Pathophysiology of Persistent Pulmonary Hypertension ofthe Newborn

Changes in Pulmonary Vascular Resistance and Pulmonary Blood Flow With Gestation

Rasanen and colleagues used direct measurements of PBF in the right and left pulmonary arteries and found that it is approximately 21% of combined ventricular output by 38 weeks in human fetuses. Phase-contrast cine-MRI in late-gestation human fetuses demonstrated that PBF is 74 ± 43 mL/kg/min or approximately 16% ± 9% of combined ventricular output. There was a 10-fold difference in PBF between subjects (2% to 30% of combined ventricular output). It is possible that PBF is dynamic and varies between different fetal subjects, at different times within the same subject, and with advancing gestation.

Doppler flow studies in human fetuses have demonstrated that flow into the left and right pulmonary arteries is 13% of combined ventricular output at 20 weeks of gestation (canalicular stage); it increases to 25% at 30 weeks (saccular stage) and decreases to 21% at 38 weeks (alveolar stage) ( Fig. 154.2 ). The fetal PVR is high during the canalicular stage secondary to the paucity of a pulmonary vascular network, leading to a reduced cross-sectional area of the immature pulmonary vascular bed. Experiments in fetal lambs have shown that the PBF does not increase in response to hyperoxia at 94 to 101 days’ gestation (term ∼147 days). At this gestation, fetal hypoxia results in very minimal change in PVR. Similarly, Rasanen and colleagues demonstrated that, between 20 and 26 weeks of gestation, maternal hyperoxygenation using 60% oxygen by face mask does not result in pulmonary vasodilation in the human fetus. These findings suggest a lack of sensitivity to oxygen and high PVR in early gestation. Interestingly, birth at this gestational age (23 to 26 weeks in humans) is associated with a much higher risk (2%) of pulmonary hypertension compared with term gestation (0.2%) ^, and high rates of clinical use of inhaled nitric oxide (iNO). In an Australia–New Zealand database of neonatal intensive care unit admissions requiring invasive ventilation, the U-shaped curve of PVR during fetal life (see Fig. 154.2 ) resembled the U-shaped curve of iNO ( Fig. 154.3 ) use: 15.4% at 24 to 25 weeks, 3.8% at 30 to 31 weeks, and 19% at 37 to 44 weeks of gestational age at birth. ^, Similar trends in iNO use were observed among preterm infants in the Ohio Perinatal Network (17.5% at 22 to 24 weeks and 3.7% at 31 to 33 weeks’ gestational age at birth) and California Perinatal Quality Care (4.9% at 22 to 24 weeks, 1.1% at 31 to 33 weeks, and 6.2% at 38 to 43 weeks). During the early saccular stage, the rapid proliferation of pulmonary vessels decreases fetal PVR; during late gestation, there is a marked increase in cross-sectional area of the pulmonary vascular bed. However, pulmonary vessels become more sensitive to vasoconstrictive mediators such as endothelin and hypoxia during this period, resulting in active pulmonary vasoconstriction (see Fig. 154.2 ) ^, and dilation in response to increased oxygen. ^, In late-gestation lambs (136 to 146 days of gestation), maternal hyperbaric hyperoxia increased pulmonary arterial P o ₂ from 19 ± 1.5 to 48 ± 9 mm Hg, leading to an increase in PBF from 34 ± 3.3 to 298 ± 35mL/kg per minute. Similarly, maternal hyperoxygenation increased PBF in late-gestation (31 to 36 weeks) human fetuses. The maternal hyperoxygenation test (administered with 60% oxygen by face mask) has been proposed to measure the ability of fetal pulmonary arteries to vasodilate in response to oxygen in late gestation and predict pulmonary vascular reactivity and survival in cases of CDH.

In fetal lambs, pulmonary vasodilation in response to endothelium-independent mediators such as NO precedes response to endothelium-dependent mediators such as acetylcholine and oxygen. Response to NO is dependent on activity of its target enzyme, soluble guanylate cyclase (sGC), in the smooth muscle cell ( Fig. 154.4 ). In the ovine fetus, sGC mRNA levels are low during early preterm (126 days) gestation and increase markedly during late preterm and early term gestation (137 days). Low levels of pulmonary arterial sGC activity during the late canalicular and early saccular stages of lung development may partly explain the poor response to iNO observed in some extremely preterm infants.

Fetal Growth Restriction and Pulmonary Blood Flow

Fetal growth restriction is associated with chronic hypoxia and reductions in umbilical venous S o ₂ and flow. Lower S o ₂ in the ascending aorta is associated with higher superior vena caval flow (“brain-sparing physiology”). In contrast, lower S o ₂ in pulmonary arteries is associated with decreased PBF. Pulmonary hypertension with bronchopulmonary dysplasia (BPD) is associated with fetal growth restriction in preterm infants and with a trend toward higher morbidity and mortality during longitudinal follow-up. In the SUPPORT trial, randomization to a lower S o ₂ target was associated with increased mortality in growth-restricted infants with RDS and BPD as leading causes. However, individual patient data meta-analysis of all the oxygen saturation trials in preterm infants did not show a similar association. Other mechanisms in addition to hypoxemia may also contribute to a higher incidence of PPHN in growth-restricted infants.

Fetal Pulmonary Vascular Resistance and Left Ventricular Filling

The shunt across the foramen ovale and PBF are the two sources of left ventricular filling during fetal life (see Fig. 154.1 ). Left ventricular preload is an important determinant of blood flow to the heart and brain and of left ventricular development. Prsa et al. found a strong inverse correlation between foramen ovale shunt and PBF in human fetuses. ^, The physiologic mechanism behind this finding is not clear. One potential explanation is that fetal PVR is very sensitive to small changes in P o ₂ . Arraut et al., working with nonhuman primate fetuses, evaluated the effect of maternal hypoxemia (by the administration of 12% oxygen) and hyperoxemia (by the administration of 100% oxygen) on the fetal right pulmonary arterial pulsatility index (PI) (PI = [peak systolic velocity − end-diastolic velocity] ÷ time-averaged maximum velocity over the cardiac cycle). An increase in right pulmonary arterial PI suggests an increase in peripheral pulmonary vasoconstriction with decreased flow. Maternal hypoxemia increased the fetal right pulmonary arterial PI fivefold, suggesting fetal pulmonary vasoconstriction. Maternal hyperoxemia decreased the right pulmonary arterial PI fourfold and also decreased blood flow through the ductus arteriosus. Maternal oxygenation status did not affect the umbilical arterial or ductus venosus PI, suggesting that umbilical flow is neither influenced by nor regulates fetal oxygenation. Similarly, Konduri et al. showed that an increase in pulmonary arterial P o ₂ of 7 mm Hg resulted in a threefold increase in PBF in fetal lambs. However, the variability of PI changes in response to maternal hyperoxygenation have limited the utility of PI as a diagnostic tool.

These studies indicate that fetal PVR is dynamic and an important regulator of the distribution of cardiac output and the relative contributions of the pulmonary circulation and foramen ovale shunt to left ventricular filling. The S o ₂ of blood in the left atrium (and left ventricle) is dependent on the relative contributions of oxygenated blood from the foramen ovale and deoxygenated blood from the pulmonary veins. The mean value is usually around 65%. During periods of hypoxemia, fetal PVR increases markedly ^, and the left ventricle is filled with better oxygenated umbilical venous blood shunted across the foramen ovale (see Fig. 154.1 ). Conversely, during maternal hyperoxemia, PBF increases and flow through the ductus arteriosus and foramen ovale decreases. ^, These changes in PVR will determine the distribution of fetal cardiac output and oxygen delivery to the brain and heart. Furthermore, reduced pulmonary venous return and left ventricular filling in fetuses with CDH may contribute to left ventricular hypoplasia, emphasizing the role of PBF during fetal life. ^,

Factors Contributing to Fetal Pulmonary Vascular Resistance

Numerous factors—such as mechanical factors (compression of the small pulmonary arterioles by the fluid-filled alveoli and a lack of rhythmic distension) and a relative lack of vasodilators— contribute to the high PVR in utero. Low oxygen tension and elevated levels of vasoconstictor mediators, such as endothelin-1 (ET-1) and thromboxane, play a crucial role in maintaining the elevated fetal PVR.

Modulation of Fetal Pulmonary Vascular Resistance

Conditions such as CDH, antenatal closure of the ductus arteriosus, and idiopathic PPHN are often associated with vascular remodeling and elevated PVR during fetal life. Studies in animal models and human populations have suggested that maternal therapy can alter fetal PVR. Two classes of medications, selective serotonin receptor inhibitors (SSRIs) and nonsteroidal antiinflammatory agents (NSAIDs), have been relatively well studied.

Serotonin infusions increase PVR in fetal lambs, ^, and exposure of pregnant rats to the SSRI fluoxetine produced pulmonary hypertension, hypoxia, and increased mortality in rat pups. ^, The use of SSRIs during the last half of pregnancy has been associated with an increased incidence of PPHN in at least three human studies. Although the mechanism by which SSRIs induce pulmonary hypertension in the newborn is not known, it is speculated that drug-induced elevation in serotonin levels results in pulmonary vasoconstriction. Some studies have questioned the association between maternal SSRI intake and PPHN. ^, Furthermore, the severity of PPHN has not been well described; a report observed no differences in right pulmonary artery Doppler PI in fetuses of mothers exposed to SSRI antidepressants. In addition, the risk appears to be more with exposure beyond 20 weeks of gestation. Alternate antidepressants, such as selective serotonin norepinephrine reuptake inhibitors (SNRIs), are not well studied, and their association with PPHN in offspring is not known at this time. At present, maternal physical and psychological well-being should be the primary factor guiding antidepressant therapy during pregnancy and the postpartum period.

Ingestion of NSAIDs such as aspirin during late gestation may be associated with closure of the fetal ductus arteriosus. Experimental ligation or constriction of the ductus arteriosus in lambs during fetal life is associated with the rapid development of pulmonary vascular remodeling and PPHN. Prostaglandins maintain ductal patency in utero and are important mediators of pulmonary vasodilation in response to ventilation at birth. Pharmacologic blockade of prostaglandin production by NSAIDs can result in PPHN. Analysis of meconium from newborn infants with PPHN revealed the presence of a NSAID in approximately half of the samples, linking antenatal NSAID exposure to PPHN. This association has been questioned, although aspirin use during late pregnancy remains a risk factor for PPHN.

Maternal medications also have the potential to correct pathologic fetal vascular development. Maternal betamethasone reduced oxidative stress and improved the relaxation response to adenosine triphosphate and NO donors in fetal lambs with PPHN induced by ductal ligation. In fetal rats with nitrofen-induced CDH, antenatal administration of sildenafil to the dam improved lung structure (decreased mean linear intercept) and reduced pulmonary hypertension (decreased right ventricle/left ventricle + septum ratio). However, the use of sildenafil during pregnancy may be associated with adverse effects on the fetus. The Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction (STRIDER), an international consortium of randomized placebo-controlled trials, explored the effects of sildenafil for treatment of fetal growth restriction in four trials. The Dutch STRIDER trial was suspended evoking significant global interest in media reports due to a signal of potential harm relating to increased PPHN and a nonsignificant trend towards an increase in neonatal death. In contrast, the UK and New Zealand/Australia STRIDER trials found no evidence of PPHN or neonatal death but did not find any beneficial effect of sildenafil therapy on fetal growth restriction. This consortium strongly recommends not to prescribe sildenafil for fetal growth restriction outside clinical trials until more data are available.

Circumstances That Result in Abnormal Vascular Transition at Birth