Pregnancy, neonates and children

Embryology

The lungs develop in four stages, under the control of a host of transcriptional factors: ^,

• 1.

  Pseudoglandular stage (5–17 weeks’ gestation). A ventral outgrowth from the foregut first appears about 24 days after fertilization, and at around week 5 of gestation this begins to form the basic airway and vascular architecture. The branching patterns of the adult airways and vasculature are believed to develop by a common process of branching morphogenesis, ensuring the two components remain closely related in the lung tissue. Dividing epithelial cells lengthen the airways, and their ability to do this is influenced by physical factors relating to the lung liquid (LL) and fetal breathing described next.

• 2.

  Canalicular stage (16–26 weeks’ gestation). The primitive pulmonary capillaries now become more closely associated with the airway epithelium, and the connective tissue architecture of the lung is formed. Fibroblasts and other cells involved in morphogenesis of the lung undergo apoptosis, reducing the wall thickness of the embryonic lung structures.

• 3.

  Saccular stage (24 weeks’ gestation to term). Distal airways now develop primitive alveoli in their walls to become respiratory bronchi (see Fig. 1.6 ). Saccules form at the termination of airways, these being primitive pulmonary acini.

• 4.

  Alveolar stage. Saccules on embryonic bronchioles now expand, and septation occurs to form the groups of alveoli seen in adult pulmonary acini. This phase of development begins at 36 weeks’ gestation, and in humans is believed to be mostly complete around 2 years of age, although there is some evidence the process may continue throughout childhood, particularly in infants born prematurely. In humans at full term all major elements of the lungs are therefore fully formed, but the number of alveoli present is only about 15% of that in the adult lung. This postnatal maturation of lung structure is only seen in altricial mammals (humans, mice and rabbits) that have the luxury of being able to remain ‘helpless’ after birth. Precocial species such as range animals are born with a structurally mature lung, ready for immediate activity. Once alveolarization is complete, further lung growth is dimensional, that is, simple enlargement of existing structures.

The lungs begin to contain surfactant and are first capable of function by approximately 24 to 28 weeks, this being a major contributor to the viability of premature infants, although the factors influencing surfactant development, particularly of the surfactant proteins, are poorly understood.

Lung liquid

Fetal lungs contain LL which is secreted by the pulmonary epithelial cells and flows out through the developing airway into the amniotic fluid or gastrointestinal tract, flushing debris from the airways as it does so. A more important function of LL seems to be to prevent the developing lung tissues from collapsing. It is thought that LL maintains the lung at a slight positive pressure relative to the amniotic fluid, and that this expansion is responsible for stimulating cell division and lung growth, particularly with respect to airway branching. The respiratory tract in late pregnancy contains about 40 mL of LL, but its turnover is rapid, believed to be of the order of 500 mL per day. Its volume corresponds approximately with the FRC after breathing is established.

Fetal breathing movements also contribute to lung development. In humans they begin in the middle trimester of pregnancy, and are present for over 20 minutes per hour in the last trimester, normally during periods of general fetal activity. During episodes of breathing, the frequency is about 45 breaths per minute, and the diaphragm seems to be the main muscle concerned, producing an estimated fluid shift of about 2 mL at each ‘breath’.

Maintenance of a positive pressure in the developing lung requires the upper airway to offer some resistance to the outflow of LL. During apnoea, elastic recoil of the lung tissue and continuous production of LL are both opposed by intrinsic laryngeal resistance and a collapsed pharynx. Fetal inspiratory activity, as in the adult, includes dilation of the upper airway. With quiet breathing this would allow increased efflux of LL from the airway, but simultaneous diaphragmatic contraction opposes this. During vigorous breathing movements with the mouth open, pharyngeal fluid may be ‘sucked’ into the airway, thus contributing to the expansion of the lungs. Thus fetal breathing movements are believed to contribute to maintaining lung expansion, and their abolition is known to impair lung development.

Lung development and lung function later in life

As the lungs develop in utero, they face a variety of environmental challenges associated with the pregnancy that can affect their development and influence the individual’s lung function in both childhood and adult life. Adverse effects on lung function arising during pregnancy include a greater likelihood of developing childhood wheeze (which may or may not be asthma), developing asthma or having lower lung volumes as an adult. The more well-studied factors contributing to these lung problems include:

• Low birth weight . This is associated with lower lung volumes as both a child and adult, with the greatest effect seen when aged 21 years, and results in a greater likelihood of developing asthma and requiring hospitalization for respiratory disease as an adult. The cause of these effects remains uncertain, but it most likely results from poor fetal lung growth in the first trimester, although early postnatal growth also influences future lung health.

• Prematurity . Birth at less than 37 weeks’ gestation leads to lower lung volumes in childhood, with values lower still in neonates who develop and survive bronchopulmonary dysplasia (page 180). Pulmonary gas transfer remains lower than control subjects at 21 years of age, although this does not adversely affect exercise capacity.

• Maternal tobacco smoking . This leads to lower birth weight and earlier birth, meaning these babies will therefore have poorer lung function. Babies whose mothers smoked during pregnancy also have a higher incidence of childhood wheeze and asthma, with smoking during the first trimester having the greatest effect; of course postnatal passive smoking also plays a role (page 239). Nicotine is believed to play a major role in the effects of smoking on in utero lung development, leading to concern that use of e-cigarettes (page 239) may be similarly harmful to the fetus. In utero smoke exposure also causes epigenetic changes in the fetus (resulting from changes to DNA by its methylation) that mean a susceptibility to respiratory disease may be passed down to subsequent generations.

• Maternal stress during pregnancy . Stress, particularly in overweight mothers, leads to children being more likely to develop wheeze at 2 to 3 years old. Raised maternal cortisol levels may directly influence early lung development, but maternal stress also has much broader effects on fetal well-being relating to placental function and immune system development.

• Indoor air pollution (page 242). Prenatal exposure to indoor carbon monoxide is associated with impaired lung function for the child in the first year of life.

Fetal circulation

The fetal circulation differs radically from the postnatal circulation ( Fig. 12.1 ). Blood from the right heart is deflected away from the lungs, partly through the foramen ovale and partly through the ductus arteriosus. Less than 10% of the output of the right ventricle reaches the lungs, the remainder passing to the systemic circulation and the placenta. Right atrial pressure exceeds left atrial pressure, and this maintains the patency of the foramen ovale. Finally, because the vascular resistance of the pulmonary circulation exceeds that of the systemic circulation before birth, pressure in the right ventricle exceeds that in the left ventricle, and these factors control the direction of flow through the ductus arteriosus.

The umbilical veins drain via the ductus venosus into the inferior vena cava, which contains better-oxygenated blood than the superior vena cava. The anatomy of the atria and the foramen ovale is such that the better-oxygenated blood from the inferior vena cava passes preferentially into the left atrium, and then to the left ventricle, and so to the brain. (This is not shown in Fig. 12.1 ). Overall gas tensions in the fetus are of the order of 6.4 kPa (48 mmHg) for P co ₂ and 4 kPa (30 mmHg) for P o ₂ . The fact that the fetus remains apnoeic for much of the time in utero with these blood-gas levels is probably in part attributable to central hypoxic ventilatory depression (page 53).