Normal Development of the Lung and Premature Birth

Paediatric Respiratory Reviews 11 (2010) 135–142

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-Symposium: Chronic Neonatal Lung Disease CNLD/BPD Normal Development of the Lung and Premature Birth

Lucia J. Smith 1,2, Karen O. McKay 1,2, Peter P. van Asperen 1,2, Hiran Selvadurai 1,2, Dominic A. Fitzgerald 1,2,*

1 Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag 4001 Westmead NSW Australia 2145 2 Discipline of Paediatrics and Child Health, Faculty of Medicine, The University of Sydney, Sydney NSW Australia

ARTICLE INFO SUMMARY

Keywords: The following review focuses on the normal development of the lung from conception to birth. The alveoli deﬁned periods of lung development–Embryonic, Pseudoglandular, Canalicular, Saccular and Alveolar– bronchopulmonary dysplasia will be explored in detail in relation to gestational age. Cellular differentiation, formation of the lung development conducting airways and respiratory zone and development of the alveoli will be reviewed. Pulmonary premature birth vascular development will also be examined within these periods to relate the formation of the blood-air barrier to the lungs for their essential function of gas exchange after birth. The development of the surfactant and cortisol systems will also be discussed as these need to be mature before the lungs are able to take on their role of respiration following birth. It is clear that premature birth interrupts normal lung development so the effect of preterm birth on lung development will be examined and the respiratory consequences of very preterm birth will be brieﬂy explored. Crown Copyright ß 2009 Elsevier Ltd. All rights reserved.

INTRODUCTION of lung growth were conﬁrmed by the International Congress of Anatomists meeting in Leningrad, 1970 (Nomina Embryologica).1 Investigations into the structure and function of the lung began While it is agreed there is some overlap of the beginning and end of over a century ago. These investigations led to detailed descrip- each of these periods, it is generally accepted that weeks 0 to 6 of tions of each period of lung development and the realisation that gestation comprise the embryonic period, weeks 6 to 16 the the lung is a complex structure in which steady development pseudoglandular period, weeks 16 to 24 the canalicular period and begins during the embryonic period at 0 to 7 weeks gestation and weeks 24 to term (40 weeks) the saccular period.2 continues into early childhood. In fact, there is still great debate as Development of the pulmonary circulation occurs in parallel to when lung development is complete. with lung development (Figure 1). During foetal life there is an It has become clear from these investigations that premature increase in vessel length and diameter but no change in density.3 birth interrupts the normal development of the lung. Infants born By the 20th week of gestation the full number of pre-acinar prematurely have underdeveloped lungs and often require pulmonary vessels is present in each segment. During each period assistance to maintain adequate respiration. While many strate- of gestation structural remodelling and changes in growth and gies that accelerate lung development and assist in providing maturation take place. Lung vascular growth involves two basic adequate gas exchange have beneﬁted a large number of infants, processes, vasculogenesis–formation of new blood vessels from the smallest and most preterm infants are still at the greatest risk endothelial cells4 and angiogenesis–formation of new vessels from of developing Bronchopulmonary Dysplasia capillaries via sprouting.5 The following review explores normal development of the lung and the effect premature birth has on this development. Embryonic Period (weeks 0 to 6)

PRENATAL LUNG DEVELOPMENT This is the period of organ development–organogenesis. At the end of the fourth week of gestation the lung appears as a ventral The growth and development of the lung is divided into four bud of the oesophagus.6 By the end of the sixth week lobar and characteristic periods (Figure 1). The nomenclature of the periods segmental portions of the airway tree are preformed as tubes of ‘‘high columnar epithelium’’.6 By seven weeks subsegmental branching is evident.7 Alescio and Cassini8 originally documented, * Corresponding author. Department of Respiratory Medicine, The Children’s in mouse lung, that the branching pattern is driven by signals from Hospital at Westmead, Locked Bag 4001 Westmead NSW Australia. 2145. Tel.: +61 2 98453397; Fax: +61 2 98453396. the mesenchyme to the budding airway. Their investigations E-mail address: [email protected] (D.A. Fitzgerald). showed that the pulmonary mesenchyme consists of a bronchial

Figure 1. Overview of Gestation. portion, which induces budding from the epithelium and a tracheal vascular plexus.6 The pulmonary vein appears as a small tubule portion that does not. They also demonstrated that without the growing out from the left atrial portion of the heart.2 By the sixth bronchial mesenchyme, branching of the epithelium does not week of gestation, the adult pattern of central vascular and airway occur.8 structures consisting of lobar and segmental branches is present.9 Vasculogenesis occurs within the immature mesenchyme. The After the age of seven weeks the lung resembles a primitive pulmonary arteries bud off the 6th pair of aortic arches growing small gland (giving the next stage its name) and has so entered the down to the mesenchyme and surround the lung tubules as a Pseudoglandular period of development.6 L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142 137

Pseudoglandular Period (weeks 6 to 16) epithelial cells.13 This stretches the intervening cytoplasm into a flange-like film through which, after birth, gases will be exchanged Detailed examination of human foetal tissue has allowed a between blood and air.1 precise definition of this stage of development. Early investiga- Pulmonary vascular development is characterised in this period tors10,11 shared the view that all conducting airways of the by increased vessel proliferation and organisation into a capillary respiratory tree down to the terminal bronchioles were present at network around airspaces.15 Increasing numbers of capillaries birth with no new airways formed postnatally. It is now accepted accompany the small clusters of short tubules and buds that are that all the conducting airways are created during this stage.12 the acinus with the capillaries forming a loose three-dimensional Investigators in the 1960’s concluded that all non-respiratory network in the mesenchyme. At 12 to 14 weeks the capillary portions of the bronchial tree had been formed by the 16th week.6 network is separated from the acinus by the mesenchyme Thirty five years later Kitaoka and colleagues12 confirmed this view however, by about 23 weeks this network closely approaches with their investigations of foetal airways that had been the alveolar epithelium.16 reconstructed three-dimensionally from serial histologic sections. The formation of the thin blood-air barrier starts peripherally.17 Their results showed that 20 generations of branching were Capillaries induce overlying epithelial cells to flatten and completed by 16 weeks. They concluded that airway branching differentiate into type I alveolar epithelial cells via various reaches the level of the acinus by the late Pseudoglandular period. regulatory factors.18 At this time, formation of the blood-air The acinus is a collective term for the respiratory zone of the barrier does not involve the terminal segment of the last tubule lung. It contains the respiratory bronchiole, which by definition branch because the undifferentiated cuboidal epithelium is needed contains no cartilage in the wall, the alveolar ducts and the alveolar for further growth.6 sacs.7 Flattening of the alveolar epithelium is evident by 20 weeks.19 Vascular development is complete by the end of this stage. The This represents differentiation of cuboidal cells into type I arterial tree branches in accord with the airways3 with the veins epithelial cells7 and type II epithelial cells that contain lamellar running through connective tissue septa. By the end of this period bodies, which are the intracellular storage units of surfactant.17 the pre-acinar vascular pattern corresponds to that of the adult Some investigators have suggested that alveolar type II cells lung.2 Capillaries of a 3 to 4 month old foetus had no ultra- appear initially and then differentiate into alveolar type I cells.17 structural differences from those of adults, apart from a thicker The type II alveolar epithelial cell is crucial for normal lung endothelium.13 development as it is the precursor to surfactant production and During this period cellular differentiation of the conducting secretion which is essential for normal respiration after birth. Early airways commences from the proximal end to the distal end.7 investigations using the electron microscope determined it was Growth also occurs from a proximal to distal direction.14 Airway possible to distinguish two types of epithelial cells from about 24 tubes are lined with high columnar epithelium. By 12 weeks of weeks. Type I cells lined the greater part of the alveolar surface gestation cartilage and smooth muscle cells are seen in the trachea including the blood-air barrier and showed a small peri-nuclear and segmental bronchi. Mucous glands are also present. Sparse body with long attenuated cytoplasmic extensions; type II cells differentiation into cuboidal epithelium also commences in the were larger and rounder without extensions and contained distal region.2 ‘‘lamellar inclusions’’.13 These ‘‘inclusions’’ were later shown to Unlike bronchiolar epithelial cells, distal cuboidal epithelial contain surfactant. cells are filled with glycogen (Claude Bernard, 1859; reference Later investigations used staining for surfactant-associated unavailable).2 Glycogen appears in the sites of rapid epithelial proteins to determine when the type II cell appeared in human division (first noted by Sorokin in 1961) and as such is the fuel for gestation. Sparse staining of the cuboidal or low columnar cellular differentiation2. Glycogen is also an essential component epithelial cells lining the distal segments of foetal lung occurred of surfactant which will later line the alveoli. These distal cuboidal around the 12th week of gestation. Flattening of these cells cells represent immature type II alveolar epithelial cells that will appeared to commence around 16 weeks and by 19 weeks a eventually secrete surfactant into the alveoli reducing the surface combined cellular and linear pattern was seen.19 Some of the distal tension in the lungs, preventing alveolar collapse and as such are epithelial cells begin to synthesise and release surfactant towards essential for normal functioning of the lung. These most distal the end of this stage.18 Surfactant production begins around the areas of the conductive airways will eventually be remodelled to 26th week of gestation and slowly propagates through the give rise to the alveolar region of the lung. However, at this point, parenchyma.6 The two main achievements in this period are the there is no alveolar formation.2 formation of a thin air-blood barrier and the beginning of secretion of surface-active material (surfactant) into the air spaces. Canalicular Period (weeks 16 to 24) Saccular Period (weeks 24 to 40) This period is characterised by the early development of the pulmonary parenchyma (non-airway tissue) and the multiplication The beginning of the saccular period represents the current of capillaries (Dubreuil et al., 1936; reference unavailable).2 At the limit of viability for premature birth. At the beginning of this end of the 17th week of gestation the acinus is a stem tubule, period the airways end in clusters of thin-walled terminal saccules. prospective terminal bronchiole, 2-4 future respiratory bronchioles These saccules produce, by term, the last generations of airways, and small clusters of short tubules and buds. These clusters grow via alveolar ducts and at the periphery the alveolar sacs.6 True alveoli peripheral branching, lengthening and a marked widening of distal can be seen as early as 32 weeks however are generally more airspaces at the expense of intervening mesenchyme.6 recognisable at 36 weeks.14 As a result of widening, distal air spaces come into close contact After the formation of the type I and type II epithelial cells in the with cuboidal epithelium which simultaneously begins to flatten Canalicular Period, increasing amounts of tubular myelin in the so that regions with a thin air-blood barrier appear.2 Investigations airspace is evidence of the increasing secretory activity of the type of lung specimens from 13 human foetuses of 1 to 6 months II cells. Tubular myelin has been shown to form directly from gestation using light and electron microscopy determined that lamellar bodies and is considered to correspond to the reserve pool capillaries progressively establish contacts with, and penetrate in a of surface-active material with these lamellar bodies being the wedgelike manner into, the epithelium separating the flattened intracellular storage units of surfactant.20 138 L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142

Figure 2. An Alveolus; Illustrating Surface Tension Properties A: Without and B: With Surfactant. Adapted from Fig13-1545.

Marked vascular expansion is characteristic of the saccular the strong attractive forces between water molecules. The period as blood vessels grow in length and diameter.15 Along with surfactant lipids coat the thin layer of fluid that remains in the expansion of respiratory tissue, new arteries and veins are also lungs after the majority is reabsorbed at the first breath (Figure 2). formed.6 The gas exchange surface increases markedly in size This provides the alveoli with stability, reduces the work of which leads to a thinning of interstitial tissue. Changes in the breathing and prevents alveolar collapse at low lung volumes and capillary network result in the formation of a double capillary layer over-inflation at high lung volumes.21 which is a prerequisite for alveolar formation within the Many studies have focussed on the composition and function of parenchyma2 and formation of the thin air-blood barrier con- the surfactant system and it is generally recognised that it tinues. comprises phospholipids (80%), neutral lipids (12%) and protein (8%). Four surfactant proteins have been isolated: Surfactant Surfactant System protein-A (SP-A), SP-B, SP-C and SP-D. All have varying functions and appear at different stages of gestation as summarised in The pulmonary surfactant system is one of the last systems to Table 1.21–23 In infants born prematurely the surfactant system is develop before birth and in humans it matures between the 29th immature and generally does not show signs of genetic deficiency and 32nd week of gestation.21 Type II cells containing lamellar which would lead to Pulmonary Alveolar Proteinosis. A discussion bodies appear between 20 to 24 weeks gestation while later in regarding Pulmonary Alveolar Proteinosis is beyond the scope of gestation (around 30 weeks) surfactant begins to be secreted into this review. the airway lumen.7 The surfactant system was initially described following the Surfactant lines the alveoli and its role is to decrease surface suggestion that alveolar collapse, which had been observed in tension at the air-liquid interface and so facilitate expansion of the some infants, may be the result of high surface tension in the lungs.1 This is crucial for maintaining the functional integrity of lungs.24 Indeed, some 30 years later, following autopsies of alveoli. If water molecules alone lined each alveolus the surface children who had died from hyaline membrane disease, the lack of tension would be so great the lungs would collapse. This is due to a surface-active film was considered partly responsible for the

Table 1 Properties of Surfactant Proteins SP-A Large, hydrophilic glycoprotein & most abundant surfactant protein Involved in host defence against pathogens Blocks the inhibitory effects of serum proteins on surfactant surface tension lowering properties Deficient mice have normal lung structure and function but are more susceptible to infection Perhaps involved in recycling of surfactant lipids Also expressed in submucosal glands of conducting airways Not detected until 30th week of gestation SP-B Small, hydrophobic protein Facilitates spreading of surfactant proteins on alveolar surface Deficient mice and humans die due to respiratory distress soon after birth46 Also expressed in Clara cells of conducting airways Pre-proteins detected by 15th week of gestation SP-C Small, hydrophobic protein Perhaps involved in surfactant synthesis Deficient mice have normal respiratory function however, humans with mutations in SP-C genes and decreased levels of this protein have interstitial lung fibrosis Is not expressed elsewhere Pre-proteins detected by 15th week of gestation SP-D Large, hydrophilic glycoprotein Involved in host defence ie aiding lung immunity Deficient mice have abnormalities in surfactant metabolism and accumulate large amounts within the alveoli. Surface tension lowering properties appear normal however, they develop emphysema by 1 year of age by unknown mechanism L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142 139 regions of alveolar collapse seen in the respiratory distress syndrome (RDS).25

Cortisol System

Within the saccular stage there is also a natural increase in foetal concentrations of circulating cortisol. There is widespread recognition that this increase is critical to mature the lungs in readiness for gas exchange although the mechanisms involved are still unclear.26 The response of the immature lung to cortisol is complex and involves stimulation not only of surfactant synthesis Figure 3. Schematic Structure of Alveoli. and secretion but also tissue remodelling, alveolar epithelial cell Adapted from Fig 13-345. differentiation and the reabsorption of lung liquid.27 Stimulating the foetal adrenal cortex accelerates lung maturation28 and foetal sheep infused with sufficient cortisol to increase circulating levels not begin until late in gestation and is predominantly a postnatal to those normally present at term, respond within 72 hours with event. The precise time in life when alveolar development is lung development from immaturity to morphological and func- complete is still a matter of great debate. The fact that alveoli are so tional maturity approaching that found at term.29 small (150 mm diameter) and that varying morphometric methods are used by investigators contribute to differing opinions. BIRTH A large study by Merkus and colleagues14 found that alveolar numbers increase little beyond the age of 2 years and that boys had The First Breath more alveoli than girls. The consensus currently is that alveolarisation is likely to be completed by 18 to 24 months of age with The role of respiratory gas exchange before birth is performed most alveolar formation completed by about 6 months.2 by the placenta. At the time of birth the lungs take over this role. Over the years investigators have described in detail the process The lungs need to be appropriately mature and have developed a of alveolarisation and it is now generally accepted that it is divided large internal surface area, which is closely apposed to a large into three phases.18 The first phase is termed Secondary Septation vascular bed to facilitate postnatal gas exchange.27 and is characterised by the formation of new alveolar septa within the terminal sacs. As the secondary septa develop there is an POSTNATAL LUNG DEVELOPMENT increase in the secretion of surfactant within the alveoli.2 The second phase is characterised by extensive remodelling of the The lung of a newborn human at 40 weeks (term) is functional double capillary network into the single capillary system and although it is not simply a smaller version of the adult lung. further lengthening and thinning of the secondary septa occurs.2 Remodelling occurs within the parenchyma and capillary network During this phase the area for gas exchange increases dramatically and alveolar development continues. While the number of airway and for many years it was believed that remodelling of the generations and their branching pattern is complete at birth, the microvasculature was the final step of pulmonary development.32 most peripheral airways are quite short with the lung parenchyma However, while this phase continues at least until 2 years in containing several generations of transitory ducts which end in humans2 the lung then enters the third phase of alveolar transitory saccules. These structures will eventually be trans- formation, in which growth of all lung components occurs. This formed into alveoli. phase is believed to continue until the growth of long bones The human lung at birth is therefore within the Alveolarisation ceases.18 period.2 As greater insights into the process of alveolarisation were At approximately 36 weeks of human gestation, the pattern of gained it was proposed that the stages of intrauterine lung growth arteries and veins surrounding the conducting airways (pre- be redefined to include an Alveolar period from 36 weeks.30 Most acinar) is complete and the lung is now able to support respiration. authors now agree over 85% of alveolarisation takes place after The lung is still developing however, with accelerated vascular birth and so this period is considered mainly postnatal. growth occurring as new vessels form within the respiratory zone (acinus) in formation with the gas-exchange surface.33 Fusion of Alveolar Period (week 36 prenatal to 2 years postnatal) the double capillary network occurs with thinning of septae and remodelling of vessels increases the surface area for gas-exchange Alveoli are tiny, thin-walled sacs that facilitate the exchange of more than 20-fold.15 This intra-acinar pattern continues to develop oxygen and carbon dioxide between capillaries in the alveolar wall through childhood.34 and air brought into the lung during inspiration. The structure of Postnatal growth of blood vessels occurs in proportion to the alveoli is very simple but extremely effective (Figure 3). The alveolar formation and thus the gas exchange surface of the lung is alveolar epithelium consists of the type I alveolar epithelial cell and expanded. In the first 4 months as alveoli form and increase in size, the type II alveolar epithelial cell. The type I cells are thin, flattened the number of arteries per unit area of lung and density of capillary cells that cover about 90% of the alveolar surface area. The networks increase. These vessels are thought to form and grow by basement membrane of these type I cells fuse with the basement angiogenesis (pre-existing capillaries form capillary-like sprouts) membrane of the capillary endothelial cell to form the blood-air and the increase in complexity of the capillary networks by barrier. The type II cells are roughly cuboidal and often found in the intussusceptive growth.5 In this process the capillary bed grows by corner of the alveolus and occupy only 10% of the alveolar surface formation of slender intravascular tissue pillars across the capillary area. These cells are able to divide and so are able to renew lumen to form an interendothelial bridge, which eventually damaged alveolar epithelium.31 The type II cells also secrete becomes a normal capillary mesh.5 surfactant which lines the alveolus to reduce surface tension. At full term the respiratory saccules (primitive alveoli) are Alveolarisation is a complex process. While the foundations of supplied by the double-capillary network but within 2 weeks these the alveoli are laid down in the canalicular period with alveolar fuse into a single network. After 18 months, the number of new type I and type II cell differentiation, formation of true alveoli does vessels forming slows along with alveolar growth.34 140 L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142

Figure 4. Schematic Cross-Section of the Alveolar-Capillary Network Showing the Air-Blood Barrier.

An infant born after 37 weeks of gestation is considered full airways and blood vessels are formed along with the conducting term and is usually able to breathe spontaneously. Oxygen airways and related blood vessels. Respiratory bronchiole and reaching the alveolar duct diffuses into the alveoli because the alveolar duct formation, type II epithelial cell differentiation and inspired air has a higher oxygen concentration than alveolar gas. the intrusion of capillaries into the alveolar wall mesenchyme Oxygen then diffuses through the air-blood barrier into the red are almost complete. However, division of the alveolar saccules blood cells where it combines with haemoglobin as the red blood and ducts into true alveoli is yet to occur and proliferation of the cells flow along the capillaries. capillary network is still incomplete. The surfactant and cortisol The air-blood barrier consists of alveolar epithelium, its systems are also not mature in the saccular period and if these subjacent basal lamina, alveolar wall interstitium, basal lamina do not activate after delivery and function appropriately (along of the capillary endothelium, the capillary endothelium, plasma, with immature alveoli and an underdeveloped surface area for and the membrane of the red blood cells (Figure 4). The average gas exchange) respiratory distress ensues; therefore the lungs width of this barrier is about 1.5 mm in a normal adult lung and gas are far from ready for their essential role in gas exchange after exchange takes place so rapidly that the partial pressures of oxygen birth. and carbon dioxide are the same throughout the terminal While it was suggested that alveolar properties must influence respiratory unit.35 the function of the lungs in 1929,24 investigators did not focus their The foetal lung is not required for gas exchange prior to delivery attention on the alveolar surface area until 1955 when Pattle as the placenta fulfils this role. The lung structure does not fully demonstrated, via the behaviour of microscopic bubbles removed develop to facilitate gas exchange until term when the lung will from the lungs, that the lungs are lined with a substance that assume sole responsibility for gas exchange. The terminal greatly reduces surface tension–Surfactant.37 respiratory units (alveolar saccules and alveoli) of an infant born If the surfactant system is not activated soon after birth, prematurely are incompletely developed so that the air-blood fibroblasts may invade the alveoli resulting in a (hyaline) barrier is too thick to allow efficient gas exchange. This structural membrane which is thick and stiff.21 The initial description of problem is greatest in more immature preterm infants because the pulmonary hyaline membranes (PHM) was in 1903 and thought to development of the terminal respiratory units occurs during the be associated with aspiration of amniotic fluid38,39 while the first second half of gestation, with the thickness of the gas-exchange English description was in 1923 in association with neonatal barrier inversely related to gestational age.35 pneumonia.39 This alteration in the membranes compromises the ability of the alveoli to exchange oxygen and carbon dioxide and PREMATURE BIRTH results in respiratory distress or failure. The connection of PHM and neonatal death was first described An infant born before 37 completed weeks of gestation is in 1951 by Bruns and Sheilds39 and the term Hyaline Membrane considered premature (full term is 37 to 42 weeks). Standard Disease (HMD) evolved. Surfactant deficiency was then identified definitions categorise the period of gestation of an infant’s birth. as the primary reason infants develop HMD. The authors suggested Infants born before 32 weeks gestation are ‘‘very preterm’’ while that the disease could be associated with the absence or delayed infants born before 28 weeks gestation are considered ‘‘extremely appearance of some substance which, in an infant not suffering preterm’’.36 HMD, enables the internal alveolar surface capable of attaining low When an infant is born between 24 to 32 weeks of gestation, surface tension at low lung volumes thereby preventing alveolar lung development is within the saccular period. The major collapse.25 A few years later this link between surfactant deficient L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142 141

Figure 5. A Century of Research. [NSW: New South Wales, state in Australia]. lungs and HMD was confirmed with experiments demonstrating Without surfactant the lungs have high surface tension, which that the surface tension of the lung extract is dependent on the predisposes the alveoli to collapse at end expiration. In the adult quality and quantity of surfactant in it. The authors concluded that the stiffness and natural tendency of the chest wall to spring alterations in the alveolar surfactant layer may be responsible for outwards reduces the extent of lung collapse. In the newborn the unstable alveoli seen in the disease.37 however, the reverse occurs as the ribs are so compliant and As the surfactant system is not completely mature alveolar fluid significant collapse of the alveoli (atelectasis) occurs.21 This greatly may remain leading to an increase in the diffusion distance for gas increases the work of breathing as the infant struggles to expand exchange. This contributes to hypoxaemia (low oxygenation in the the lungs with air and leave them open long enough for efficient blood), which in turn reduces the extent of arterial dilation and gas exchange. This increased work of breathing occurs with each pulmonary hypertension may result.21 breath not just the first breath, as is normally the case. ‘‘Infants 142 L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142 with these characteristics usually go on to develop Respiratory 28. Liggins G, Howie R. A Controlled Trial of Antepartum Glucocorticoid Treatment 35 for Prevention of the Respiratory Distress Syndrome in Premature Infants. Distress Syndrome (RDS)’’. RDS essentially describes the Pediatrics 1972 Oct 1;50:515–25. symptoms of HMD and over the years RDS has become 29. Liggins G. The Role of Cortisol in Preparing the Fetus for Birth. Reprod Fertil Dev synonymous with HMD. However, it is now apparent that while 1994;6:141–50. 30. Langston C, Kida K, Reed M, Thurlbeck W. 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