The fetus to newborn transition is a complex physiologic process that requires close monitoring. Approximately 10% of all newborns require some support in facilitating a successful transition after delivery. Clinicians should be aware of the physiologic processes and pay close regard to the newborn’s cardiopulmonary transition at birth to provide appropriate treatment and therapies as required. Trained Personnel in the Neonatal Resuscitation program should be available at the delivery for all newborns to ensure that immediate and appropriate care is provided to achieve the best possible outcomes for those babies not smoothly transitioning to extrauterine life.
Key points
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The fetus to newborn transition is complex and depends on several factors, including maternal health and chronic medical conditions, the status of the placenta, gestational duration, presence of fetal anomalies, and delivery room care.
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Although the vast majority of infants do well, approximately 10% require intervention to facilitate the transition from fetus to newborn.
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Clinicians caring for newborns should be well-versed in the recommendations of the Neonatal Resuscitation Program.
Introduction
The adaptation from the intrauterine to extrauterine environment is complex and likely among the most remarkable and difficult physiologic transitions known, all the more noteworthy because it is also a normal and required process for our species. Although all systems of the human body undergo extensive changes, the initial and most crucial adaptations occur in the pulmonary and cardiovascular systems ( Box 1 ). Clinicians who take care of newborns during this transition must be prepared to help neonates having difficulty during this changeover. Maternal medical and fetal conditions can have a profound effect on a successful transition. Understanding how these issues affect a neonate’s ability to adapt ex utero are essential for informing a clinician’s ability to shepherd a newborn through this process. Up to 10% of newborns require some clinical intervention during birth, and approximately 1% require more extensive resuscitation. It is imperative that clinicians be prepared to provide needed interventions and understand why some neonates have difficulty transitioning.
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Fetal lung fluid resorption
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Expansion of lungs and establishment of functional residual capacity
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Increased systemic vascular resistance
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Decreased pulmonary vascular resistance and increased pulmonary blood flow
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Closure of right to left shunts
Introduction
The adaptation from the intrauterine to extrauterine environment is complex and likely among the most remarkable and difficult physiologic transitions known, all the more noteworthy because it is also a normal and required process for our species. Although all systems of the human body undergo extensive changes, the initial and most crucial adaptations occur in the pulmonary and cardiovascular systems ( Box 1 ). Clinicians who take care of newborns during this transition must be prepared to help neonates having difficulty during this changeover. Maternal medical and fetal conditions can have a profound effect on a successful transition. Understanding how these issues affect a neonate’s ability to adapt ex utero are essential for informing a clinician’s ability to shepherd a newborn through this process. Up to 10% of newborns require some clinical intervention during birth, and approximately 1% require more extensive resuscitation. It is imperative that clinicians be prepared to provide needed interventions and understand why some neonates have difficulty transitioning.
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Fetal lung fluid resorption
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Expansion of lungs and establishment of functional residual capacity
- •
Increased systemic vascular resistance
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Decreased pulmonary vascular resistance and increased pulmonary blood flow
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Closure of right to left shunts
Fetus to newborn transition physiology
The fetus to newborn physiologic transition begins in utero. This transition depends on several factors, including maternal health and chronic medical conditions, the status of the placenta, gestational duration, and the presence of fetal anomalies. The physiology of this transition is complex and requires an understanding of the cardiovascular and pulmonary systems in utero and ex utero.
Fetal Cardiopulmonary Physiology
In utero, the fetus depends on the placenta for all gas exchange and nutrient delivery from the maternal circulation. The placenta has low vascular resistance and receives approximately 40% of fetal cardiac output. Because the fetal lungs are not required for gas exchange, only approximately 10% of cardiac output passes through the pulmonary circulation. Blood flows through the umbilical artery to the placenta, where it is oxygenated and then delivered back to the fetus through the umbilical vein with an oxygen saturation of approximately 80% (PaO 2 30–35 mmHg). Blood in the umbilical vein is mixed with portal venous blood from the fetus, and reaches the right atrium via the inferior vena cava with an oxygen saturation of about 67%. Owing to the dynamics of blood flow and the anatomic location of the foramen ovale, this relatively well-oxygenated blood is preferentially shunted across the foramen into the left atrium and subsequently pumped from the left ventricle into the aorta. This fetal shunt allows for the favored delivery of more highly oxygenated blood to the brain (carotid arteries) and heart (coronary arteries). Similarly, blood returning to the heart via the superior vena cava is directed to the right ventricle, where it is pumped into the pulmonary artery. Owing to relative fetal hypoxia, the pulmonary arteries are vasoconstricted, resulting in high pulmonary vascular resistance. Secondary to this high resistance and the low systemic resistance (secondary to the placenta), the majority of red blood cells traverse the ductus arteriosus to the descending aorta where they are delivered to the placenta for reoxygenation.
Fetal lung growth and maturation revolve around fetal lung fluid. This fluid is detected as early as the first trimester, although secretion depends on gestational age until its significantly reduced production before labor. The active transport of chloride has been elucidated as the mechanism of fetal lung fluid secretion. Owing in part to closed vocal cords, the secretion of fetal lung fluid results in increased bronchoalveolar intraluminal pressure, allowing developing lung airway structures to stay open while also contributing to elevated pulmonary vascular resistance.
Fetus to Newborn Cardiovascular and Pulmonary Changes
Many textbooks promote the incorrect belief that the fetus to newborn transition begins when the umbilical cord is clamped or cut; however, transition is initiated before the onset of labor. The successful transition begins with fetal lung fluid clearance. Cortisol production, which plays a role in multiple organ systems preparing the fetus for transition to ex utero, increases dramatically at the end of the third trimester as the fetal adrenal gland matures. One mechanism by which cortisol prepares the fetus is via its effect on pulmonary maturation. Surfactant production increases, which allows for a reduction in alveolar surface tension while maintaining alveolar expansion. Cortisol likewise increases β-adrenergic receptors within the lung and increases the transcription of genes that produce epithelial sodium channels. Epithelial sodium channels transform the lung from a chloride-secreting organ into one that reabsorbs sodium, thereby pulling fetal lung fluid out of the alveolar air spaces and into the interstitium and intravascular spaces. Studies in sheep have demonstrated that this transition begins before the onset of labor, but then significantly increases during labor. Bland and colleagues found that sheep delivered after labor had 45% less lung fluid than those delivered without going through labor.
After delivery, the remainder of the fetal lung fluid is resorbed via several mechanisms. Increased blood oxygen concentration increases epithelial sodium channels gene expression, which improves the ability of the epithelium to transport sodium and water into the interstitium. The initial breaths of the infant also generate elevated intrapulmonary pressure, which drives alveolar fluid into the interstitium. Pressures between −50 and 70 cm H 2 O have been measured in term infants in the delivery room. Finally, although it was previously believed that the thoracic squeeze while the fetus travels through the birth canal cleared fetal lung fluid, it is now thought that this mechanism plays a very minor role.
In the near-term fetus, cardiac output is approximately 450 mL/kg per minute with two-thirds of the output performed by the right ventricle. Soon after birth, however, there is a marked increase in cardiac output by both the right and left ventricles, increasing blood flow to the lungs, heart, kidney, and intestines. Although this marked increase is secondary to multiple factors, the increased levels of cortisol, as described, likely plays a major role.
Another cardiovascular change after delivery includes the closure of several vascular shunts ( Table 1 ). Once an infant starts to breathe, oxygen content within the blood is higher than it is in utero. This reduction in hypoxia leads to vasoconstriction of the umbilical artery and, because oxygen is a potent pulmonary dilator, pulmonary vascular resistance falls. This allows for an increase in pulmonary blood flow, further increasing oxygen delivery throughout the body. In a duration of approximately 10 minutes, a newborn’s oxygen saturation increases from a fetal level of approximately 60% to well over 90% ( Box 2 ). Additionally, as oxygenation improves, calcium channels are activated in the smooth muscle of the ductus arteriosus leading to ductal constriction, limiting blood flow and functionally closing the ductus arteriosus. As systemic vascular resistance increases and pulmonary vascular resistance decreases, the pressure gradient at the atrial level changes and the foramen ovale physiologically closes, stopping the right-to-left atrial shunt.
| Vessels | In Utero Function | Response to Delivery |
|---|---|---|
| Umbilical artery | Blood from descending aorta to placenta | Vasoconstrict with increased oxygenation |
| Umbilical vein | Blood from placenta to inferior vena cava | Collapse with absent blood flow |
| Ductus arteriosus | Shunt from pulmonary artery to descending aorta | Functionally closes with increased oxygenation and loss of prostaglandin E2 from placenta |
| Ductus venosus | Shunt from umbilical vein to inferior vena cava | Collapse with absent blood flow |
| Foramen ovale | Allows blood flow between right and left atria | Closes when systemic pressure is greater than pulmonary pressure |
| Pulmonary arteries | Minimal—vasoconstricted in hypoxic environment | Vasodilate with elevated oxygen levels |
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1 minute: 60%–65%
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2 minutes: 65%–70%
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3 minutes: 70%–75%
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4 minutes: 75%–80%
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5 minutes: 85%–90%
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10 minutes: 85%–95%
The timing of umbilical cord clamping also plays a role in the success of this transition and recent data suggest that transition may be adversely effected by premature cord cutting or clamping. Charles Darwin’s grandfather, Erasmus Darwin, a British physician, noted in 1801:
Another thing very injurious to the child, is the tying and cutting of the navel string too soon; which should always be left till the child has not only repeatedly breathed but till all pulsation in the cord ceases. As otherwise the child is much weaker than it ought to be, a portion of the blood being left in the placenta, which ought to have been in the child.
Although the umbilical artery constricts with increasing oxygenation, preventing further blood flow to the placenta from the newborn, the umbilical vein remains dilated, allowing blood to continue to flow from the placenta in the direction of gravity. There is increasing evidence that delaying cord clamping until the onset of respirations is important and beneficial in newborn transition. In preterm lambs, Bhatt and colleagues demonstrated that delaying cord clamping for 3 to 4 minutes until ventilation was established resulted in improved cardiac function. Lambs whose cords were immediately clamped had a significant, although transient, increase in pulmonary and carotid artery pressures and blood flow, and a significant decrease in right ventricular output and heart rate. Lambs whose cords were clamped after establishing ventilation had no change in heart rate and ultimately a much more stable cardiovascular transition at birth. In a cohort study of more than 15,000 infants in Tanzania, neonates were more likely to die or require hospital admission when cord clamping occurred before or immediately after onset of spontaneous respirations compared with infants who were breathing before cord clamping. For every 10 seconds cord clamping was delayed after initiation of spontaneous respiration, the risk of death or admission decreased by 20% across birth weight groups. This evidence suggests that the cardiopulmonary transition of a neonate is much smoother and more stable when cord clamping occurs after the establishment of ventilation. Several trials evaluating this process are currently registered at Clinicaltrials.gov .
Neonatal problems of transition
As previously cited, although the majority of infants successfully transition from intrauterine to extrauterine life, approximately 10% require some resuscitation at birth owing to difficulty in adaptation. The issues surrounding these difficulties can be divided into several categories, of which the clinician should be aware to anticipate the potential need for resuscitative support both in the delivery room and in the early hours and days after birth.
Maternal Conditions Affecting the Newborn Transition
Maternal conditions can significantly affect a newborn’s ability to transition effectively; clinicians should be aware of them whether they are chronic medical conditions, or issues that arise during prenatal screening or over the course of the pregnancy ( Box 3 ). Although it is beyond the scope of this article, clinicians should be well aware of chronic medical conditions that require early initiation of therapy to the newborn. This includes several chronic infections, such as maternal human immunodeficiency virus and hepatitis B virus infection. Other conditions include Rh incompatibility, which can lead to hemolytic disease of the newborn, and immune thrombocytopenic purpura, which may lead to cerebral and other organ bleeding, secondary to thrombocytopenia. Additionally, prenatal screening results may require the clinician to manage the newborn differently. The prenatal findings of fetal hydronephrosis or echogenic cardiac foci may suggest further imaging is needed. Therefore, clinicians caring for the newborn should be knowledgeable of the entire maternal medical history, both prepregnancy and prenatal.
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Hypertensive disorders (primary [essential] and secondary hypertension, preeclampsia, hemolysis, elevated liver enzymes, low platelets [HELLP])
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Diabetes mellitus
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Perinatal substance abuse
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Lupus
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Myasthenia gravis
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Advanced maternal age
Certain, more acute maternal medical conditions may also cause difficulties in transition for the newborn for which the newborn clinician should be aware and anticipate the need for resuscitative measures. Hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, eclampsia, hemolysis, elevated liver enzymes, low platelets (HELLP syndrome), or previously diagnosed chronic hypertension, are not uncommon worldwide. Preeclampsia complicates up to 10% of pregnancies in the United States alone and is thought to be even greater in underdeveloped countries. This spectrum of hypertensive disorders can all contribute to intrauterine growth restriction (decreased birth weight/small for gestational age status) likely secondary to decreased uteroplacental blood flow and ischemia. Fetal intrauterine growth restriction is a significant risk factor for fetal demise and neonatal death. Associated with these hypertensive disorders are 2 common hematologic manifestations in the neonate: neutropenia (absolute neutrophil count <500/μL) and thrombocytopenia (platelet count <150,000/μL). Newborns of mothers with preeclampsia have up to a 50% incidence of neutropenia, but it is generally thought to be self-limited. Although the pathogenesis of neonatal thrombocytopenia in preeclampsia is unknown, it may be clinically significant, necessitating 1 or more platelet transfusions. Therefore, newborns of preeclamptic women should be monitored closely with examination of a complete blood count with differential even if asymptomatic. Finally, if low birth weight, clinicians should monitor the neonate’s ability to tolerate feedings and maintain thermoregulatory homeostasis while transitioning; such difficulties are not infrequent and often require admission to special care nurseries.
Maternal diabetes mellitus can also have a profound influence on the fetus to newborn transition. Glucose levels in the fetus are entirely dependent upon facilitated diffusion across the placenta from the maternal serum. When the fetus lives in a chronic state of abnormally elevated glucose levels (poorly controlled diabetes), fetal insulin levels increase and glucagon levels decrease. This can result in hyperinsulinsim in the fetus. At birth, after the maternal glucose supply is acutely interrupted, newborn insulin levels decrease and glucagon levels increase. However, insulin levels may not decrease quickly enough in the setting of the acute glucose shortage, resulting in hypoglycemia. Frequent checking of blood glucose levels in the newborn is warranted to detect hypoglycemia and to ensure appropriate response to treatment. Early breastfeeding (within 1 hour of delivery) to prevent hypoglycemia has been studied and should be encouraged. Additionally, when hypoglycemic events do occur, dextrose gel therapy may be considered to prevent recurrent events.
Other conditions associated with maternal diabetes are not insignificant. Uncontrolled diabetes results in increased risk of newborn hyperbilirubinemia, polycythemia, asymmetric septal hypertrophy, and hypocalcemia, all of which must be anticipated by the clinician responsible for the newborn to treat or prevent long-term morbidity. Macrosomic neonates of diabetic mothers are also at greater risk of birth injuries and hypoxic–ischemic encephalopathy. Focusing on ensuring adequate cardiorespiratory transition at birth, infants of diabetic mothers are at higher risk of developing respiratory distress syndrome (RDS) compared with similarly aged infants of nondiabetic mothers. The pathogenesis of RDS in infants of diabetic mothers stems from a relative surfactant deficiency. In a study examining more than 3000 deliveries after 34 weeks’ gestation, gestational diabetes was identified as an independent risk factor for admission to a neonatal intensive care unit or the need for ventilator support at 24 hours of age with an adjusted odds ratio of 11.55. Although the authors did not evaluate the immediate need for aggressive resuscitation, it is likely that many of the neonates receiving ventilator support required significant respiratory support in the delivery room.
Clinicians should also be aware of other maternal conditions that can affect a neonate’s ability to transition effectively from the in utero environment. Mothers of advanced maternal age (>35 years) are at greater risk not only for maternal morbidities, but their newborns face greater risks for neonatal morbidities and mortality. The risks of preterm birth, small for gestational age stature, low Apgar score, fetal death, and neonatal death increase as maternal age advances over the age of 30. There is also increased risk of gestational diabetes and hypertensive disorders in mothers over the age of 45 years.
Maternal substance abuse is another significant contributor to increased perinatal morbidities. In a single-center study of 85 pregnancies complicated by illicit drug abuse, premature delivery, congenital anomalies, low birth weight, and Apgar scores of less than 7 were all increased in neonates of mothers abusing drugs. In addition, there was an increased risk of maternal hepatitis infections and neonatal abstinence syndrome. Clinicians should be well aware of the potential need for closer observation in these infants.
Another chronic medical condition that can affect neonatal management is myasthenia gravis. Antibodies to acetylcholine receptors (typically immunoglobulin G, which crosses the placenta) are found in up to 90% of mothers with myasthenia gravis. Approximately 10% to 20% of newborns born to these mothers can present with sequelae, including arthrogryposis, respiratory distress, and poor feeding. Symptoms typically occur 12 to 48 hours after birth and can last for several weeks, although earlier symptomatology can occur. Finally, maternal lupus is the most likely cause of fetal heart block that can cause significant cardiopulmonary disease at birth owing to poor cardiac output. It is paramount that clinicians understand and are knowledgeable about the maternal medical history of the newborns that are under their care.
Fetal/Newborn Conditions Affecting Transition
Several conditions in the fetus and newborn can adversely affect the transition from intrauterine to extrauterine life ( Box 4 ). The most problematic transitional medical condition for the clinician is persistent pulmonary hypertension of the newborn (PPHN, formerly called persistent fetal circulation). PPHN is characterized by elevated pulmonary vascular resistance that results in extrapulmonary shunting across the ductus arteriosus and continued right-to-left shunting through the foramen ovale, leading to significant hypoxemia. Risk factors that are independently associated with PPHN include late preterm or postterm birth, large for gestational age, and cesarean delivery. Maternal risk factors include black or Asian race, diabetes, and asthma. Although direct causation has not been shown with these risk factors, clinicians need to be alert to the increased susceptibility to developing PPHN and the need for close monitoring and interventions required in the immediate neonatal period for these newborns to minimize its potential morbidity.
