Michael T. Parsons

Forward shift in the initiation of the nocturnal estradiol surge in the pregnant baboon: Is this the genesis of labor?

Daily (9 AM and 6 PM) blood samples were obtained from the inferior vena cava during the last trimester of pregnancy in a tethered baboon model. In addition, three 24-hour (hourly blood sampling) studies were performed at days 143 to 147, 158 to 162, and 172 to 177 of pregnancy. Dramatic 24-hour rhythms in progesterone and estradiol were detected, with both steroids surging nocturnally. Early in the third trimester the estradiol surge followed the progesterone surge. However, approximately 10 to 12 days before delivery, the initiation of the nocturnal estradiol surge shifted forward, thus preceding the progesterone surge. This forward shift in the estradiol surge created a daily (3 to 5 hours) window of elevated estradiol-to-progesterone ratio and appears to coincide with the initiation of nocturnal uterine contractions. The nocturnal uterine contractions can be inhibited by an oxytocin antagonist. We hypothesize that this forward shift in the initiation of the estradiol surge induces nocturnal uterine contractions by oxytocin release and/or increase in uterine oxytocin receptors and generates molecular messages that are the genesis for labor and delivery in the baboon.

Inhibition of spontaneous uterine contractions during the last trimester in pregnant baboons by an oxytocin antagonist

The effect of a potent oxytocin antagonist, produced in our laboratories, on spontaneous uterine contractions in the pregnant baboon was examined. Three types of uterine contractions were studied: immediately after operation, during the nocturnal period, and near or at labor. Bolus intravenous injections of oxytocin antagonist were given and uterine activity was examined +/- 1 hour after the injection. The oxytocin antagonist caused a precipitate decrease (approximately 70%) in contractile force (mean amplitude x frequency) in the first 15 minutes after injection (p less than 0.05); this force diminished to approximately 90% at the end of 1 hour for both nocturnal and labor contractions. In contrast, uterine contractions immediately after operation were diminished by only 60% within 60 minutes after the oxytocin antagonist. These results indicate that the oxytocin antagonist is a potent inhibitor and suggest that oxytocin is a primary regulator of spontaneous nocturnal and labor uterine contractions in the pregnant baboon.

Effect of pregnancy on the metabolic clearance rate and the volume of distribution of oxytocin in the baboon

Pharmacokinetic parameters of oxytocin (OT) metabolism were determined during the last third of pregnancy and again 4-8 wk after delivery in the baboon. Animals were placed on a tether system with venous and arterial access and a continuous monitoring of uterine contractions during gestation. Two methods of determining OT pharmacokinetics were utilized (bolus injection vs. continuous infusion). The metabolic clearance rate of OT as determined during the bolus trials (n = 7) was 22.2 +/- 1.5 ml.min-1.kg-1 in pregnancy and 16.3 +/- 1.4 ml.min-1.kg-1 postpartum (P < 0.05), respectively, and 23.7 +/- 2.8 vs. 16.9 +/- 3.7 ml.min-1.kg-1 (P < 0.05), respectively, as determined during the 1-h infusion trials (n = 4). The initial dilution volume and the volume of distribution at steady state of OT after administration did not differ between pregnant and postpartum animals (P > 0.05). The mean residence time (MRT) of OT was shorter during pregnancy, 7.7 +/- 0.8 vs. 10.8 +/- 1.2 min postpartum (P < 0.05). In summary, OT metabolism during pregnancy in the baboon is characterized by 1) increased clearance rate (1.4-fold), 2) accelerated turnover due to the shorter MRT, and 3) unaltered distribution.

Assessment of the alveolar-arterial oxygen gradient as a screening test for pulmonary embolism in pregnancy.

OBJECTIVE The objective of the study was to determine whether the alveolar-arterial (A-a) oxygen gradient is an adequate screening test for pulmonary embolism (PE) in pregnancy and postpartum. STUDY DESIGN A chart review was performed at Tampa General Hospital. Patients who had a workup for a PE consisting of a computed tomography pulmonary angiogram and an arterial blood gas from 2002 to 2009 were included in the analysis. Sensitivity, specificity, and negative and positive predictive values were calculated. Additionally, common clinical signs and symptoms were assessed for their ability to accurately predict PE. RESULTS Of 102 patients, there were 13 PEs (2 antepartum and 11 postpartum). The best sensitivity, specificity, and negative and positive predictive values for A-a gradients were 76.9%, 20.2%, 80.0%, and 11.5%, respectively. CONCLUSION The A-a gradient is a poor screening test for PE in pregnancy and postpartum. Suspicion of PE should prompt early imaging studies to rapidly make the diagnosis and begin treatment.

Oxytocin antagonist inhibitory effect on the rat and baboon uterus may be overcome by prostaglandins

OBJECTIVE A potent, long-acting oxytocin antagonist produced in our laboratory (ANTAG-III) can inhibit uterine response to oxytocin in the rat and baboon for hours and even days. The purpose of this study was to evaluate uterine response to prostaglandins subsequent to the administration of ANTAG-III. STUDY DESIGN For the rat study one cannula was inserted in the jugular vein, and another cannula to measure uterine activity was inserted in the uterus. In study 1 saline solution or 5 micrograms of ANTAG-III was administered to five rats each, followed by 100 mU of oxytocin at 0.1, 1, and 2 hours. In study 2 six rats each were infused with saline solution of 5 micrograms of ANTAG-III, followed 1 hour later by 5 micrograms of 15-methyl-prostaglandin F2 alpha and uterine activity monitored. After baseline activity returned to normal 100 mU of oxytocin was infused and the uterine response reassessed. For the baboon study ANTAG-III was administered into the aorta of tethered pregnant baboons (n = 2). An oxytocin challenge test was performed starting with 10 mU/min and going up to 400 mU/min. After a significant uterine contractile response was established and activity returned to baseline, a 15-methyl-prostaglandin F2 alpha challenge test was performed. RESULTS During the period in which the response to oxytocin was inhibited the uterine response to 15-methyl-prostaglandin F2 alpha of the estrous rat and pregnant baboon was maintained. CONCLUSIONS The inhibition of the estrous rat and pregnant baboon uterus to oxytocin caused by ANTAG-III may be prolonged. During this period uterine response to prostaglandins is not altered.

Comparison of the in vivo activity of different oxytocin antagonists in the pregnant baboon.

Objective: To ascertain the relative activity of five oxytocin antagonists (OTAs) in vivo in a tethered pregnant baboon model and compare these results to previously reported affinities in human and rat oxytocin receptor assays and median effective dose in rat uterotonic bioassay. Methods: Pregnant tethered baboons between days 130 and 160 of pregnancy were given an oxytocin challenge test 1 minute after infusion of 1 mg of one of five randomly selected OTAs: ANTAG I, ANTAG II, ANTAG III, L366948, and Atosiban. Once the uterine response to exytocin returned to normal (1-8 days) the OCT was repeated with one of the remaining, untested OTAs during the 130-160 day period. Uterine activity, the time until the first significant response, and the dose of oxytocin needed to induce this response were all factored into one expression, the antagonist-response interval (ARI). Results: When expressed as ratio to ANTAG I the relative ARI for the OTAs were 0, .5, 1.0, 2.4 and 59.2 for L366948, Atosiban, ANTAG I, ANTAG II, and ANTAG III, respectively. ANTAG III and L366948 were significantly different from each other and the three other OTAs (P < .05). The log10 ARI for the 4 active OTAs when correlated with the log10 of the human and rat oxytocin receptor affinities and the rat uterotonic bioassay were all highly correlated (r = .99; P < .05). Conclusion: ANTAG III is a potent, long-acting OTA in vivo in the pregnant baboon and has the potential as a tocolytic in humans.

Diurnal changes in plasma prolactin during the last one third of pregnancy in the baboon.

Previous studies in our laboratory revealed that daily plasma prolactin (Prl) levels were higher in the evening than in the morning in the pregnant baboon suggesting a diurnal variation. The goal of this study was to examine in more detail the diurnal alterations in plasma Prl levels. A tethered pregnant baboon model was utilized for these studies. Hourly venous blood samples were taken from 0700 to 2400 hr (n=10) or until 0700 hr the following day (n=5). The studies were performed at various days of pregnancy from day 135 until delivery. Plasma samples were analyzed for Prl by radioimmunoassay. A surge in plasma Prl was detected, starting around 1500 to 1600 hr and lasting for 3 to 5 hr. The surge occurred before the lights went off in the colony (1800 hr). Baseline Prl levels were higher in animals < 15 days before delivery compared to those > 15 days before delivery (P < 0.05). In contrast, no differences were found in the average peak Prl values between these two groups of animals. In summary, in the pregnant baboon during the last one‐third of pregnancy plasma Prl surges, beginning around 1500 to 1600 hr and lasting for 3 to 5 hr. Less than 15 days before delivery the mean baseline Prl levels are higher compared to animals greater than 15 days before delivery. Am. J. Primatol. 47:231–239, 1999.

Surgical repair of atrial septal defect with severe pulmonary hypertension during pregnancy: a case report with literature review.

We are reporting a case of a 37-year-old pregnant woman with a large secundum atrial septal defect with left-to-right shunt and severe pulmonary hypertension. Her atrial septal defect was undiagnosed before this pregnancy. After carefully considering all the options, we repaired her atrial septal defect with an open heart surgical closure at 20 weeks of gestation. A substantial and consistent reduction in pulmonary arterial pressure after the surgery and subsequent uneventful delivery indicate that surgical repair of atrial septal defects is a viable option that should be considered for such patients.

Vibroacoustic Stimulation and Auditory Acuity in Preterm Infants

Vibroacoustic stimulation (VAS) is widely accepted as a simple and inexpensive adjunctive antenatal test for fetal well-being. However, possible adverse effects of VAS on auditory acuity are not completely known and are of concern, especially for infants delivered prematurely. The purpose of our study was to evaluate neonatal hearing with the brain stem auditory evoked response (BAER) in 33 preterm neonates exposed to acoustic stimulation in utero and to compare the results with those of 33 preterm neonates who were not exposed to acoustic stimulation. Of the 33 exposed neonates, four had abnormal BAER results, indicating an apparent hearing loss. In three of four cases, an infectious etiology was found, suggesting a lack of association between antenatal VAS and hearing loss. By comparison, of the 33 preterm infants not exposed to VAS antenatally (control group), one infant had an abnormal BAER result and was subsequently diagnosed to have suffered a congenital hearing loss.Thus, the risk of acoustic trau...