The Effects of Vasopressin and Oxytocin on the Fetoplacental Distal Stem Arteriolar Vascular Resistance of the Dual-Perfused, Single, Isolated, Human Placental Cotyledon.

BACKGROUND: Vasoactive agents administered to counter maternal hypotension at cesarean delivery may theoretically intensify the hypoxemic fetoplacental vasoconstrictor response and, hence, negatively impact transplacental oxygen delivery to the fetus. Yet, this aspect of their pharmacodynamic profiles is seldom mentioned, let alone investigated. We hypothesized that vasopressin, a potent systemic vasoconstrictor, and oxytocin, a uterotonic agent administered routinely at cesarean delivery, which, in contrast to vasopressin, possesses significant systemic vasodilator properties, would not influence distal stem villous arteriolar resistance. METHODS: The dual-perfused, single, isolated cotyledon, human placental perfusion model was used to examine the resistance response of the fetoplacental circulation to oxytocin and vasopressin in placentae harvested from healthy women. Twelve of a total of 17 individual experiments were conducted successfully during which either oxytocin (n = 6) or vasopressin (n = 6) was introduced into the fetal reservoir in concentration increments of 10 M. Fetoplacental distal stem villous arteriolar perfusion pressure (FAP) was measured continuously. The fetal circuit concentration of either oxytocin or vasopressin was raised in a stepwise fashion from 10 to 10 M or 10 to 10 M, respectively. Both reservoirs were then purged of drug, after which 1-mL 1.0 mM 5-hydroxytryptamine (2.5 µM), an agent well known to manifestly increase fetoplacental distal stem villous arteriolar resistance, was introduced into the fetal circuit. A significant increase in FAP from baseline in response to exposure to 5-hydroxytryptamine confirmed that the fetoplacental vasoconstrictor response remained reactive. The primary outcome of this study was changes in FAP after incremental dosing of vasopressin and oxytocin. RESULTS: No changes in FAP were observed with either oxytocin or vasopressin regardless of the drug concentration tested. For each drug and concentration, a mean pressure change greater than ±10 mm Hg was excluded with 95% confidence. In contrast, 5-hydroxytryptamine significantly increased perfusion pressure in all 12 successful experiments. CONCLUSIONS: Oxytocin and vasopressin do not influence human fetoplacental distal stem villous arteriolar resistance. The neutral impact of vasopressin noted here is thus analogous to the reported negligible influence of the drug on human pulmonary arteriolar resistance. Neither drug seems likely to adversely influence the compensatory hypoxemic fetoplacental vasoconstrictor response.

The diverse effects of vasopressors on the fetoplacental circulation of the dual perfused human placenta.

BACKGROUND: We studied the effects of 5 vasopressors on fetal arterial perfusion pressure (FAP) in vitro using the dual perfused, single isolated cotyledon, human placental model. METHODS: In 29 separate experiments, epinephrine (75 mg), norepinephrine (75 mg), ephedrine (50 mg), phenylephrine (2 mg), and methoxamine (40 mg) were introduced into the 250-mL reservoir serving the maternal perfusion circuit to determine the effect of each drug on FAP. The duration of drug exposure for each placental cotyledon was approximately 180 minutes. RESULTS: After 180 minutes, FAP (mean +/- sd) increased significantly with ephedrine from 64 +/- 3 to 172 +/- 71 mm Hg (P < 0.001) and with phenylephrine from 81 +/- 4 to 132 +/- 11 mm Hg (P = 0.003). No changes in FAP were seen with epinephrine, norepinephrine, and methoxamine. CONCLUSIONS: In the dual perfused, single isolated cotyledon, human placental model, exposure of the maternal circulation to ephedrine and phenylephrine caused an increase in FAP, whereas exposure to norepinephrine, epinephrine, and methoxamine did not. The pharmacodynamic mechanisms underlying these differences have yet to be explained. Thus, the clinical implications of the findings are as yet unclear.

Hypoxemic fetoplacental vasoconstriction: a graduated response to reduced oxygen conditions in the human placenta.

We investigated the characteristics of hypoxemic fetoplacental vasoconstriction (HFPV) in the dual perfused, single isolated human placental cotyledon. Fetal arterial blood pressures (FAP) were measured in four cotyledons (Group 1) equilibrated with 21% oxygen (O2), 5% carbon dioxide (CO2), and nitrogen (N2) [control] followed by 5% CO2 in N2 for 30 min. FAP (mean +/- sd) increased from 69.8 (+/- 6.4) to 105 (+/- 3.0) mm Hg (P < 0.05), confirming the utility of HFPV in the human placenta. Eight more cotyledons (Group 2) were exposed sequentially and alternately at 15-min intervals to the control gases and to gas blends containing 15%, 12%, 5%, and 0% O2 with 5% CO2 and N2. FAP increased significantly (P < 0.05) in a stepwise fashion from 68.7 (+/- 3.7) to 70.5 (+/- 3.3) mm Hg with 15% O2; from 69.3 (+/- 3.8) to 72.4 (+/- 4.3) mm Hg with 12% O2; from 67.8 (+/- 3.2) to 74.5 (+/- 3.4) mm Hg with 5% O2; and from 69.7 (+/- 3.4) to 77.9 (+/- 5.9) mm Hg with 0% O2, suggesting that HFPV is a graduated response to reduced O2 conditions in the human placenta.

Reducing perinatal complications and preterm delivery for patients undergoing in utero closure of fetal myelomeningocele: further modifications to the multidisciplinary surgical technique.

UNLABELLED: OBJECT.: As more pediatric neurosurgeons become involved with fetal myelomeningocele closure efforts, examining refined techniques in the overall surgical approach that could maximize beneficial outcomes becomes critical. The authors compared outcomes for patients who had undergone a modified technique with those for patients who had undergone fetal repair as part of the earlier Management of Myelomeningocele Study (MOMS). METHODS: Demographic and outcomes data were collected for a series of 43 delivered patients who had undergone in utero myelomeningocele closure at the Fetal Center at Vanderbilt from March 2011 through January 2013 (the study cohort) and were compared with data for 78 patients who had undergone fetal repair as part of MOMS (the MOMS cohort). For the study cohort, no uterine trocar was used, and uterine entry, manipulation, and closure were modified to minimize separation of the amniotic membrane. Weekly ultrasound reports were obtained from primary maternal-fetal medicine providers and reviewed. A test for normality revealed that distribution for the study cohort was normal; therefore, parametric statistics were used for comparisons. RESULTS: The incidence of premature rupture of membranes (22% vs 46%, p = 0.011) and chorioamnion separation (0% vs 26%, p < 0.001) were lower for the study cohort than for the MOMS cohort. Incidence of oligohydramnios did not differ between the cohorts. The mean (± SD) gestational age of 34.4 (± 6.6) weeks for the study cohort was similar to that for the MOMS cohort (34.1 ± 3.1 weeks). However, the proportion of infants born at term (37 weeks or greater) was significantly higher for the study cohort (16 of 41; 39%) than for the MOMS cohort (16 of 78; 21%) (p = 0.030). Compared with 10 (13%) of 78 patients in the MOMS cohort, only 2 (4%) of 41 infants in the study cohort were delivered earlier than 30 weeks of gestation (p = 0.084, approaching significance). For the study cohort, 2 fetal deaths were attributed to the intervention, and both were believed to be associated with placental disruption; one of these mothers had previously unidentified thrombophilia. Mortality rates did not statistically differ between the cohorts. CONCLUSIONS: These early results suggest that careful attention to uterine entry, manipulation, and closure by the surgical team can result in a decreased rate of premature rupture of membranes and chorioamnion separation and can reduce early preterm delivery. Although these results are promising, their confirmation will require further study of a larger series of patients.

Review: Potential druggable targets for the treatment of early onset preeclampsia.

Placental delivery is the only known cure for early onset preeclampsia, a major cause of maternal and neonatal morbidity and mortality worldwide. Prolonging pregnancy beyond 25weeks without undue maternal risk favors fetal survival, improves neonatal outcome and saves money. In vitro experiments using human placental tissue and in vivo studies employing "preeclamptic" animal models reveal the presence of likely druggable targets, especially within the maladapted intracellular nucleotide transduction pathways of preeclampsia. This review focuses on some novel pharmacological treatment options targeting early onset severe preeclampsia. Human and animal derived experimental data support the possible roles of nitric oxide donors (glyceryltrinitrate), aspirin, dietary supplements (calcium, l-Arginine, anti-oxidant vitamins), phosphodiesterase-5 inhibitors, statins, carbon monoxide and most recently, hydrogen sulfide. Extension of pregnancy or improvement of the disorder using means applicable in under resourced areas of the world would have a major positive impact on women's health globally. We therefore advocate the immediate launch of clinical trials testing simple innovative therapies in large obstetric units of developing countries such as South Africa or Brazil where preeclampsia is endemic and a regular killer of both mothers and offspring.