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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.

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.

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., (Copyright © 2013 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

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.

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.

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.

Context: Intrauterine closure of exposed spinal cord tissue prevents secondary neurologic injury in animals with a surgically created spinal defect; however, whether in utero repair of myelomeningocele improves neurologic outcome in infants with spina bifida is not known., Objective: To determine whether intrauterine repair of myelomeningocele improves patient outcomes compared with standard care., Design: Single-institution, nonrandomized observational study conducted between January 1990 and February 1999., Setting: Tertiary care medical center., Participants: A sample of 29 study patients with isolated fetal myelomeningocele referred for intrauterine repair that was performed between 24 and 30 gestational weeks and 23 controls matched to cases for diagnosis, level of lesion, practice parameters, and calendar time. All infants were followed up for a minimum of 6 months after delivery., Main Outcome Measures: Requirement for ventriculoperitoneal shunt placement, obstetrical complications, gestational age at delivery, and birth weight for study vs control subjects., Results: The requirement for ventriculoperitoneal shunt placement for decompression of hydrocephalus was significantly decreased among study infants (59% vs 91%; P = .01). The median age at shunt placement was also older among study infants (50 vs 5 days; P = .006). This may be explained by the reduced incidence of hindbrain herniation among study infants (38% vs 95%; P<.001). Following hysterotomy, study patients had an increased risk of oligohydramnios (48% vs 4%; P = .001) and admission to the hospital for preterm uterine contractions (50% vs 9%; P = .002). The estimated gestational age at delivery was earlier for study patients (33.2 vs 37.0 weeks; P<.001), and the birth weight of study neonates was less (2171 vs 3075 g; P<.001)., Conclusions: Our study suggests that intrauterine repair of myelomeningocele decreases the incidence of hindbrain herniation and shunt-dependent hydrocephalus in infants with spina bifida, but increases the incidence of premature delivery.

Unlabelled: This study compares the placental transfer of ropivacaine and bupivacaine using the dual perfused, single cotyledon human placental model. We studied the effects of maternal/fetal protein binding, maternal ropivacaine concentration, and fetal pH on ropivacaine transfer. At a clinically relevant maternal concentration (1 microg/mL), the calculated transfer ratios (local anesthetic percent transfer/antipyrine percent transfer) of ropivacaine (0.82 +/- 0.03) and bupivacaine (0.74 +/- 0.01) were comparable at the completion of the perfusion experiment (120 min). When the perfusates were modified to simulate actual in vivo plasma protein binding values, the maternal-to-fetal transfer of ropivacaine and bupivacaine decreased significantly (P < 0.05) as indicated by transfer ratios of 0.42% +/- 0.07% and 0.40% +/- 0.03%, respectively. No saturation of the transfer process was observed for either drug at the maternal concentrations investigated. The placental transfer of both local anesthetic agents increased significantly as the fetal pH decreased. This investigation shows that ropivacaine and bupivacaine cross the human placenta at a similar rate, despite their differences in lipophilicity and stereochemistry. Placental transfer of both compounds is highly influenced by maternal and fetal protein concentration and the fetal pH., Implications: The placental transfer of ropivacaine was shown to be similar to that of bupivacaine, and is thus highly influenced by the degree of maternal and fetal protein binding and fetal pH.

Factors affecting lidocaine transfer across the normal term human placenta were studied using the dual perfused isolated single cotyledon. Experiments were performed using perfusates which provided equal protein binding in both the maternal and fetal circuits as well as perfusates that approached the actual in vivo maternal/fetal protein binding gradient. Additional experiments were performed to investigate the effects of increasing maternal lidocaine concentration (5, 10, 40, 80 microg/mL) on maternal to fetal (M-->F) lidocaine transfer across the human placenta. Lidocaine crossed the placenta rapidly in both the M-->F and fetal to maternal (F-->M) directions. When protein binding was similar in the two circuits, M-->F transfer ratios (lidocaine transfer/antipyrine transfer) were significantly lower than the transfer ratios seen in the F-->M direction (0.59+/-0.04 versus 0.84+/-0.06, P<0.05). Transfer ratios (M-->F: 0.83+/-0.06, F-->M: 0.96+/-0.06) were not reduced when the physiological maternal/fetal protein binding gradient was present. Lidocaine transfer was not diminished by increasing maternal concentrations and, in contrast to bupivacaine, was not significantly affected by its binding.

This study investigated factors that influence the placental transfer of sufentanil using the dual-perfused, single-cotyledon human placental model. Placentas were collected from healthy women. Experiments were designed to elucidate the effects of maternal protein binding, changing maternal sufentanil concentration (1, 10, 20, and 100 ng/mL) and decreasing fetal pH (fetal acidemia 7.2, 7.0, 6.8) on the placental transfer of sufentanil. Sufentanil crossed the placenta rapidly at a rate two-thirds that of the transfer marker, antipyrine. Sufentanil transfer increased linearly with the maternal concentration (r = 0.999). Sufentanil/antipyrine maternal to fetal (M-->F) transfer ratios were significantly reduced (0.66 +/- 0.05 vs 0.40 +/- 0.04, P < 0.05) when fresh frozen plasma was added to the maternal circuit to enhance protein binding. Fetal pH and sufentanil transfer were related because sufentanil M-->F clearance increased significantly as the fetal pH decreased (r = 0.973, P < 0.05). Sufentanil appears to cross the placenta by passive diffusion but is modulated by the degree of maternal protein binding. Sufentanil M-->F transfer is enhanced by fetal acidemia.

Background: Fetal acidemia increases umbilical venous bupivacaine concentrations in the in situ rabbit model. The authors studied the effects of decreasing fetal pH on the rate of maternal to fetal (M-->F) clearances of lidocaine, bupivacaine, 2-chloroprocaine, and antipyrine (a nonionic marker of placental transfer) across the isolated, dual perfused, human placental cotyledon., Methods: Maternal to fetal clearances of bupivacaine, lidocaine, 2-chloroprocaine, and antipyrine were determined at fetal pH (7.4), during progressive fetal acidemia (pH 7.2-->7.0-->6.8), and after recovery to fetal pH 7.4 in experiments with both low protein state and in those with in vivo maternal and fetal protein-binding potentials., Results: Placental transfer of all three agents increased linearly as the fetal pH decreased. Antipyrine transfer was unaffected. Clearance of lidocaine and bupivacaine, but not 2-chloroprocaine, returned to baseline when fetal pH was restored to 7.4. When maternal and fetal protein-binding potentials were increased, clearance at fetal pH 7.4 of bupivacaine, but not lidocaine, decreased significantly. During fetal acidemia, the transfer of both agents increased, but to a lesser extent than in the low protein concentration experiments., Conclusions: Increasing the pH difference between maternal and fetal perfusates promotes M-->F passage of unionized lidocaine, bupivacaine, and 2-chloroprocaine. This likely results from an increased proportion of ionized local anesthetic in the acidemic fetal perfusate and consequent widening of the M-->F concentration gradient of the unionized form. Transfer of lidocaine and bupivacaine was limited by the maternal protein binding.