Effects of intravenous isoxsuprine and ritodrine, with and without concomitant dexamethasone, on fetoplacental and pituitary hormones and cyclic adenosine monophosphate during late pregnancy.

Beta sympathomimetic drugs are used to inhibit preterm labor and glucocorticoids to accelerate fetal pulmonary maturation. A study was designed to investigate the hormonal effects of intravenous infusion of isoxsuprine 150 to 200 mcg. per minute or ritodrine 100 to 150 mcg. per minute in a series of 28 women at 28 to 40 weeks' gestation, with and without concomitant dexamethasone therapy. Serial serum samples taken before and during the six hours of infusion were assayed for cyclic adenosine-3,5-monophosphate (AMP), estradiol, estriol, progesterone, human placental lactogen (hPL), thyrotropin (TSH), follicle-stimulating hormone (FSH), and human growth hormone (gGH). Ritodrine was more potent than isoxsuprine in increasing the circulating levels of cyclic AMP. The levels of placental steroid hormones decreased slightly, as did the ratio of progesterone to estradiol. Human placental lactogen and pituitary hormones showed no consistent changes. Simultaneous administration of dexamethasone did not modify these results.     

Effect of dexamethasone on prolactin secretion in late pregnancy.

It is established that PRL secretion is regulated by estrogens. Glucocorticoids, on the other hand, suppress estrogen secretion during pregnancy and may also inhibit PRL by direct hypothalamopituitary action. In this study PRL and estradiol were determined with specific radioimmunoassays in 14 women during gestational weeks 28 to 34 prior to, during, and following short-term intramuscular dexamethasone administration (12, 8, and 4 mg on three consecutive days) used for prophylaxis of RDS in preterm infants. There were no significant alterations in PRL serum concentrations; estradiol showed a significant drop (P less than 0.001) during all 3 days of treatment, returning to the pretreatment level on posttreatment day 1. The PRL and TSH responses to 200 micrograms of intravenous TRH on day 2 or 3 of dexamethasone treatment in six women during late pregnancy were not inhibited. Short-term dexamethasone treatment with pharmacologic doses does not suppress the physiologic secretion and release of PRL or the release induced by TRH during late pregnancy.     

Metabolic effects of intravenous ritodrine infusion during pregnancy

The effect of intravenous administration of ritodrine on blood glucose, insulin, free fatty acids and electrolytes in 17 third-trimester gravidas was investigated.A highly significant increase in blood glucose, insulin and free fatty acids and a marked decrease in serum potassium levels were registered. No significant changes during ritodrine infusion were recorded in serum levels of sodium, chloride, calcium, phosphorus and magnesium.No cardiac arrhythmias or electrocardiographic deteriorations occurred.While intravenous ritodrine administration seems to be safe in normal pregnancy, there may be a risk in diabetic patients, digitalized cases and those patients being treated with diuretics.     

Maternal circulatory response to a single dose of ritodrine hydrochloride during orthostasis in normal and hypertensive late pregnancy

Placental blood perfusion, the maternal heart rate, and arterial blood pressure were measured before and after a single intramuscular dose of ritodrine hydrochloride during orthostasis in 11 healthy pregnant women, 10 pre-eclamptic patients, and 11 pregnant patients with essentially hypertension. There was a slight increase in placental blood perfusion in the healthy subjects and a significant rise in the pre-eclamptic patients and the women with essential hypertension. The heart rate increased significantly in all groups. No greater changes in the systolic and diastolic blood pressures were observed. The clinical significant of the results is discussed briefly.     

Genotoxic effect of tocolytic drug ritodrine in combination with smoking during pregnancy

Objective: Tocolytic drugs are used widely in order to prevent preterm birth. Ritodrine, is the only food and drug administration (FDA) approved drug for tocolytic use. We estimated the cytogenetic effect of ritodrine administered as maternal therapy, alone or in combination with smoking, in women and their neonates.

Methods: Lymphocyte and fibroblasts cultures were evaluated and three indices were analyzed; sister chromatid exchanges (SCEs), proliferation rate index (PRI) and mitotic index (MI) as well as average generation time (AGT) and population doubling time (PDT). Campothacin (CPT-11) was used as a positive control.

Results: Administration of ritodrine up to a month revealed significant reduction of SCEs/cell in neonates in the presence or absence of the mutagenic agent. A statistical significant increase on SCEs, for mothers and neonates, was noticed in neonate’s lymphocytes when tocolytic therapy was over a month. Ritodrine revealed a cytoprotective action against smoking when the two factors were combined, but the synergistic action of ritodrine with smoking increased genotoxicity, cytostaticity and cytotoxicity of neonates after long administration (1–3 months).

Conclusions: The time-depended genotoxic, cytostatic and cytotoxic action of ritodrine alone or in combination with smoking suggests that its administration should not exceed the time period of a month.     

Follicular development during late human pregnancy.

In contrast to the accepted view of ovarian quiescence during pregnancy, the ovaries of preparturient women are covered with a dense population of small superficial follicles. In this study we have measured the follicular size and status of the oocytes and cumulus oophorus in 298 follicles from the ovaries of 30 women. The samples were taken at cesarean section and were examined with Nomarski differential interference microscopy. No oocyte was recovered from 50% of the follicles; 79% of the recovered oocytes and 78% of their cumuli were degenerative. Degeneration was correlated with appearance of phagocytes in the follicular fluid. These findings suggest that the endocrine status of gestation does not prevent early follicular development, but induces premature atresia.     

Acute coronary syndrome associated with oral administration of ritodrine hydrochloride during pregnancy: a case report.

We report a case of acute coronary syndrome associated with the oral administration of ritodrine hydrochloride. Ten days following the administration of ritodrine hydrochloride, the patient complained of chest pain, and an electrocardiogram showed ST elevation and ST depression. Intensive care was initiated. She recovered without chest pain.     

Pulmonary edema after ritodrine therapy during pregnancy and subsequent cesarean section with epidural anesthesia

Ritodrine, a beta-sympathicomimetic drug that is frequently used for the prevention of preterm birth. Preterm delivery is an important cause of low birth weight. One of the most important side-effects of ritodrine is pulmonary edema. In patients developing pulmonary edema after ritodrine therapy, aggressive fluid resuscitation during the operation period should be avoided. Successful epidural anesthesia can be achieved with a slow-onset epidural block after moderate fluid infusion. We report the management of a pregnant patient developing pulmonary edema after ritodrine therapy and undergoing cesarean section with epidural anesthesia.     

Allergic dermatitis associated with administration of isoxsuprine during premature labor.

We have measured the absorbance of centrifuged amniotic fluids at 650 nm. and found reasonably good correlation between the absorbance and the L/S ratio. In 87 fluids studied, an absorbance of greater than 0.100 predicted correctly an L/S ratio of 2 or more in 98 per cent of the cases. When the absorbance was less than 0.100, 70 per cent of the fluids had an L/S ratio of less than 2.     

Cholecystectomy during pregnancy without fetal loss.

Cholecystectomy in the pregnant patient has been generally avoided because of the reported high incidence of associated fetal loss that has been linked to spontaneous and elective abortion during the first trimester and premature labor during the third trimester. Recent developments relating to diagnostic and anesthetic management and the use of tocolytic agents have altered the over-all approach to patients. We have, therefore, retrospectively reviewed the medical records of all women discharged from four area hospitals during 1982 to 1987 with a concurrent diagnosis of cholelithiasis and pregnancy. Twenty-two patients met the review criteria. The incidence of biliary stone disease among gravid patients during the time interval was 0.05 per cent. Of 22 patients, none underwent radiation for diagnosis. Nine patients underwent cholecystectomy while pregnant; two were operated upon during the first trimester, four during the second and three during the third. Three required common bile duct exploration and three had intraoperative cholangiograms. Elective abortion was not recommended to the six patients because of radiation exposure. Two of nine had premature contractions develop that were controlled with tocolytic agents. There were no spontaneous abortions. The mean Apgar scores for neonates born subsequent to cholecystectomy was virtually identical to neonates born to patients in whom cholecystectomy was deferred. It is concluded that the diagnosis and surgical treatment of cholelithiasis can be safely undertaken in the pregnant patient without fetal loss. Delaying appropriate surgical therapy no longer seems warranted.     

Pulmonary edema associated with ritodrine and dexamethasone treatment of threatened premature labor. A case report

Pulmonary edema occurred in association with the use of ritodrine and steroids to treat threatened premature labor. Twin gestation, intravenous ritodrine infusion longer than 24 hours and excessive fluid administration appear to be risk factors for the development of pulmonary edema. Careful case selection, scrupulous attention to the principles of fluid and electrolyte management and central venous pressure monitoring may help to diminish the incidence and severity of this complication of pregnancy.     

Double blind trial of ritodrine and placebo in twin pregnancy.

In a double blind trial, 25 patients with twin pregnancy were given 40 mg of ritodrine hydrochloride by mouth daily and 24 similar patients received a placebo. The ritodrine group had no significant prolongation of pregnancy nor increase in birth weight, and a high incidence of side effects occurred.     

Caffeine consumption during pregnancy and association with late spontaneous abortion

In a prospective cohort study, 3135 pregnant women were followed to evaluate the association of caffeine consumption during pregnancy with late first- and second-trimester spontaneous abortion. Almost 80% of pregnant women used some caffeine; among users the average daily intake was 99.3 mg from all sources. Sources of caffeine were nonherbal tea (used by 49.4% of women), coffee (41.2%), colas (35.0%), and drugs (6.6%). In all, 28% of pregnant women consumed greater than or equal to 151 mg of caffeine daily, and these "moderate-to-heavy" caffeine users were significantly more likely to experience late first- or second-trimester spontaneous abortion when compared with nonusers and light users (0 to 150 mg). Demographic characteristics, reproductive and medical history, contraceptive use, and smoking and drinking habits were taken into consideration. The adjusted relative risk of miscarriage after moderate-to-heavy caffeine consumption was 1.73 (p = 0.03). Light caffeine use (1 to 150 mg daily) was associated with increased risk for spontaneous abortion only among women who aborted in their last pregnancy (RR = 4.18, p = 0.04). Replicative studies are necessary before the association of caffeine with spontaneous abortion can be confirmed.     

Concentrations of ritodrine hydrochloride in maternal and fetal serum and amniotic fluid following intravenous administration in late pregnancy

Seven healthy pregnant volunteers undergoing elective cesarean section at 39-40 weeks of gestation were studied for transplacental passage of ritodrine hydrochloride, which was administered by intravenous infusion at the rate of 72-149 micrograms/min for 161-335 min. The concentrations of ritodrine in the collected maternal and fetal blood and the amniotic fluid were radioimmunoassayed. The levels of ritodrine in maternal serum were between 22.5 and 51.0 ng/ml one hour after the initiation of infusion, 33.7-66.4 ng/ml after 2 h, 18.2-73.6 ng/ml after 4 h and 45.7-189.6 ng/ml at delivery, respectively. The umbilical blood and amniotic fluid concentrations of ritodrine at delivery were between 15.6 and 35.1 ng/ml in arterial blood, 12.5-29.6 ng/ml in venous blood and 10.0-49.1 ng/ml in amniotic fluid. The ratio of umbilical venous blood concentrations to maternal venous concentrations (CV/MV) ranged from 0.066 to 0.544 with the mean of 0.263 +/- 0.063 (M +/- S.E.). The results obtained substantiate the rapid and appreciable transfer of ritodrine to the fetus and amniotic fluid.