Jeffrey D. Stewart

Placebo-controlled comparison between a single dose and a multidose of betamethasone in accelerating lung maturation of mice offspring

OBJECTIVE Our purpose was to determine, in a placebo-controlled manner with a mouse model, whether a multidose of betamethasone is more beneficial than a single dose in accelerating fetal lung maturation. STUDY DESIGN Ninety gravid CD-1 mice were randomly assigned to 1 of 3 groups (n = 30) to receive either a placebo (0.25 mL subcutaneously) or betamethasone (0.1 mg subcutaneously) as a single dose on gestational day 14 or as a multidose twice daily on gestational day 14 and 15. Ten pregnancies in each group were terminated at gestational day 16.5 to observe the neonatal breathing pattern (scale 0 to 5; 5 is unlabored breathing) and the lung histologic findings (scale 0 to 5; 5 is alveolar budding). The lungs of the offspring belonging to the remaining 20 pregnancies in each group were removed and weighed at postnatal day 1, 3, 5, or 120. RESULTS Fetuses exposed to a multidose of betamethasone displayed a higher breathing score at gestational day 16.5 than either to a single dose or to the placebo (mean score 4.6 vs 3.8 or 1.3; P <. 001). Alveolar development was greater after exposure to a multidose of betamethasone than after a single dose or after a placebo (mean score 4.4 vs 3.5 or 1.6; P <.001). The lung weights at gestational day 16.5 were less after a multidose of betamethasone than after a single dose of either betamethasone or a placebo (18.3 +/- 1.0 g vs 21.4 +/- 1.3 g or 23.3 +/- 1.3 g; P <.02). The lung/body weight ratio was similarly affected. This reduced weight of the lungs persisted postnatally into adulthood. CONCLUSIONS With a CD-1 mouse model, a multidose of antenatal betamethasone accelerated fetal lung maturation more than after a single dose but was accompanied with a decrease in lung weight that persisted into adulthood.

Pre-eclampsia and induction of labor: A randomized comparison of prostaglandin E2 as an intracervical gel, with oxytocin immediately, or as a sustained-release vaginal insert

OBJECTIVE Our purpose was to compare the efficacy of commercial prostaglandin E2 products, in combination with oxytocin, for the initiation of labor among pregnancies with pre-eclampsia. STUDY DESIGN Patients with pregnancy-induced hypertension and with either proteinuria or other end-organ damage were enrolled if they had an unfavorable Bishop score (</=4) and were eligible to undergo labor. Each was randomly assigned to receive prostaglandin E2 either as a 0. 5-mg intracervical gel (Prepidil) or as a 10-mg controlled-release vaginal insert (Cervidil). Oxytocin was begun either immediately after instillation of the gel or was delayed until after removal of the insert. RESULTS Of the 70 patients, there were no differences between the Prepidil (n = 34) and the Cervidil (n = 36) groups in maternal demographics, gestational age, parity, and predose Bishop score. There was a mean 14.3-hour difference in the duration from beginning therapy until vaginal delivery in the Prepidil group than in the Cervidil group (11.5 +/- 2.3 hours vs 25.8 +/- 6.9 hours, P <. 001). This time difference, which favored use of Prepidil-immediate oxytocin, remained significant after parity (nulliparous: 20 hours, P <.005; multiparous: 12 hours, P <.01) and gestational age were controlled (preterm: 15.5 hours, P <.01; term: 13.3 hours, P <.01). CONCLUSION Use of combined intracervical prostaglandin E2 gel-immediate oxytocin therapy was more effective in shortening the induction-to-vaginal delivery time than use of a controlled-release prostaglandin E2 vaginal insert.

Effect of In Utero Exposure to Betamethasone on Motivation/Anxiety Testing in Mice Offspring

In utero exposure to a single dose of the long-acting corticosteroid betamethasone at GD 14 has been shown to induce specific differences in motivation/anxiety testing among offspring. Because multidosings are desired to enhance fetal lung maturation, our objective was to compare effects of multidosings of betamethasone with a placebo on postnatal tests of motivation and anxiety. Sixty gravid CD-1 mice were randomly assigned to receive one of six treatment regimens (n = 10) that consisted of a single or a double SC dosing of either betamethasone (Celestone soluspan 0.2 mg on GD 14; 0.1 mg on GD 13 to 16; 0.1 mg b.i.d. on GD 14 and 15; 0.1 mg b.i.d. on GD 13 to 16) or saline (0.25 ml on GD 13 to 16; 0.25 ml b.i.d. on GD 13 to 16). The percent of pups exhibiting separation vocalization was temporarily less at PND 5 after betamethasone exposure to four doses (p < 0.05) and to eight doses (p < 0.01). The percents of pups being successful in homing (PND 9) and in responding to startle stimulation (PND 12-15) were not different between the betamethasone-exposed and placebo-exposed groups. Exploratory performance in the radial arm maze revealed no delay in the activities of juvenile and adult offspring exposed to betamethasone. The percent of male offspring that fought as juveniles and as adults was not different between the betamethasone-exposed and the placebo-exposed groups. The previously reported altered responses using the elevated plus maze, among juvenile and adult offspring, after a single dose of betamethasone was not replicated in this multidose study. These data indicate that prenatal exposure to betamethasone did not affect the mouse offsprings long-term responses to motivation/anxiety testing.

Effect of Antenatal Exposure to Paroxetine (Paxil) on Growth and Physical Maturation of Mice Offspring

OBJECTIVE Our purpose was to determine, in a placebo-controlled manner, whether antenatal exposure to paroxetine affected long-term growth and physical maturation of mice offspring. METHODS Forty-one CD-1 mice consumed paroxetine (n = 21) or a placebo (n = 20) for 2 weeks before conception and throughout gestation. The daily dose of paroxetine (Paxil; 30 mg/kg/d) was known to achieve concentrations in the serum equivalent to the upper therapeutic level in humans and in the fetal brain equivalent to that of the adult mouse. Growth and physical maturation of the offspring were compared by paired t-test, Welchs corrected test, and Fishers exact test. RESULTS The maternal weight gain, litter sizes, number of fetal resorptions, and gestational age at delivery were not different between the paroxetine and the placebo-exposed offspring. Newborn pups exposed to paroxetine were more likely to have low birthweights (1.65 gm vs. 1.70 gm; P < 0.05) and narrower heads (7.7 mm vs. 8.1 mm; P < 0.05). Body weight, body length, and head circumference measurements increased in a manner that was indistinguishable between the two groups of offspring, regardless of gender. No differences in achievement of physical milestones (lower incisor eruption, eye opening, and development of external genitalia) were noted between the two groups. The reproductive capability and the perinatal outcomes of the second-generation offspring were unaffected by paroxetine exposure. CONCLUSION A clinically relevant dose of paroxetine, when given throughout gestation, did not affect long-term growth and physical maturation of mice offspring.

Impact of antenatal exposure of mice to fenfluramine on cardiac development and long-term growth of the offspring.

The objective of this investigation was to determine, in a placebo-controlled manner, whether antenatal exposure to formulations of fenfluramine and dexfenfluramine impacted cardiac development and long-term growth of exposed mice offspring. One hundred forty-four CD-1 mice were randomized to six treatment groups (n =23 or 25) to obtain, per group, 5 gravids for killing on gestational day (GD) 15 and ≤ 10 deliveries for assessing growth of the offspring. Either fenfluramine preparation was administered in feed bars in two doses: 1 and 3.2 times the equivalent human daily dosage according to body surface area. The drugs were given from 2 weeks before mating until GD 15. The mice ingested each drug at target values, averaging 10.5 ± 0.3 and 31.8 ± 1.9 mg/kg/d for fenfluramine and 5.0 ± 0.2 and 16.2 ± 0.4 mg/kg/d for dexfenfluramine. The drug concentration was about 36% in the fetal brain compared with the adult brain. The maternal and the offspring hearts, including mitral and aortic valves, of fenfluramine-exposed mice were indistinguishable from the placebo-exposed mice. The duration of gestation and the litter size were the same between the treatment groups. The mean body weights, body lengths, and head circumferences and early functional testing did not differ significantly between the fenfluramine or dexfenfluramine-exposed offspring and the placebo-exposed offspring. There were no significant treatment differences in growth measured as body weights to PND 120. Neither fenfluramine formulation, given before conception and during gestation, impacted cardiac development and long-term growth of the mice offspring.