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Human Milk Composition and Function in the Infant

Introduction Lactation is the defining characteristic of “mammal” and has enabled the wide distribution of more than the 4000 species. The evolution of a large brain that consumes approximately 23% of resting energy has given humankind a significant competitive intellectual advantage over all other mammals. Unlike other mammals, most brain growth in humans occurs after birth and is facilitated by the nutrients present in human milk…

Endocrine Factors Affecting Neonatal Growth

Introduction Growth reflects a complex interaction of genetic, epigenetic, endocrine, and nutritional factors that regulate cell division, differentiation, and function (see Meler et al. for a recent compilation of genetic and epigenetic conditions leading to fetal growth restriction). Various phases of growth appear “programmed” to occur within specific time intervals. If missed, growth may not be fully recoverable. Ever-increasing evidence indicates that the pattern and rapidity of…

Placental and Fetal Circulatory and Metabolic Changes Accompanying Fetal Growth Restriction

Introduction During fetal life, factors associated with maternal, placental, and fetal environments interact to ensure optimal fetal metabolism and growth. However, in 3% to 7% of pregnancies these interactions become suboptimal and growth of the fetus does not align with its in utero genetic growth potential, resulting in a reduced growth trajectory and the outcome at birth often termed fetal growth restriction (FGR) . To ensure…

Drug Transfer During Breastfeeding

Introduction Since the early 2000s, researchers and clinicians have greatly expanded the knowledge base of drug entry kinetics as they relate to human milk. Most of the physiochemical properties that affect a drug’s transfer into milk are well known and understood today. , For the busy clinician, the National Institutes of Health and others have published reference works that consolidate the evidence supporting the relative safety…

Drug Distribution in Fetal Life

Introduction Drug distribution and clearance determine the concentration of drug that will be attained at the site of drug action. Drug targets include cell surface receptors, intracellular receptors, enzymes, transcriptional mechanisms, ion channels, and molecular transport systems. These targets may be within the circulatory system, in well-perfused tissues, in less well-perfused tissues, or behind specialized endothelial or epithelial barriers. The fetus lies behind one of these…

Pharmacogenomics

Introduction Pharmacogenetic variants are DNA variants that influence the metabolism and elimination or the action of medications. Research in pharmacogenetics seeks to understand how these variants influence variability in medication response. For the perinatal pharmacologist, genetic variations that affect drug disposition in the fetus, the mother, and the neonate must be considered as one of many sets of variables, along with developmental changes in fetal and…

The Physiology of Placental Drug Disposition

Introduction: From a Passive Filter Barrier Concept to an Active Drug Handling Organ When deconstructed to its basic structure, the placenta is an active (“drug handling”) barrier between two separated systems (maternal, fetal) with placental drug disposition driven by differences in concentration-time profiles between both systems, and the maternal and fetal blood flow to and from the filter. This setting is somewhat similar to hemodialysis or…

Principles of Pharmacokinetics

Introduction Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of drugs. The pharmacokinetic parameters of a drug are used to characterize the drug concentrations reached within the body after a dose and the changes in those concentrations over time. Clinical pharmacokinetics is the discipline that applies pharmacokinetic principles to individualize dosage regimens, optimize the therapeutic effects of a medication, and minimize the chances of an adverse…

Basic Pharmacologic Principles

Introduction Pharmacology is a science concerned with the interaction of substances (e.g., drugs) with cells, tissues, and organisms. The in vivo efficacy of a drug is guided by two principles of pharmacology, namely pharmacokinetics and pharmacodynamics. Pharmacokinetics deals with the processes of drug concentration in the tissue compartments and therefore involves absorption, distribution, biotransformation, and excretion. Pharmacodynamics applies to the study of mechanisms of action of drugs.…

Placental Function in Intrauterine Growth Restriction

Acknowledgments We thank the previous authors, Yi-Yung Chen and Thomas Jansson, for their foundational work and expertise in writing the previous version of this chapter, many of the sections and figures which have been preserved in this revision. Introduction Definitions of Intrauterine Growth Restriction Intrauterine growth restriction (IUGR) remains one of the leading causes of perinatal and neonatal morbidity and mortality worldwide, with significant implications for…

Fetal Origins of Adult Disease: A Classic Hypothesis With New Relevance

Introduction In the late 1980s the late Dr. David J. P. Barker used historical birth records to pioneer the concept that the origins of adult disease could be strongly associated with fetal environmental exposures in pregnancy that resulted in low birth weight (BW) and modified both structure and function of tissues regulating human diseases later in life. Over the past several decades the fetal programming or…

Intra-Amniotic Infection/Inflammation and the Fetal Inflammatory Response Syndrome

Introduction Infection is the greatest killer in human history. The microbial theory of disease is probably the greatest advance in medicine, for it has made possible the identification of the cause of many diseases, the development of diagnostic modalities (i.e., cultivation of microorganisms), treatment with antimicrobial agents, and the development of vaccines. The achievements of the microbial theory of disease in medicine and public health are…

Endocrine and Paracrine Function of the Human Placenta

Introduction The placenta produces a greater diversity of hormones in greater quantity than any other single endocrine tissue. Near term, steroid hormones (primarily estrogens and progestins) are being made at the rate of 0.5 g/day, and protein hormones (lactogens, growth factors, and other hormones similar to those of the hypothalamic-pituitary-adrenal axis) are being made at more than twice this rate. Although the secretory nature of the…

Mechanisms of Transfer Across the Human Placenta

Introduction Transfer of solutes across the placenta is essential for fetal growth and development. Placental transfer occurs in both directions, with maternal nutrients transferred to the fetus and fetal wastes to the mother. A wide range of nutrients and wastes must be transported across the placenta requiring multiple different transport processes. Insufficient placental transfer of nutrients or wastes can impair fetal growth and development. When poor…

Regulation of the Placental Circulation

Acknowledgments Research on which this chapter is based was supported by National Institutes of Health grant HD-008783-39 and the George L. MacGregor Professorship in Pediatrics. I thank the many co-investigators and students who, while in my laboratories, facilitated many of our studies. Overview Pregnancy is associated with numerous alterations to the maternal cardiovascular system; however, it is the development of the low-resistance, high-flow placental vascular bed…

Placental Development

Acknowledgments This chapter is a rewritten and updated form of a chapter appearing in a prior edition of this work, written by Dr. Hans-Georg Frank. Portions of the figures and writing remain Dr. Frank’s words. The authors are indebted to Dr. Frank’s contribution to the knowledge of placental structure, histopathology, and development as the scientific community understands it today. Introduction For millennia, the remarkable ability of…

Prenatal Diagnosis

Introduction The prenatal diagnosis of a fetal genetic disorder or a chromosome abnormality generally requires invasive testing; all of the invasive tests carry small but recognized risks of miscarriage. Accordingly, an important aspect of prenatal care is screening to identify those women who face an increased risk of a pregnancy complicated by aneuploidy, genetic syndrome, or congenital malformation. Screening modalities include review of the clinical history…

Angiogenesis

Introduction Embryologically, the cardiovascular system is the first to develop. The vasculature, composed of endothelial cells and their support cells, is critical not only for circulation of blood, but also for the organization, maintenance, and regeneration of multiple organ systems. The embryo forms a primary vascular plexus so that blood vessels first arise through a process called vasculogenesis. Further vessels are generated via sprouting and nonsprouting…

The Extracellular Matrix in Development

Introduction During embryonic patterning, individual cells divide, migrate, differentiate, and respond to environmental cues. The extracellular matrix (ECM) is effectively involved in all these dynamic processes during development, maintenance, and disease. Cells are continuously connected with the ECM, a latticework of glycoproteins that provides structural support and spatial arrangement and directs tissue morphogenesis. The ECM provides a specialized microenvironment that regulates cell behavior by interacting with…

Regulation of Embryogenesis

Introduction Embryogenesis results from the divergent proliferation, migration, survival, and differentiation of cells derived from a single cell, the fertilized egg. Regulatory signals, applied to successive generations of cells, establish the architecture of the early embryo. The same processes are recapitulated during the subsequent development of limbs, organs, and craniofacial structures. Consequently, disruption of these reiterative mechanisms distorts seemingly unrelated structures, as observed in human malformation…