Foetal circulation

The foetal pulmonary circulation is characterized by high PVR and low blood flow. Despite high pulmonary artery pressure, the lungs are perfused with less than 10% of the combined ventricular output during late gestation . Owing to high PVR in the foetus, most of the right ventricular output crosses the ductus arteriosus into the descending aorta, thereby increasing umbilical–placental flow and gas exchange.

Mechanisms that maintain high PVR in utero are incompletely understood, but include low foetal oxygen pressure (PO ₂ ) , lack of a gas–liquid interface and production of vasoconstrictor mediators such as endothelin-1 . Nitric oxide (NO) production also modulates foetal pulmonary vascular tone in response to diverse stimuli, including acute changes in haemodynamic forces . In foetal lambs, acute compression of the ductus arteriosus abruptly increases blood flow and pressure, and causes acute pulmonary vasodilation through the shear stress-induced release of NO . However, despite maintenance of constant pressure, pulmonary blood flow progressively falls and PVR increases over time . Therefore, the foetal pulmonary circulation is characterized by an ability to oppose vasodilation over time and to regulate its flow.

Pulmonary adaptation at birth

At birth, pulmonary blood flow increases dramatically, by 8–10-fold, and PVR drops immediately. Several stimuli, including drainage and absorption of foetal lung liquid, rhythmic distension of the lung, increased PO ₂ and altered production of several vasoactive products, including NO, are known to contribute to pulmonary vasodilation at birth . The effects of several birth-related stimuli, including increased blood flow or shear stress, increased PO ₂ and ventilation are partly dependent upon activation of nitric oxide synthase (NOS) .

The increase in NO production accounts for nearly 50% of the abrupt fall in PVR at birth in foetal lambs . NO mediates vasodilatation by stimulating soluble guanylate cyclase-induced cyclic guanosine monophosphate (cGMP) production . cGMP is downregulated by phosphodiesterase 5 activity. Phosphodiesterase 5, which is abundantly expressed in lung tissue, particularly during foetal life, is a key regulator of perinatal pulmonary circulation ( Fig. 2 ).

NO/cGMP pathway. NO, produced by endothelial NOS, diffuses towards the smooth muscle cell in which it stimulates soluble guanylate cyclase to produce cGMP. The mechanism whereby increased cGMP regulates pulmonary vascular tone includes activation of K+ channels, causing smooth muscle cell membrane hyperpolarization and inactivation of VOCC. Closure of VOCC causes a decrease in cytosolic Ca++ concentration and vasorelaxation. Intracellular concentration of cGMP is downregulated by PDE5 activities. Ca ⁺⁺ : calcium; cGMP: cyclic guanosine monophosphate; eNOS: endothelial nitric oxide synthase; GMP: guanosine monophosphate; K ⁺ : potassium; NO: nitric oxide; NOS: nitric oxide synthase; PDE 5: phosphodiesterase 5; SMC: smooth muscle cell; VOCC: voltage-operated calcium channels.

Maladaptation of the pulmonary circulation at birth

PPHN is a clinical syndrome that is associated with diverse neonatal cardiopulmonary diseases, including birth asphyxia, sepsis, meconium aspiration and respiratory distress syndrome, or it can be idiopathic .

The usual clinical expression of PPHN consists of an unstable refractory hypoxaemia with pre- and postductal saturation of peripheral oxygen (SpO ₂ ) gradient. Pulmonary hypertension can be associated with a systemic hypotension and symptoms of shock, termed ‘obstructive’ shock, the clinical and biological signs of which are non-specific: grey colour, tachycardia, refill capillary time more than 3 seconds, oliguria, systemic hypotension and lactic acidosis. Doppler echocardiography is required to determine the main component of the shock. Management priority is not to normalize postductal SpO ₂ , but to optimize the circulatory function. A rigorous clinical and echocardiographic assessment is required for early diagnosis of circulatory failure. More relevant than changes in postductal SpO ₂ , reflecting right-to-left ductus arteriosus shunting, the decrease in preductal SpO ₂ results from an increase in the right-to-left shunting through the foramen ovale. It occurs when the pulmonary venous return decreases (which reduces the left atrial pressure) or in case of right cardiac failure (leading to elevation of right atrial pressure). Both are markers for potential circulatory failure. In most cases, low postductal SpO ₂ alone (i.e. with normal preductal SpO ₂ ) does not cause tissue hypoxia. In contrast, a drop in preductal SpO ₂ is usually associated with symptoms of shock and an increased lactate concentration.

Experimental studies of chronic pulmonary hypertension in newborn animals have demonstrated impaired endothelial release of NO and increased production of vasoconstrictors (e.g. endothelin-1) . In normal foetal lambs, acute compression of the ductus arteriosus causes progressive pulmonary vasodilation, which is blocked by NOS inhibition, suggesting that NO mediates shear stress-induced vasodilation. After NOS inhibition, acute ductus arteriosus compression causes a marked pulmonary vasoconstrictor response, suggesting that NOS blockade unmasks a potent myogenic response in the normal foetal lung . In contrast, exposure to chronic pulmonary hypertension for 2 days impairs flow-induced vasodilation and enhances the myogenic response during acute ductus arteriosus compression in the absence of NOS inhibition . Therefore, with prolonged pulmonary hypertension during the perinatal period, pulmonary blood flow is autoregulated and independent of pulmonary artery pressure. The most striking feature of perinatal pulmonary hypertension is the loss of the normal vasodilator response to birth-related stimuli causing a paradoxical vasoconstriction to acute haemodynamic stress.

Several investigators have suggested that an increase in PDE5 activity may contribute to this phenomenon. Lung PDE5 activity increased by 150% in foetal lambs with ductus arteriosus ligation for 8 days compared to control lambs . Sildenafil attenuates the progressive elevation of basal pulmonary vascular tone observed during chronic pulmonary hypertension, and preserves, at least in part, the physiological pulmonary vascular response to vasodilators .

More recently, the role of vascular endothelial growth factor (VEGF) in foetal lung development and the pathogenesis of PPHN have been reported. VEGF is a potent endothelial cell mitogen and regulator of angiogenesis. In vivo inhibition of VEGF receptors in normal foetal sheep results in impaired vascular growth and pulmonary hypertension . Impaired alveolarization and vessel growth in chronic intrauterine pulmonary hypertension are associated with decreased VEGF protein expression .

Antenatal smoke exposure

Cotinine concentrations in cord blood – a biological marker for nicotine exposure – have been found to be higher in infants with PPHN than in healthy control newborn infants . Prenatal cigarette smoke has been found to increase the risk of PPHN among premature infants less than 30 weeks gestational age, suggesting a toxic effect on the pulmonary vascular development and maturation . Studies of lungs exposed in utero to cigarette smoke have shown marked structural and functional changes, such as decreased alveolar attachments to the airway wall and increased airways responsiveness. Endothelial dysfunction in intrapulmonary arteries has been found during exposure to tobacco smoke contributing, at least in part, to vasoconstriction and smooth muscle cell proliferation . In an experimental model of foetal lambs, we found that prenatal exposure to cigarette smoke causes a potent and sustained pulmonary vasoconstriction in the foetus, and blunts the vasodilator response to an increase in oxygen tension . These effects are associated with a marked decrease in foetal oxygenation. As the postnatal circulatory adaptation is highly dependent on the decrease in PVR and the vasodilator response to birth-related stimuli, such as oxygen, we speculate that prenatal exposure to tobacco smoke increases the risk of PPHN through failure of the pulmonary circulation to dilate at birth.

Role of stress or pain

Corticosteroids and catecholamine are the main stress hormones. Their effects on lung parenchyma maturation, lung fluid clearance and surfactant release at birth have been widely investigated. Evidence has emerged that the stress hormones promote normal circulatory adaptation at birth. Several experimental and clinical studies have shown that norepinephrine improves circulation in the perinatal lung. In foetal lambs, norepinephrine has been shown to increase lung blood flow and reduce PVR . Norepinephrine induces an NO-dependent pulmonary vasodilation in the ovine foetus through activation of α ₂ -adrenoceptors . In a large retrospective review of nearly 30,000 consecutive deliveries over 7 years, the incidence of PPHN in newborn infants delivered by elective Caesarean was almost five times higher than among those delivered vaginally . A likely hypothesis for PPHN after Caesarean is that there might be an advantage to labour and vaginal delivery for the pulmonary vascular bed of the neonate. Mechanisms explaining the increase in PPHN after Caesarean remain unclear. A surge of catecholamines, especially norepinephrine, is observed at birth. However, neonatal norepinephrine concentrations are significantly lower after Caesarean section than after vaginal delivery. Lower levels of circulating norepinephrine after Caesarean section may explain, at least in part, the high incidence of PPHN in newborn infants delivered by Caesarean section .

In contrast, evidence exists that painful stimuli impair normal adaptation at birth and promote PPHN. Hypoxaemia is usually observed during stressful intensive care procedures in newborn infants with respiratory failure, the duration of which may be reduced by opioid analgesia . In foetal lambs, nociceptive stimuli increase pulmonary artery pressure and PVR . This vasoconstrictive response is abolished by analgesia and by α ₁ -adrenoceptor blockade . These results provide new insights into the mechanisms by which stressful events may worsen hypoxaemia in newborn infants with PPHN. Nociceptive stimulation, through α ₁ -adrenoceptor activation, may elevate pulmonary vascular tone leading to increased right-to-left shunting through the ductus arteriosus and the foramen ovale and to severe hypoxaemia.

Drug exposure

Drug administration during pregnancy may increase the risk of maladaptation at birth.

The likelihood of PPHN increases after antenatal exposure to aspirin or other non-steroidal anti-inflammatory drugs . Mechanisms of antenatal non-steroidal anti-inflammatory-induced PPHN may include antenatal closure of the ductus arteriosus or decreased production of vasodilator prostaglandins. Similar risks exist after birth: ibuprofen administration has the potential to cause PPHN in preterm infants with patent ductus arteriosus .

Selective serotonin reuptake inhibitors (SSRIs), used to treat maternal depression, elevate the basal vascular tone in the foetal lung . Pulmonary vascular remodelling and right ventricular hypertrophy have been observed in rat pups after maternal exposure to fluoxetine . A case-control study to assess whether PPHN is associated with exposure to SSRIs has been conducted during late pregnancy . A total of 377 women whose infants had PPHN and 836 matched control women were enrolled in the study. Fourteen infants with PPHN had been exposed to antenatal SSRI, as compared with six control infants (adjusted odds ratio 6.1, 95% confidence interval 2.2–16.8) . These data support an association between the maternal use of SSRIs in late pregnancy and PPHN in the offspring.

In case of severe respiratory failure, early initiation of inotropic and vasoactive agents is warranted to increase cardiac output, maintain adequate blood pressure and enhance oxygen delivery to the tissue . Dopamine is the sympathomimetic amine most frequently used for septic shock in newborn infants. The ability of dopamine to raise systemic blood pressure has been clearly documented. However, dopamine has also been suggested to increase pulmonary artery pressure and pulmonary/systemic mean arterial pressure ratio in experimental models and in human . Caution should therefore be advocated in the use of dopamine in newborn infants at risk of, or with, PPHN.

Perinatal nutrition

It has been well established that maternal obesity and diabetes are associated with increased risks of maladaptation at birth . The exact mechanisms are unclear, but include perinatal asphyxia, parenchymal disease and polycythaemia. Studies have highlighted that infants with PPHN are deficient in the amino acid, L-arginine, which is required for NO synthesis . Evidence exists that differential vascular effects can be expected according to lipid intake. Indeed, dietary fish oils have beneficial effects on cardiac and vascular function, including effects on platelet/vessel wall interactions, endothelial function and inhibition of smooth muscle cell proliferation. The n3 polyunsaturated fatty acids (PUFAs) are metabolized by several enzymes, including cyclooxygenase, to produce prostaglandins (PGE ₃ , PGI ₃ ), which are known potential vasodilator mediators. In addition, n3 PUFA competes with arachidonic acid (n6 PUFA) for enzymatic conversion. This competition decreases formation of vasoactive arachidonic acid metabolites such as thromboxane A2, a potent pulmonary vasoconstrictor. Thus, some evidence suggests that n3 PUFA may be beneficial in conditions associated with pulmonary hypertension. Also, n3 PUFA induces a potent pulmonary vasodilatation in the perinatal lung . This effect is abolished by cytochrome 450 epoxygenase, but not by NOS inhibitors. Our data provide evidence for potential beneficial effects of n3 PUFA on the pulmonary circulation through production of epoxides. n3 PUFA supplementation may help to prevent maladaptation at birth, in particular in conditions with prolonged pulmonary hypertension such as CDH or pulmonary hypoplasia.

Oxygen and hyperoxia

While oxygen stimulates endothelial nitric oxide synthase (eNOS) and NO production and contributes to pulmonary adaptation at birth , high concentrations of oxygen, such as are used to treat PPHN, may produce reactive oxygen species. For instance, hydrogen peroxide (H ₂ O ₂ ) could decrease eNOS promoter activity, associated with an endothelin-1-mediated downregulation of eNOS expression . Uncoupled eNOS has been shown to increase superoxide radicals, which rapidly combine with NO to form peroxynitrite, a potent pulmonary vasoconstrictor and potential cellular toxin. Furthermore, hyperoxia may blunt NO-mediated pulmonary vasodilation through increasing phosphodiesterase 5 activity. In accordance with these studies, recombinant human superoxide dismutase enhances vasodilation after birth in experimental models of PPHN .