Closure: The Flip Side of ParacetamolIngrid Anne Mandy Schierz, MD, Mario Giuffrè, MD, Ettore Piro, MD, Simona La Placa, MD, Giovanni Corsello, MD

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.‍

abstract

To cite: Schierz IAM, Giuffrè M, Piro E, et al. A Case of Cardiomyopathy Due to Premature Ductus Arteriosus Closure: The Flip Side of Paracetamol. Pediatrics. 2018;141(1):e20163850

Neonatal ICU, Azienda Ospedaliera Universitaria Policlinico “Paolo Giaccone, ” Department of Sciences for Health Promotion and Mother and Child Care “Giuseppe D’Alessandro, ” University of Palermo, Palermo, Italy

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.

DOI: https:// doi. org/ 10. 1542/ peds. 2016- 3850

Accepted for publication Mar 24, 2017

Address correspondence to Ingrid Anne Mandy Schierz, MD, Neonatal ICU, AOUP “P. Giaccone, ” Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro, ” University of Palermo, via Alfonso Giordano 3, I-90127 Palermo, Italy. E-mail: inschier@tin.it

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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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.‍

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

SCHIERz et al2

FIGURE 1Closed 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.

FIGURE 2Hypertrophic 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.

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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.‍

REFERENCES

1. Agenzia Italiana del Farmaco. N02BE – Anilidi. In: Farmaci e gravidanza. Roma, Italy: AIFA; 2004:514–516

2. Feldkamp ML, Meyer RE, Krikov S, Botto LD. Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study. Obstet Gynecol. 2010;115(1):109–115

3. Terrin G, Conte F, Oncel MY, et al. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2016;101(2):F127–F136

4. Simbi KA, Secchieri S, Rinaldo M, Demi M, zanardo V. In utero ductal

closure following near-term maternal self-medication with nimesulide and acetaminophen. J Obstet Gynaecol. 2002;22(4):440–441

5. Momma K, Takao A. Transplacental cardiovascular effects of four popular analgesics in rats. Am J Obstet Gynecol. 1990;162(5):1304–1310

6. Van Marter LJ, Hernandez-Diaz S, Werler MM, Louik C, Mitchell AA. Nonsteroidal antiinflammatory drugs in late pregnancy and persistent pulmonary hypertension of the newborn. Pediatrics. 2013;131(1):79–87

7. Sridharan S, Archer N, Manning N. Premature constriction of the fetal ductus arteriosus following the maternal consumption of camomile herbal tea. Ultrasound Obstet Gynecol. 2009;34(3):358–359

8. zielinsky P, Piccoli AL Jr, Manica JL, et al. Maternal consumption of polyphenol-rich foods in late pregnancy and fetal ductus arteriosus flow dynamics. J Perinatol. 2010;30(1):17–21

9. zielinsky P, Busato S. Prenatal effects of maternal consumption of polyphenol-rich foods in late pregnancy upon fetal ductus arteriosus. Birth Defects Res C Embryo Today. 2013;99(4):256–274

10. Kapadia V, Embers D, Wells E, Lemler M, Rosenfeld CR. Prenatal closure of the ductus arteriosus and maternal ingestion of anthocyanins. J Perinatol. 2010;30(4):291–294

11. Tanaka M, Miyakoshi K, Yamada M, Kadohira I, Minegishi K, Yoshimura Y. Functional foods for the fetus? Acta Obstet Gynecol Scand. 2011;90(10):1172–1173

12. 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(8):1285–1291

PEDIATRICS Volume 141, number 1, January 2018 3

AbbREvIATIONS

APAP:  paracetamolDA:  ductus arteriosusNSAID:  nonsteroidal antiinflam-

matory drugPP:  polyphenols

FIGURE 3Tricuspid regurgitation (PG = 26 mm Hg) is measured by using a continuous-wave Doppler in the apical 4-chamber view. PG, pressure gradient.

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DOI: 10.1542/peds.2016-3850 originally published online January 17, 2018; 2018;141;Pediatrics 

Giovanni CorselloIngrid Anne Mandy Schierz, Mario Giuffrè, Ettore Piro, Simona La Placa and

Flip Side of ParacetamolA Case of Cardiomyopathy Due to Premature Ductus Arteriosus Closure: The

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