The discovery of prostaglandins and their effect on ductal patency

In 1935, Swedish physiologist and Nobel Prize laureate Ulf von Euler and British physiologist M. W. Goldblatt identified hormone-like compounds in seminal fluid capable of inducing uterine smooth muscle contraction. ^{Reference Euler1,Reference Goldblatt2} Suspected to arise from the prostate gland, “prostaglandins” became the focus of robust investigation for decades to follow. Though Ragnar Eliasson clarified seminal vesicles as the primary source of prostaglandins in seminal fluid in 1959, ^{Reference Eliasson6} the name stuck, and researchers isolated prostaglandins throughout the body, including the central nervous system, gastrointestinal system, cardiovascular system, and the placenta. In 1969, American chemist and Nobel Prize laureate Elias Corey achieved the first total synthesis of prostaglandins. ^{Reference Corey, Vlattas and Harding7} In the 1960s and 1970s, Sune Bergström and Bengt Samuelsson of Sweden described prostaglandins’ chemical structure, formation, and metabolism and would ultimately share the 1982 Nobel Prize in Physiology with British pharmacologist John Vane who, in 1971, illuminated aspirin’s inhibition of prostaglandin synthesis via cyclooxygenase blockade as the mechanism for its anti-inflammatory properties. ^{Reference Vane8} Flavio Coceani’s work in 1973 demonstrated the marked responsiveness of anoxic ductal arteriosus tissue to prostaglandins, ^{Reference Coceani and Olley9} highlighting their role as a primary regulator of ductal patency. Harnessing prostaglandins’ capacity for maintaining ductal patency in CHD would immediately and profoundly decrease pre-operative morbidity and mortality, ^{Reference Olley, Coceani and Bodach10–Reference Leoni, Huhta and Douglas13} transforming and broadening the therapeutic landscape across previously fatal conditions.

Ductus arteriosus development and physiology

During normal cardiovascular development, the ductus arteriosus arises from the distal sixth embryonic aortic arch, connecting the main pulmonary artery and the descending aorta distal to the subclavian artery. ^{Reference Schneider and Moore14} During fetal life, the ductus arteriosus diverts blood flow from the main pulmonary artery to the aorta due to high pulmonary vascular resistance and relatively low systemic vascular resistance. Placental-derived prostaglandins and low arterial oxygen content together maintain ductal patency via intracellular signalling pathways that culminate in reduced intracellular calcium, smooth muscle cell relaxation, and resultant vasodilatation. ^{Reference Backes, Hill and Shelton5} Circulating prostaglandins typically undergo metabolism in the lungs, but due to low pulmonary blood flow in the fetal circulation, clearance of prostaglandins is diminished.

After birth, the onset of respiration leads to an increase in alveolar oxygen concentration and a steep decline in pulmonary vascular resistance. Increased pulmonary blood flow leads to enhanced prostaglandin metabolism. Simultaneously, the umbilical cord is clamped, separating the baby from the placenta, resulting in a rise in systemic vascular resistance and a fall in prostaglandin concentration. Together, these molecular and haemodynamic changes increase intracellular calcium levels within the ductus arteriosus, initiating the process of constriction and ultimately closure by several days of life. ^{Reference Backes, Hill and Shelton5}

Prostaglandins’ life-saving impact on critical CHD

Categories of critical CHDs, characterised by “ductal-dependence,” are shown in Table 1.

Table 1. Ductal-dependent, critical CHDs, by category

Ductal-dependent pulmonary blood flow

In the late 1960s and early 1970s, despite years of progress in developing palliative systemic-to-pulmonary shunts for cyanotic, right-heart obstructive lesions, such as tetralogy of Fallot, critical pulmonary stenosis, and pulmonary atresia (with or without a ventricular septal defect), mortality rates of surgically palliated infants remained high at 30–56%. ^{Reference Olley, Coceani and Bodach10,Reference Miller, Nadas and Bernhard11} Furthermore, surgical shunt operations performed in moribund infants carried a high risk for comorbidities, including cerebrovascular accidents, congestive heart failure, and distortion of the pulmonary arteries. In 1976, Olley and colleagues evaluated prostaglandin administration for so-called “ductal-dependent pulmonary blood flow” (Figure 1( a )). ^{Reference Olley, Coceani and Bodach10} Providing prostaglandins immediately after birth prevented ductal closure and preserved left-to-right blood flow across the ductus arteriosus, deferring the need for an emergent surgical shunt or high-risk attempt at complete repair in an unstable patient. In the era immediately following the introduction of prostaglandins, survival of infants undergoing surgical shunt palliation improved to 90%. ^{Reference Al Jubair, Al Fagih and Al Jarallah12} Combined with enhanced perioperative care, the authors attributed much success to pre-operative stability afforded by prostaglandins. A 2023 Swedish registry analysis of patients with tetralogy of Fallot reported increased overall survival from 69 to 96% from the 1970s to the 2010s. ^{Reference Persson, Gyllencreutz Castellheim and Dellborg15} Over this same time interval, surgeries performed during childhood increased from 72 to 92%, and among those who underwent surgery, the mortality rate decreased from 27 to 2%. ^{Reference Persson, Gyllencreutz Castellheim and Dellborg15}

Figure 1. ( a ) Pulmonary atresia with intact ventricular septum and ductal-dependent pulmonary blood flow, in which blood flows left-to-right across the ductus arteriosus from the aorta to the main pulmonary artery to maintain pulmonary blood flow and oxygenation. ( b ) Hypoplastic left heart syndrome with ductal-dependent systemic blood flow, in which blood flows right-to-left across the ductus arteriosus from the pulmonary artery to the aorta to supply blood to the lower half of the body. In aortic atresia, the ductus arteriosus also supplies the coronary and cerebral arteries. ( c ) Complete transposition of the great arteries with ductal-dependent mixing, in which increased pulmonary blood flow promotes atrial mixing of deoxygenated and oxygenated blood. Materials developed by the CDC are available in the public domain.

Other indications for prostaglandin administration

Limitations of prostaglandin administration

Although prostaglandin therapy revolutionised congenital cardiac medicine, it is essential to be aware of its risks and limitations. Because observational studies conclusively support prostaglandins as the standard of care for ductal-dependent heart disease, randomised controlled trials to evaluate their safety and efficacy have never been performed and are unlikely to be performed in the future. ^{Reference Akkinapally, Hundalani and Kulkarni43} Continuous infusion requires intravenous access and mandates hospitalisation in an ICU, potentially for weeks to months before the ideal time of an operation, which contributes to significant cost and resource utilisation. Common short-term adverse effects of prostaglandin infusion include fever, apnoea, hypotension, and diarrhoea. ^{Reference Lewis, Freed, Heymann, Roehl and Kensey44} Studies have reported patients receiving prostaglandins longer than five days can develop cortical hyperostosis, ^{Reference Estes, Nowicki and Bishop45} gastric outlet obstruction, ^{Reference Babyn, Peled, Manson, Dagan, Silver and Koren46} and intimal mucosal damage. ^{Reference Calder, Kirker, Neutze and Starling47} Side effects related to prostaglandins are dose-dependent. Thus, giving the lowest effective dose is recommended, typically 0.005–0.01 micrograms/kilogram/minute (mcg/kg/min). ^{Reference Huang, Lin and Huang48–Reference Ono, Yamada and Arakaki51} Sometimes, however, high-dose prostaglandin infusion (0.02–0.1 mcg/kg/min) is necessary to “spring” open a ductus arteriosus that appears to be closing clinically or echocardiographically, compromising either systemic or pulmonary blood flow. All of these factors must be carefully weighed to mitigate risk yet optimise clinical stability prior to intervention.

Finally, the availability of prostaglandin infusion may be limited in different healthcare settings, internationally and nationally, related to access and cost. For example, while prostaglandins became broadly used in the Western world in the 1970s, it was not until 1995 that they became commercially available in India, ^{Reference Sharma, Sasikumar, Karloopia and Shahi52} and parts of the world still do not have access to this critical medication. ^{Reference Saadia, Zaland, Muhammad Saad and Imran53} In healthcare settings which do not have access to intravenous prostaglandins, oral formulations can serve as effective alternatives, though given concerns about bioavailability and absorption of oral formulations and the life-threatening nature of ductal-dependent heart disease, intravenous infusion remains the preferred means of administration. ^{Reference Saadia, Zaland, Muhammad Saad and Imran53}

Prostaglandin inhibition for treatment of an isolated, haemodynamically significant patent ductus arteriosus

An isolated ductus arteriosus may fail to close after birth and remain “patent,” most commonly in preterm infants due to immature oxygen-sensing mechanisms, fewer mature contractile smooth muscle cells, and other biomechanical and environmental factors. ^{Reference Backes, Hill and Shelton5,Reference Waleh, Reese and Kajino54} After the expected fall in pulmonary vascular resistance and rise in systemic vascular resistance, patients exhibit a continuous left-to-right shunt across the patent ductus arteriosus, resulting in excessive pulmonary blood flow at the expense of adequate systemic blood flow. Haemodynamically significant shunting manifests clinically with signs of congestive heart failure, including tachypnoea, poor feeding, and poor growth, and echocardiographically with left heart dilation and hypertension, unrestrictive transductal flow, and diastolic flow reversal in the descending aorta (Figure 2). ^{Reference Backes, Hill and Shelton5} Long-standing, substantial left-to-right shunting can cause severe morbidity and mortality in preterm neonates related to pulmonary over-circulation and systemic steal and lead to irreversible pulmonary vascular disease in older children and adults. Conservative management is reasonable for a small patent ductus arteriosus, allowing time for spontaneous closure. ^{Reference Backes, Hill and Shelton5} First-line treatment of a haemodynamically significant patent ductus arteriosus in preterm infants and term neonates is medical with acetaminophen or non-steroidal anti-inflammatory drugs, which inhibit prostaglandin synthesis and facilitate ductal closure. ^{Reference Backes, Hill and Shelton5} Non-steroidal anti-inflammatory drugs-induced ductal closure can contribute to significant clinical improvement with a reduction in oxygen requirement and mean airway pressure on the ventilator. ^{Reference Jacob, Gluck and Disessa55} In infants for whom medical closure is unsuccessful and in older children and adults with haemodynamically significant patent ductus arteriosus, transcatheter closure or surgical ligation is recommended. ^{Reference Mosalli and Alfaleh56,Reference Mitra, de Boode, Weisz and Shah57}

Figure 2. Echocardiographic images obtained in a patient with a large patent ductus arteriosus with the ductus seen from a suprasternal plane by ( a ) two-dimensional imaging (MPA = main pulmonary artery; LPA = left pulmonary artery; DA = ductus arteriosus; and Ao=aorta) and ( b ) colour Doppler imaging with left-to-right shunting (red flow) seen through the patent ductus arteriosus from the aorta to the MPA and antegrade flow (in blue) through the LPA and aorta. ( c ) Continuous wave Doppler image of the patent ductus arteriosus demonstrating continuous left-to-right shunting and a peak velocity of approximately 1.5 m/s, consistent with unrestricted flow. ( d ) Apical four-chamber, two-dimensional image demonstrating left atrial (LA) and left ventricular (LV) dilation, consistent with a haemodynamically significant patent ductus arteriosus (RA = right atrium and RV = right ventricle).

Summary

Ninety years after their “seminal” discovery, prostaglandins play an essential role in CHD management. Leveraging prostaglandin infusion after birth mitigates the onset of cyanosis, renal failure, and cardiogenic shock, allows time for surgical planning and coordination, and avoids morbidities associated with suboptimal palliative strategies or timing. Conversely, inhibiting prostaglandin production with non-steroidal anti-inflammatory drugs in preterm infants can close an isolated, haemodynamically significant patent ductus arteriosus. Without the aforementioned researchers’ investigations into prostaglandins and their effect on ductus arteriosus patency, countless advances in paediatric cardiology and cardiothoracic surgery would have never been conceivable, and critical CHD would have largely remained a death sentence. The legacy of investigation into these small molecules will be remembered for its profound, enduring impact on the lives of countless children.