Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy.

OBJECTIVE: Antipsychotic medications are used by increasing numbers of women of reproductive age. The safety of these medications during pregnancy has not been well described. We undertook a systematic review and meta-analysis of the adverse obstetric and neonatal outcomes associated with exposure to antipsychotics during pregnancy. DATA SOURCES: PubMed, Reprotox, and ClinicalTrials.gov were searched to identify potential studies for inclusion. METHODS OF STUDY SELECTION: Case-control or cohort studies estimating adverse birth outcomes associated with antipsychotic exposure during pregnancy were included. Pooled odds ratios (ORs) were used for dichotomous outcomes and weighted mean differences were used for neonatal birth weight and gestational age. Thirteen cohort studies, including 6,289 antipsychotic-exposed and 1,618,039 unexposed pregnancies, were included. TABULATION, INTEGRATION, AND RESULTS: Antipsychotic exposure was associated with an increased risk of major malformations (absolute risk difference [ARD] 0.03, 95% confidence interval [CI] 0.00-0.05, P=.04, Z=2.06), heart defects (ARD 0.01, 95% CI 0.00-0.01, P<.001, Z=3.44), preterm delivery (ARD 0.05, 95% CI 0.03-0.08, P<.001, Z=4.10), small-for-gestational-age births (ARD 0.05, 95% CI 0.02-0.09, P=.006, Z=2.74), elective termination (ARD 0.09, 95% CI 0.05-0.13, P<.001, Z=4.69), and decreased birth weight (weighted mean difference -57.89 g, 95% CI -103.69 to -12.10 g, P=.01). There was no significant difference in the risk of major malformations (test for subgroup differences: χ²=0.07, degrees of freedom=1, P=.79) between typical (OR 1.55, 95% CI 1.21-1.99, P=.006) and atypical (OR 1.39, 95% CI 0.66-2.93, P=.38) antipsychotic medications. Antipsychotic exposure was not associated with risk of large-for-gestational-age births, stillbirth, and spontaneous abortion. Although antipsychotic exposure during pregnancy was associated with increased risk of adverse obstetric and neonatal outcomes, this association does not necessarily imply causation. This analysis was limited by the small number of included studies and limited adjustment in studies for possible confounders. CONCLUSION: Women requiring antipsychotic treatment during pregnancy appear at higher risk of adverse birth outcomes, regardless of causation, and may benefit from close monitoring and minimization of other potential risk factors during pregnancy.

Antidepressant use in pregnant and postpartum women.

Women in their reproductive years are at risk of experiencing depressive and anxiety disorders. As such, it is likely that pregnant women will undergo treatment with antidepressants. We review the risk of adverse birth outcomes and neonatal complications subsequent to antidepressant use in pregnancy. An inconsistent literature shows that antidepressant exposure is associated with shortened gestations and diminished fetal growth; these effects are small. Transitory neonatal signs are seen in some neonates after exposure to antidepressants in utero. No specific pattern of malformations has been consistently associated with antidepressants, with the possible exception of paroxetine and cardiac malformations. There is inconclusive evidence of a link between antidepressants in late pregnancy and persistent pulmonary hypertension in the newborn. Extensive study finds that antidepressants cannot be considered major teratogens. It is likely that confounding factors contribute to a number of the adverse effects found to be associated with antidepressant use in pregnancy.

Prostaglandins in bone: bad cop, good cop?

Prostaglandins (PGs) are multifunctional regulators of bone metabolism that stimulate both bone resorption and formation. PGs have been implicated in bone resorption associated with inflammation and metastatic bone disease, and also in bone formation associated with fracture healing and heterotopic ossification. Recent studies have identified roles for inducible cyclooxygenase (COX)-2 and PGE(2) receptors in these processes. Although the effects of PGs have been most often associated with cAMP production and protein kinase A activation, PGs can engage an extensive G-protein signaling network. Further analysis of COX-2 and PG receptors and their downstream G-protein signaling in bone could provide important clues to the regulation of skeletal cell growth in both health and disease.

Bone morphogenetic protein 2 enhances PGE(2)-stimulated osteoclast formation in murine bone marrow cultures.

Bone morphogenetic protein 2 (BMP-2) is used clinically to stimulate bone formation and accelerate fracture repair. Adding prostaglandin (PG) E(2) or PGE(2) receptor agonists to BMP-2 has been proposed to improve BMP-2 efficacy. However, this may enhance bone resorption, since PGE(2) can increase receptor activator of NF-kappaB ligand (RANKL) expression and decrease osteoprotegerin (OPG) expression in osteoblasts, and the RANKL:OPG ratio is critical for osteoclast formation. We used bone marrow (BM) cultures and BM macrophage (BMM) cultures from outbred CD1 mice to examine effects on osteoclast formation of BMP-2 and PGE(2). In BM cultures, which contain both osteoblastic and osteoclastic lineage cells, BMP-2 (100 ng/ml) alone did not increase osteoclast formation but enhanced the peak response to PGE(2) by 1.6-9.6-fold. In BMM cultures, which must be treated with RANKL because they do not contain osteoblastic cells, BMP-2 did not increase osteoclast formation, with or without PGE(2). Our results suggest that BMP-2 can increase osteoclast formation in response to PGE(2) by increasing the RANKL:OPG ratio in osteoblasts, which may have therapeutic implications for the use of BMP-2.

Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin.

Oxidative stress has been implicated as an important mechanism of vascular endothelial dysfunction induced by aging. Previous studies suggested that tetrahydrobiopterin (BH4), an essential cofactor of endothelial NO synthase, could be a molecular target for oxidation. We tested the hypothesis that oxidative stress, in particular oxidation of BH4, may contribute to attenuation of endothelium-dependent relaxation in aged mice. Vasomotor function of isolated carotid arteries was studied using a video dimension analyzer. Vascular levels of BH4 and its oxidation products were measured via HPLC. In aged mice (age, 95 +/- 2 wk), endothelium-dependent relaxation to ACh (10(-5) to 10(-9) M) as well as endothelium-independent relaxation to the NO donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-5) to 10(-9) M) were significantly reduced compared with relaxation detected in young mice (age, 23 +/- 0.5 wk). Incubation of aged mouse carotid arteries with the cell-permeable SOD mimetic Mn(III)tetra(4-benzoic acid)porphyrin chloride normalized relaxation to ACh and DEA-NONOate. Furthermore, production of superoxide anion in aorta and serum levels of amyloid P component, which is the murine analog of C-reactive protein, was increased in old mice. In aorta, neither the concentration of BH4 nor the ratio of reduced BH4 to the oxidation products were different between young and aged mice. Our results demonstrate that in mice, aging impairs relaxation mediated by NO most likely by increased formation of superoxide anion. Oxidation of BH4 does not appear to be an important mechanism underlying vasomotor dysfunction in aged mouse arteries.