• The vitamin A (retinol) derivative all-trans-retinoic acid is essential for normal development and differentiation, and its absence during embryogenesis results in a constellation of malformations affecting multiple organ systems, including the eyes, genitourinary system, cardiovascular system, diaphragm, and lungs (see Chapter 8 for vitamin A deficiency in the postnatal period). Conversely, excessive exposure to retinoic acid also is teratogenic. Infants born to mothers treated with retinoic acid for severe acne have a predictable phenotype (retinoic acid embryopathy), including CNS, cardiac, and craniofacial defects, such as cleft lip and cleft palate. The last entity may stem from retinoic acid–mediated deregulation of components of the transforming growth factor-β (TGF-β) signaling pathway, which is involved in palatogenesis. Mice with knockout of the TGFB3 gene uniformly develop cleft palate, once again illustrating the functional relationship between teratogenic exposure and signaling pathways in the causation of congenital anomalies.
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Congenitalanomaliesresultfromintrinsicabnormalities(malformations)aswellasextrinsicdisturbances(deformations,disruptions).
Congenitalanomaliescanresultfromgenetic(chromosomalabnormalities,genemutations),environmental(infections,drugs,alcohol),andmultifactorialcauses.
Thetimingoftheinuteroinsulthasprofoundinfluenceontheextentofcongenitalanomalies,withearliereventsusuallyhavinggreaterimpact.
Theinterplaybetweengeneticandenvironmentalcausesofanomaliesisemphasizedbythefactthatteratogensoftentargetsignalingpathwaysinwhichmutationshavebeenreportedasacauseforthesameanomalies.
Infections of the fetus and neonate may be acquired transcervically (ascending infections) or transplacentally (hematologic infections).
Transcervical, or ascending, infections are caused by spread of microbes from the cervicovaginal canal and may be acquired in utero or during birth. Most bacterial infections (e.g., α-hemolytic streptococcal infection) and a few viral infections (e.g., herpes simplex) are acquired in this manner. In general, the fetus acquires the infection by “inhaling” infected amniotic fluid into the lungs or by passing through an infected birth canal during delivery. Fetal infection usually is associated with inflammation of the placental membranes (chorioamnionitis) and inflammation of the umbilical cord (funisitis). This mode of spread is typical for pneumonia and, in severe cases, sepsis and meningitis.