A newborn boy is in the neonatal intensive care unit for mechanical ventilation due to pulmonary hypoplasia. He was born via spontaneous vaginal delivery at 30 weeks gestation to a 41-year-old woman who did not receive prenatal care. The mother had assumed her amenorrhea was due to early menopause, which runs in her family. She took multiple medications for poorly controlled hypertension before realizing she was pregnant. Prenatal ultrasound demonstrated severe oligohydramnios for which delivery was induced. Examination of the infant shows an intubated and sedated boy whose weight is at the third percentile. The temporal, occipital, and parietal bones are underdeveloped, and the right lower limb is shortened and contracted. Which of the following mechanisms is the most likely cause of this neonate's abnormalities?
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This neonate's abnormalities are likely due to exposure to an ACE inhibitor and/or angiotensin II receptor blocker (ARB), which are highly teratogenic antihypertensive medications. During pregnancy, ACE inhibitors and ARBs can cross the placenta and decrease angiotensin II activity:
ACE inhibitors impair metabolism of angiotensin I to angiotensin II by inhibiting ACE activity, thereby decreasing angiotensin II levels.
ARBs block the angiotensin II receptor type 1 (AT1), which decreases angiotensin II activity.
The decrease in angiotensin II causes abnormal fetal renal development (eg, renal hypoplasia) and a reduced fetal glomerular filtration rate (GFR). Hypoplastic kidneys with reduced GFR produce low volumes of fetal urine, which, as the main component of amniotic fluid, can lead to oligohydramnios.
Because amniotic fluid enables fetal lung development and protects against limb compression, neonates with severe oligohydramnios are at risk for pulmonary hypoplasia and limb defects (ie, Potter sequence). This neonate also has hypocalvaria (eg, temporal, occipital, and parietal bone hypoplasia) due to impaired cranial vascularization and severe growth restriction (likely due to both fetal compression and maternal hypertension).
(Choices A and B) Methyldopa (alpha-2 adrenergic agonist), labetalol (beta-adrenergic antagonist), and nifedipine (calcium channel blocker) are the preferred antihypertensive medications during pregnancy. Although they can cause neonatal adverse effects (eg, hypotension [methyldopa], hypoglycemia [labetalol]), none are associated with abnormal fetal renal development or oligohydramnios.
(Choice C) Radiation causes cellular damage due to molecular bond disruption by free radicals. Fetal radiation exposure increases the risk for cancer, particularly childhood leukemia.
(Choice E) Impaired fetal oxygen delivery can occur with maternal anemia, tobacco use, or placental insufficiency (in which there is decreased placental perfusion [eg, preeclampsia, fetal chromosomal abnormalities]). Although decreased oxygenation can lead to fetal growth restriction, it does not typically cause oligohydramnios and limb deformity.
(Choice F) Nonsteroidal anti-inflammatory drugs decrease prostaglandin E1 production, causing vasoconstriction. Although the fetal GFR may decrease as a result, the associated oligohydramnios is typically mild and transient. In contrast, ACE inhibitors and ARBs cause long-lasting abnormalities in renal development.
Educational objective:
ACE inhibitors and angiotensin II receptor blockers are teratogens. Both decrease angiotensin II activity, leading to abnormal fetal renal development, oligohydramnios, and potential neonatal Potter sequence (ie, pulmonary hypoplasia, limb deformity).