Foetal ductus arteriosus constriction unrelated to non-steroidal anti-Inflammatory drugs: a case report and literature review

Abstract Foetal ductus arteriosus (DA) constriction can be found in complex foetal heart malformations, but rarely as an isolated defect. Although many cases of DA constriction are usually related to Non-steroidal Anti-Inflammatory Drugs (NSAIDs) maternal intake, other causes remain without an established aetiology and are referred to as idiopathic. Recently, a wide range of risks factors or substances (polyphenol-rich foods intake, naphazoline, fluoxetine, caffeine and pesticides) showed a definitive effect upon the pathway of inflammation, causing DA constriction. We report a case of a premature DA constriction in a woman whose possible risk factor was identified in her maternal occupational exposure to solvents and a comprehensive literature review of 176 cases of NSAID-unrelated DA constriction. A 30-year-old Asian woman was referred to our institution at 33 gestational weeks and 0 days because of suspicion of premature DA constriction. The woman had no history of medication intake, including NSAIDs, alcohol, tobacco or polyphenol-rich-food consumption during pregnancy. A detailed foetal echocardiography revealed a normal cardiac anatomy with hypertrophic, hypokinetic and a dilated right ventricle due to right pressure overload, holosystolic tricuspid regurgitation, and, at the level of the DA, high systolic and diastolic velocities, indicating premature ductal restriction. The right outflow showed dilatation of the pulmonary artery with narrow DA. An urgent caesarean section was performed at 33 gestational weeks and 4 days due to worsening of DA PI and signs of right pressure overload, despite the interruption of exposure to solvents. We assume a relationship exists between premature DA constriction and a maternal occupational exposure to solvents. This hypothesis is reinforced by the presence of associated foetal malformations in in two of the patient’s children. Further research is needed to confirm the role of exposure to solvents and toxic chemicals in the pathogenesis of DA constriction, also with experimental animal models. KEY MESSAGES Many cases of DA constriction are usually related to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) maternal intake. A wide range of risks factors or substances (polyphenol-rich foods intake, naphazoline, fluoxetine, caffeine and pesticides) can cause foetal DA constriction. Further investigation are needed to confirm the role of maternal exposure to solvents in the pathogenesis of DA constriction.

to postnatal closure [6]. This histological maturation process starts at the second trimester and consists of the thickening of muscular layer [7].
Premature intra-uterine DA constriction could be diagnosed in complex congenital heart malformations, including Tetralogy of Fallot and truncus arteriosus. As an isolated defect, it is usually secondary to the use of medication like NSAIDs, isoxsuprine, fluoxetine and some foods rich in polyphenol like herbal teas, dark chocolate, orange juice, red/purple grapes, berries and coffee [8][9][10][11][12].
The mechanism of NSAID action is inhibition of prostaglandin production by direct constriction of the enzyme cyclooxygenase (COX). Production of prostaglandins is dependent on two enzymes which act in different states, cyclo-oxygenase-1 (COX-1), expressed endogenously, and cyclo-oxygenase-2 (COX-2), locally induced during the inflammatory processes [13]. Both animal and human studies have demonstrated constriction of the ductus after administration of prostaglandin synthetase inhibitors. This effect was not shown to depend on foetal serum concentration of the drug [14,15]. In recent years, also the antiinflammatory and antioxidant effects of foods rich in polyphenol have been demonstrated [16]; these effects are secondary to inhibition of the metabolic route of prostaglandins, especially of COX-2, preventing the transformation of arachidonic acid into prostaglandin [9]. Other possible risk factors could be the exposure to solvents or chemicals, but more case confirmations are required [17][18]. Idiopathic premature ductal constriction is considered a rare event.
We describe the case of a premature DA constriction in a woman whose possible risk factor was identified in her maternal occupational exposure to solvents. Moreover, we report, for the first time, a literature review on all cases of DA constriction unrelated to NSAID or congenital heart defects, to investigate the role of others risk factors.

Case presentation
A 30-year-old Asian woman was referred to our institution at 33 gestational weeks and 0 days because of a suspicion of premature DA constriction on a routine third trimester ultrasound. The patient signed a standard written informed consent form for the use of data, pictures, and videos used for teaching and research purposes. This was the third pregnancy. The first newborn was affected by a lip and palate cleft, while the second one was healthy. The current pregnancy had no complications. The woman had no history of medication intake, including NSAIDs, alcohol, tobacco or polyphenol-rich-food consumption during pregnancy. In particular, in order to quantify the polyphenol ingestion, a food frequency questionnaire for consumption of polyphenol-rich foods in pregnant women was performed [19][20]. The total dietary amount of flavonoids was calculated from the USDA Database for the Flavonoid Content of Selected Foods [21], considering the 27 items with higher concentrations of polyphenols higher than 30 mg/100 g of food (green and black tea, mate tea, grape derivatives, dark chocolate, orange juice, fruit teas, olive oil, soy beans, berries, tomato, apples, spinach, and others) as reported by Zielinsky et al. [22]. On the other hand, her occupational exposure to solvents and toxic chemicals, as a hairdresser, (especially cosmetic products) resulted from the maternal and paternal history. A detailed foetal echocardiography revealed a normal cardiac anatomy with hypertrophic, hypokinetic and dilated right ventricle due to right pressure overload. The effects of premature DA constriction (mild pericardial effusion and a dilated and poorly functioning right ventricle) can be seen in Figure 1. The colour and pulsed Doppler interrogation showed holosystolic tricuspid regurgitation (130 cm/s) (Figure 1(B)) with jet that reached the roof of the atrium and at the level of the DA showed high systolic (200 cm/s) and diastolic (80 cm/s) velocities with a reduction in the pulsatility index (PI) (0.8), indicating premature ductal restriction. The right outflow showed dilatation of the pulmonary artery with narrow DA (Figure 2(B)). After the administration of corticosteroids, an urgent caesarean section was performed at 33 gestational weeks and 4 days due to worsening of DA PI and signs of right pressure overload, despite the interruption of exposure to solvents. A 2250 g-male neonate born with Apgar score of 5 and 9 at 1 and 5 min respectively. Post-natal echocardiography revealed an anatomically normal heart with progressive improvement of hypertrophy and right ventricular dilatation.
The newborn was treated immediately after birth with PGE infusion with the aim of reducing the pressure overload of the right ventricle and pulmonary hypertension. This use of prostaglandins is off-label, but free from major side effects. Due to poor response to PGE treatment, it was stopped after 18 h, and therapy with inotropic agents (dopamine) and nitric oxide was initiated to reduce the pulmonary pressure. Closure of DA took place 30 h after birth. Collaterally, congenital cataract was found. Normal human karyotype was found in the newborn.

Methods: comprehensive review of the literature
The electronic medical database Medline/PubMed was used for research, combining the following terms: foetal ductus arteriosus constriction (472 articles). Titles and abstracts of these articles were screened for relevance by authors to determine which articles were to undergo full-text review (human cases of prenatal DA constriction/closure no NSAIDs or CHD induced). Animal cases of prenatal ductus arteriosus constriction, cases of NSAID related DA constriction, or related to heart defects were excluded ( Figure 3). Articles identified at this stage as potentially relevant moved into full text review ( Figure 3). The bibliographies of included studies were reviewed to identify additional publications not found through the database search.

Results
To date, 176 cases of NSAID-unrelated (and congenital hearth defects-unrelated, CHD) premature DA constriction have been reported in the English language literature (from 1946 to 2020).
Including the present report, there are 177 cases of NSAID-unrelated (and not related to hearth disease) [4,8, (Table 1). Figure 4 report the distribution of etiopathogenesis of human cases in literature no NSAIDs or CHD induced; of the 177 cases found 96 were idiopathic (54.2%), 58 were related to polyphenol rich-food, 5 to paracetamol, 4 were related to genetic arteriopathy (Alagille and Williams Syndrome), 4 cases were related to sympatomimetics drugs, 4 to corticosteroids, 4 to miscellaneous causes, 1 to SSRI consumption and 1 case to lithium consumption. In the literature, many cases are considered as idiopathic, but no one reported about maternal employment. However, it would be important to investigate whether there is a common pathogenetic mechanism form in many cases, such as occupational exposure to solvents or intake of paracetamol (acetaminophen), a drug considered safe in pregnancy. In particular, a repeated dose intake, especially in the third trimester of pregnancy, can have a vasoconstrictive effect [55].

Discussion
Patient history was accurately reviewed to identify a possible causative agent. The woman had no chronic illness and was not a smoker. The foetus's heart had no congenital defects. We asked about medications (especially NSAIDs) and polyphenol-rich foods intake. The mother denied the consumption of any kind of medicine, herbal tea, grapes or other polyphenol-rich food during pregnancy. A dietary intervention for maternal restriction of polyphenol-rich foods or suspension of NSAIDs consumption in the third trimester of pregnancy is accompanied by increase in plasma levels of PGE2 and reversal of foetal ductal constriction [10,27,39,56,57].
In the absence of the most common aetiologies, the occupational exposure to solvents or an idiopathic premature constriction of DA was suggested. The  occupation of both parents as hairdressers, which involved the daily use of organic solvents, could be suspected. Widely discussed in the literature is the association between maternal occupational exposure to solvents (as in hairdressing and cosmetology) and an increased risk of adverse obstetrics outcomes, such as spontaneous abortion, preterm birth, small for gestational age (SGA), low birth weight (LBW) and congenital malformations (especially cleft lip and palate, urinary malformations, hypospadias and eye diseases) [17,18,[58][59][60][61][62]. Our case could underline this association. The mother did not stop working before and during pregnancy and the foetus had not only the premature DA constriction but also congenital cataract, without any other risk factors. In addition, the first child was affected by lip and palate cleft.
Hairdressers are predominantly women, and many of them are of childbearing age. Hairdressers work in a complex environment where they are in daily contact with various chemical substances which can be found in hair care product used for washing, dyeing, bleaching, spraying and perming. Their main routes of exposure are dermal and respiratory. Several solvents have been shown to be teratogenic for animals. In mice, for example, toluene and xylene (petroleum solvents) have been associated with the occurrence of cleft palate [18], and ethylene glycol monomethyl ether has been associated with the occurrence of neural tube defects [62], while in zebrafish, p-phenylenediamine, often included in hair dye, it can cause  cardiovascular defects [63]. Also aromatic amines and aldehydes could have a role in COX2 inhibition that determine congenital heart defects [64]. In humans, malformations and cytogenetic effects have been observed among the offspring of women exposed to glycol ethers during pregnancy [65]. Some studies [66][67][68][69], but not others [70], report an excess risk of spontaneous abortion among women occupationally exposed to solvents. A small prospective cohort [71], and a meta-analysis [72], performed by the same research group both report associations between maternal occupational exposure to solvents and major malformations. Two occupational cohort studies of women working in laboratories suggest similar results [73][74]. Various case-control studies have shown relations between maternal occupational exposure to solvents and some subtypes of malformations, mostly oral clefts [75][76][77]. Some significant associations have also been reported between maternal exposure to solvents and cardiac malformations [75,78], visual impairment [17] and neural tube defects [75,79].

Conclusion
Premature constriction of DA is a rare event and in most cases is secondary to maternal intake of NSAIDs or foods rich in polyphenols. For the first time, the present review reported all cases of DA constriction not related to NSAIDs intake or to CHD. The gynaecologist must take into account that there are not only forms of DA constriction secondary to the intake of NSAIDs. We assume a relationship between premature DA constriction and a maternal occupational exposure to solvents. This association between a maternal occupational exposure to solvents and an increased risk of adverse obstetrics outcomes has been widely discussed in the literature. In our case report and in the previous newborns this hypothesis is reinforced by the presence of other associated foetal malformations. It is therefore important to carry out through an occupational history and inform the patient about the potential risks associated with the exposure to solvents and toxic chemicals. Further investigation is needed to confirm their role in the pathogenesis of DA constriction, as in experimental animal models, such as those already performed in pregnant rats and sheep with polyphenols. A randomized clinical trial is needed to analyse the role of solvents in inducing this condition would be desirable, respecting the ethical aspects of the research.

Disclosure statement
No potential conflict of interest was reported by the author(s).