This review deals with early neonatal medicine and its rapid development as a medical specialty, starting with the birth of neonatology in the early 19th century. Shaffer first used the term neonatology in 1963 to cover neonatal disorders and their treatment. Between the early 19th century and the 1950s, neonatal care was ensured by obstetricians, whose main goal was to reduce neonatal mortality. After the second world war, and especially the 1960s, the development of neonatal physiology and pathophysiology provided insights into neonatal diseases and their treatment, including respiratory distress, jaundice, malnutrition, and prevention of respiratory distress and brain complications, etc. Currently, neonatal mortality, regardless of birth weight, is below 2/1000, and the survival rate of premature infants, regardless of gestational age and birth weight, exceeds 85%. This represents a resounding success, despite the associated costs, ethical issues, and inevitable morbidity.

Folates are needed for synthesis of methionine, the precursor of S-adenosyl methionine (SAM). They play therefore a key role in nutrition and epigenomics by fluxing monocarbons towards synthesis or methylation of DNA and RNA, and methylation of gene transregulators, respectively. The deficiency produces intrauterine growth retardation and birth defects. Folate deficiency deregulates epigenomic mechanisms related to fetal programming through decreased cellular availability of SAM. Epigenetic mechanisms of folate deficiency are illustrated by inheritance of coat colour of agouti mice model and altered expression of Igf2/H19 imprinting genes. Dietary exposure to fumonisin FB1 acts synergistically with folate deficiency on alterations of heterochromatin assembly Deficiency in folate and vitamin B12 produces impaired fatty acid oxidation in liver and heart through unbalanced methylation and acetylation of PGC1-alpha and decreased expression of SIRT1, and long-lasting cognitive disabilities through impaired hippocampal cell proliferation, differentiation and plasticity and atrophy of hippocampal CA1 Deciphering these mechanisms will help understand the discordances between experimental models and population studies on folate supplementation.

Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min) on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP) kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.

Folates are needed for synthesis of methionine, the precursor of S-adenosyl methionine (SAM). They play therefore a key role in nutrition and epigenomics by fluxing monocarbons towards synthesis or methylation of DNA and RNA, and methylation of gene transregulators, respectively. The deficiency produces intrauterine growth retardation and birth dejects. Folate deficiency deregulates epigenomic mechanisms related to fetal programming through decreased cellular availability of SAM. Epigenetic mechanisms of folate deficiency are illustrated by inheritance of coat colour of agouti mice model and altered expression of Igf2/H19 imprinting genes. Dietary exposure to fumonisin FB1 acts synergistically with folate deficiency on alterations of heterochromatin assembly. Deficiency in folate and vitamin B12 produces impaired fatty acid oxidation in liver and heart through imbalanced methylation and acetylation of PGC1-alpha and decreased expression of SIRT1, and long-lasting cognitive disabilities through impaired hippocampal cell proliferation, differentiation and plasticity and atrophy of hippocampal CA1. Deciphering these mechanisms will help understand the discordances between experimental models and population studies on folate supplementation.

The deleterious effects of maternal drug administration on the unborn child are usually considered in terms of teratogenicity. However, few prescribers are aware of the effects that some drugs passively received at the end of pregnancy can have on neonatal adaptation. In addition to analgesics administered during labor, some 15% of pregnant women take chronic treatments. The aim of this report is to examine the possible risks of such "inherited" drug substances, in order to improve neonatal safety. Gestational modifications of drug metabolism are briefly discussed, along with the timing of embryonic and/or fetal drug exposure and the characteristics of placental drug transfer. Vital threats include effects on the central nervous system, respiration, and hemodynamics. The fetal and neonatal impacts of the main pharmacological categories are summarized, distinguishing those that are strongly contraindicated from those that can be used safely, with caution, during pregnancy. The French National Academy of Medicine stresses the need for specific warnings for healthcare professionals on neonatal hazards of intrauterine drug exposure. This information must be part of the curriculum for medical students of all specialties, and must be underlined by drug companies and regulatory authorities. It should notably be provided through websites such as the Paris Teratogenicity Reference Center (Centre de reference sur les agents teratogenes, CRAT).