Perinatal nutrition and the lung

Introduction

The causes of altered fetal and neonatal lung development are numerous, but prematurity, which affects 10% to 12% of all infants born in the United States, is among the most important. Since birth cohort studies have demonstrated that an individual (for the most part) follows a pulmonary function percentile established very early on in life, ^, optimizing maternal/perinatal nutrition and postnatal nutrition, especially to preterm infants, is critical to lifelong childhood respiratory health. As aptly stated by Dr. David Barker: “How do we build stronger people? By improving the nutrition of babies in the womb.” So simple but so profound with regard to the development of many organ systems, particularly the lung.

This chapter will present data from animal models and available clinical data of prenatal and early postnatal nutrition and potential interventions to optimize fetal and neonatal lung development, particularly in the context of preterm delivery. Optimal maternal nutrition is essential for adequate fetal nutrition to promote normal fetal lung development. This is comprised of maternal body mass index (BMI), weight gain during pregnancy, both macro- and micronutrient intakes, and adequate placental function to deliver the nutrients from the maternal circulation to the fetus. The interruption of gestation by preterm birth disrupts the maternal-fetal nutrient transfer and process of fuel store accumulation that prepares for birth and extrauterine life. The preterm infant will now depend on clinicians to provide the delicate balance of macro- and micronutrients needed for postnatal metabolic needs in addition to the demands of growth and development, while surmounting the metabolic limitations of immaturity.

Prenatal nutrition and lung development

Nutritional interventions for primary prevention of preterm birth

Since preterm birth is the most common cause of altered lung development, preventing preterm birth (PTB) is a logical strategy to optimize lung development. A number of trials in unselected populations have evaluated diet, often in combination with increased physical activity. These studies have not consistently demonstrated a decrease in PTB. A 2018 Cochrane review of randomized controlled trials (RCTs) of omega-3 long-chain polyunsaturated fatty acids (LCPUFAs), which are commonly found in fish, found an overall 11% reduction in preterm birth <37 weeks gestation and a 42% reduction in preterm birth <34 weeks. In low-risk pregnancies, it demonstrated a risk ratio of 0.31 (0.12, 0.79) in preterm births at <34 weeks.

Maternal undernutrition

Poor maternal nutrition/undernutrition/malnutrition is one of many potential causes of intrauterine growth restriction (IUGR) and/or small for gestational age (SGA), which is a common and important antecedent of altered fetal lung development. ^, IUGR is also a risk factor for reduced lung function and respiratory morbidity during infancy, childhood, and adulthood, and increases the odds of the development of bronchopulmonary dysplasia (BPD) in an infant delivered preterm. Clinical trials to examine treatment versus nontreatment are obviously unethical, but the long-term effect of poor nutrition during pregnancy is demonstrated by the increased prevalence of chronic obstructive pulmonary disease (COPD) in those born to mothers exposed to the Dutch famine in 1944 to 1945 when caloric intake decreased to less than 800 kcal/day, therefore supporting the concept that maternal nutrition should be optimized to ensure normal lung development.

In particular, IUGR in the first and second trimester has been associated with reduced vitamin E and abnormal lung function at 5 years of age and increased asthma risk. Models of fetal growth restriction in animals, induced by calorie or protein restriction, have been associated with decreased lung weight and total DNA content, decreased maturation of type II cells and subsequent surfactant maturation, decreased alveoli numbers, and thickened airway walls. Peroxisome proliferator-activated receptor gamma (PPARg) is a nuclear receptor transcription factor that is decreased in animal models of IUGR and is thought to contribute to lung development through its involvement in epithelial-mesenchymal interactions. Maternal supplementation with docosahexaenoic acid (DHA) in a rat model of IUGR increased PPARg levels and restored aberrant fetal lung development. In a rat model of IUGR due to a low-calorie maternal diet, vitamin A supplementation reversed alveolar hypoplasia. Maternal undernutrition is also often associated with other macro- and micronutrient deficits with potential ramifications as outlined in the following.

Maternal over nutrition

The worldwide incidence of obesity is projected to grow to 70% by 2025, so more women are entering pregnancy either overweight or obese, which exposes the fetus to an obesogenic intrauterine environment that impacts fetal lung development. Overall, there is an increased risk of preterm delivery and adverse respiratory outcomes with obese pregnancies. There are many factors in the obese pregnancy that can affect fetal lung development. Obese pregnancies lead to increased oxidative stress, which has implications for DNA, protein, and lipids in the maternal-placental-fetal unit. Maternal obesity in pregnancy can change the maternal hypothalamic-pituitary-adrenal axis and lead to increased fetal cortisol exposure which may impair fetal lung growth. Increased maternal cytokine production may also impact lung development. ^, The timing of weight gain during pregnancy may also be important for lung development outcomes. Several rat models of maternal high-fat diets have demonstrated increased airway hyperreactivity in the offspring and human studies have associated pre-pregnancy maternal BMI with increased bronchodilator and steroid dispensing in early childhood, implying altered lung development. The ideal time for intervention for maternal obesity is prior to pregnancy given concern for the growing fetus; however, intergenerational effects of fetal programing may still persist.

Maternal intake of micronutrients

Maternal micronutrients play a role in fetal lung development, protect against oxidant damage, are proangiogenic factors, and can modulate the inflammatory response that may impact lung development. Several micronutrients are outlined with regard to adverse in utero conditions in the following.

Vitamin C supplementation to pregnant women unable to quit smoking

Fetal lung development is very sensitive to the effects of in utero smoke, and primarily to nicotine, the major toxin in cigarettes and electronic cigarettes. Smoking during pregnancy is the largest preventable cause of low birth weight, prematurity, and IUGR, all of which affect fetal lung development. ^, In addition, in a prospective study of preterm infants, smoking during pregnancy was shown to double the risk of developing BPD in preterm infants with a birth weight of 500 to 1250 g. The incidence of smoking during pregnancy varies widely across the United States with at least 10% of pregnant women continuing to smoke, ^, and > 50% of smokers who become pregnant continue to smoke. ^, Smoking cessation during pregnancy remains the foremost goal, but a difficult intervention to improve fetal lung development.

Two separate randomized double-blind placebo-controlled trials (RCTs) have shown that supplemental vitamin C (500 mg/day) to women unable to quit smoking during pregnancy significantly improves their offspring’s pulmonary function tests (PFTs). In the first study, singleton pregnancies were randomized at <22 weeks of gestation. These offspring had significantly improved PFTs performed within 72 hours of birth with decreased airflow obstruction and increased passive respiratory compliance, and a 48% decrease in the incidence of wheeze through 12 months of age. The second RCT demonstrated improved forced expiratory flows at 3 and 12 months of age in the offspring of pregnant smokers randomized to supplemental vitamin C ( Fig. 16.1 ). ^, These results support the premise that in utero vitamin C supplementation to pregnant smokers improves fetal lung development and is associated with a persistent increase in pulmonary function early in life. These cohorts are in continued follow-up. Vitamin C may be an inexpensive and simple strategy in addition to smoking cessation efforts to decrease the effects of maternal smoking on infant lung function.