Search

We have developed a model in pregnant sheep to investigate pharmacological agents used for suppression of preterm labor. This model allows repetitive determinations of uterine contractility and simultaneous measurements of myometrial receptor and postreceptor events. We used the model to study the beta-adrenergic agent ritodrine. We infused 11 pregnant sheep with ritodrine and 3 with physiological saline for 24 h. Oxytocin boluses were given before and at 5 and 22 h after onset of the infusion. Myometrial biopsies were obtained before and immediately after the infusion. After 22 h of ritodrine infusion, uterine contractility in response to the same oxytocin bolus was 50% greater than at 5 h (P less than 0.02). Myometrial membrane beta-adrenergic receptor density decreased 49% (P less than 0.005), and catecholamine-stimulated adenylate cyclase activity was reduced 70% (P less than 0.005). The model thus demonstrates that use of the beta-adrenergic agonist ritodrine in a clinically relevant manner results in tachyphylaxis of its effects on both physiological parameters and the receptor cascade system.

The effects of dexamethasone on maternal and fetal hemodynamic states and fetal oxygenation were determined in chronically instrumented unanesthetized pregnant ewes and fetal lambs. Intravenous injections of pharmacologic doses of dexamethasone to the mother failed to alter maternal blood pressure, heart rate, blood flow in the uterine artery supplying the pregnant horn, or uterine vascular resistance. Direct administration of dexamethasone to the fetus had no effect on fetal blood pressure, heart rate, acid-base state, or oxygenation. Furthermore, direct fetal administration of dexamethasone did not produce premature parturition.

Preterm labor is responsible for a majority of cases of perinatal morbidity and deaths. Prevention of preterm labor is not usually possible; thus pharmacologic treatment is the only recourse available. Numerous agents have been used to treat preterm labor, but none has proved to be superior. This report reviews the current information available about the pharmacology of labor-inhibiting drugs and discusses the clinical approach to the management of preterm labor.

Transient acceleration of the fetal heart rate is commonly seen in the cardiotachometer tracing of the human fetus during labor. A likely cause appeared to be partial occlusion of the umbilical cord. On the basis of this hypothesis, fetal cardiovascular responses to partial occlusion of the umbilical cord or isolated intra-abdominal portion of umbilical vein were studied in near-term pregnant baboons and rhesus monkeys prior to and following sympathetic blockade with dibenzyline and propranolol. The responses were of two types. In the well-oxygenated fetus, partial occlusion resulted in transient acceleration of heart rate and a decrease in pulse pressure. This response was abolished with dibenzyline or propranolol. In the hypoxic fetus, partial occlusion resulted in either bradycardia and hypotension or hypotension with no alteration in heart rate. Thus, transient acceleration of the fetal heart rate can be explained on the basis of a sympathetic response to diminished venous return. It would appear to be an early sign of a potential cord complication. This response will not be seen if the fetus becomes asphyxiated and hypoxic.

In 101 diabetic pregnant women (Classes A through D) 146 determinations of the lecithin/sphingomyelin ( L/S ) ratio were carried out. Gestational ages were verified by serial fetal cephalometry. No L/S ratios of more than 2.0 were found before 341/2 weeks' gestation; however, in 42 per cent of patients the L/S ratio was below 2.0 at 36 weeks' gestation or later. Respiratory distress syndrome (RDS) was found in 16 neonates of women with L/S ratios of 2.0 or higher; however, RDS incidence varied depending on the mode of delivery. Abdominal delivery was performed before 37 weeks' gestation in 19 patients with L/S ratios of 2.0 or higher and resulted in neonates with RDS in 41 per cent of cases. Vaginal delivery was accomplished before 37 weeks' gestation in 10 patients with L/S ratios of 2.0 or higher and no subsequent neonatal RDS was observed. After 37 weeks' gestation neonatal RDS is rare, irrespective of mode of delivery. The data presented suggest that similar numerical values of the L/S ratio at different gestational ages have a different predictive value for the occurrence of neonatal RDS.

Human placental cells maintained were used to determine the direct effect of beta-adrenergic agonists on progesterone accumulation by the placenta. In five studies, when either of the beta-adrenergic receptor agonists, terbutaline or isoproterenol, 1.5 micrograms/ml, was incubated for 24 hours with the placental cells, significantly more progesterone was present in the culture medium than in the medium of matched controls. Compared with the medium of matched controls, progesterone in medium increased 36 +/- 6% (mean +/- SE) when cells were treated with terbutaline and 38 +/- 7% when cells were treated with isoproterenol. In two dose-response studies with terbutaline, a minimal dose of 0.15 micrograms/ml was required to significantly increase progesterone in medium compared with that in matched controls. In three studies, propranolol at a concentration of 1.5 micrograms/ml completely blocked the stimulatory effect of 1.5 micrograms/ml of terbutaline.

The recommended regimen for the infusion of ritodrine leads to unnecessarily high plasma concentrations. A review of basic pharmacologic principles provides a basis for changing the infusion regimen. A regimen is proposed that results in lower average and peak concentrations and reduces the total amount of drug given. These changes may decrease the risk of developing side effects without adversely affecting the ability to inhibit preterm labor.

We have previously demonstrated in pregnant sheep that ritodrine infusion for 24 hours reduces myometrial beta-adrenergic receptor density and isoproterenol-stimulated adenylate cyclase activity. These receptor-associated changes were accompanied by an increasing inability of ritodrine to inhibit uterine contractility induced by a bolus of oxytocin. In the present study, we evaluated whether these ritodrine-induced effects could be altered by dexamethasone. Ten pregnant sheep at gestational ages of 92 to 130 days received ritodrine 2 micrograms/kg/min for 24 hours. Five animals also received dexamethasone 10 mg intravascularly twice during the ritodrine infusion. Before and at 4 and 24 hours of ritodrine infusion, the animals were given an identical dose of oxytocin as a bolus, and the area under the uterine pressure-time curve was quantified. Myometrial biopsy specimens were obtained before and after ritodrine infusion. Dexamethasone treatment prevented ritodrine-induced reductions in beta-adrenergic receptor density and isoproterenol-stimulated adenylate cyclase activity. Despite these receptor-associated effects, dexamethasone did not prevent the loss of tocolytic efficacy associated with prolonged ritodrine infusion.

Inhibition of labor during the intrapartum period has been suggested as a method of managing acute fetal distress. In such cases, rapid tocolysis is desirable but, in high doses, beta-adrenergic-receptor agonists, such as ritodrine, may cause severe maternal hypotension that could aggravate the existing fetal distress. We undertook the present study to establish a safe infusion protocol for ritodrine that achieves high plasma concentration rapidly. Twelve nonpregnant female volunteers received, on separate days, three infusions of ritodrine, that is, 1, 2, and 3 mg, during a 2-minute period. The peak plasma concentration measured by high-performance liquid chromatography with electrochemical detection averaged 37, 74, and 100 ng/ml after the 1, 2, and 3 mg doses, respectively. Ritodrine concentrations decreased rapidly and with the 3 mg dose the ritodrine concentration was only 14 ng/ml after 15 minutes. The elimination phase half-life of ritodrine averaged 6.11 hours. None of the doses significantly affected systolic blood pressure but ritodrine increased heart rate and the plasma glucose level and decreased diastolic blood pressure and the plasma potassium concentration. Even at the highest infusion rate, the maximal changes in cardiovascular and metabolic variables were short-lived and clinically modest; heart rate increased 29 bpm, diastolic blood pressure decreased 8 mm Hg, glucose level increased 26 mg/dl, and potassium concentration decreased 0.6 mEq/L. These data indicate that high plasma concentrations of ritodrine can be achieved rapidly without serious side effects.

Perinatal outcome and obstetric practices during 1970 and 1977 were compared. None of the 6,740 fetuses delivered with birth weights of 1,000 gm or greater in 1970 had electronic fetal monitoring (EFM). In 1977, 5,987 of 8,174 fetuses delivered had EFM (72.7%). High-risk factors were significantly more frequent in the pregnant patient population in 1977. The incidence of intrapartum stillbirths and severe birth asphyxia was significantly lower in 1977. These reductions remained significant when corrected for changes in obstetric practices other than EFM as well as for changes in patient population. The neonatal death rate was not significantly changed. The primary cesarean section rate increased from 4.4% to 10.1%, mostly because of a greater number of cesarean sections done for failure to progress in labor and breech presentation. Only 15% of the overall increase in cesarean section rate was because of a greater frequency of the indication of fetal distress. The incidence of severe birth asphyxia was the same among the unmonitored patients in 1970 and 1977. In 1977, however, the monitored patients had a significantly lower incidence of severe birth asphyxia than the unmonitored patients.

This article reviews patterns of the fetal heart rate which have been linked to fetal hypoxia, discusses the possible physiologic basis of these heart rate changes, and considers the clinical management of the patient whose fetus demonstrates a heart rate pattern that may be hypoxic.

Changes in the distribution of portal venous blood flow to the left and right lobes of the liver and through the ductus venosus were determined from before birth through 9 days of age in 25 chronically catheterized fetal and newborn lambs. Blood flow distribution was calculated by means of the radionuclide-labeled microsphere technique. With umbilical cord clamping portal venous blood flow distribution to the right lobe of the liver decreased when compared to that in the term fetus; distribution to the left lobe and ductus venosus increased. More than 50% of portal blood flow was shunted through the ductus venosus during the first hour after birth. Ductus venosus shunts of at least 25% of total portal blood flow were noted in half the lambs between the second and sixth days of life. Portal venous distribution to the right lobe was inversely related to the fraction of portal blood flow shunted through the ductus venosus. The ratio of right lobe weight to total liver weight was significantly correlated with the ratio of right lobe flow to total liver flow (r = 0.73; P less than 0.001). The conclusion is that large and persistent ductus venosus shunts are normal during the first postnatal week in lambs.

Betamethasone was administered to six rhesus-sensitized pregnant women carrying seven fetuses in an attempt to accelerate fetal pulmonary maturation. A reduction in optical density of amniotic fluid at 450 mμ was observed in all cases following steroid therapy; however, only minimal changes were noted in the lecithin-sphingomyelin ratio. The implications of these findings for the management of rhesus-sensitized pregnancies are discussed.

One hundred women in preterm labor were randomly treated with ritodrine or terbutaline in a double-blind fashion. The drugs were comparably effective during intravenous therapy but, in women with intact membranes, an oral dose of terbutaline, 30 mg daily, was significantly more effective than ritodrine, 120 mg daily, in preventing recurrent labor during a 5-day course of oral therapy (one of 19 versus 12 of 23, p less than 0.001). In women with intact membranes, pregnancy was prolonged 40 +/- 25 days (mean +/- SD) in women receiving terbutaline orally and only 22 +/- 24 days in women receiving ritodrine orally (p less than 0.01). In women with intact membranes, a heart rate greater than or equal to 130 bpm occurred in in a higher proportion of women receiving intravenous treatment with ritodrine than among those receiving terbutaline (20 of 31 versus 8 of 27, p less than 0.05). Terbutaline-treated women, however, were significantly more likely to have a serum glucose level in excess of 140 mg/dl than were women treated with ritodrine (13 of 26 versus 6 of 29, p less than 0.05). Side effects commonly observed during intravenous therapy included nausea (22%), chest pain (15%), and shortness of breath (15%). Side effects were significantly (p less than 0.025) more likely to occur during periods when the infusion rate was being increased rather than during periods when the infusion rate was constant.

We studied the vascular reactivity of the systemic and uterine circulations of six pregnant sheep. We placed catheters in a maternal carotid artery and a jugular vein, and then implanted an electromagnetic flow transducer around the uterine artery of the pregnant horn. After allowing 3 days for recovery from anesthesia and operation, we measured mean arterial blood pressure, heart rate, uterine blood flow, and calculated uterine vascular resistance, then separately infused angiotensin and norepinephrine in each ewe at the rate that produced a 20 torr pressor response. Dexamethasone, 0.2 mg. per kilogram of body weight, was then injected intravenously daily for 2 to 4 days. On the day following the final injection of dexamethasone, we separately infused angiotensin and norepinephrine at a rate that, before steroid treatment, produced a 20 torr pressor response. Administration of dexamethasone for 2 to 4 days did not change mean arterial blood pressure, heart rate, uterine blood flow, or uterine vascular resistance. Prior to steroid treatment, angiotensin increased blood pressure, decreased heart rate, but had no consistent effect on uterine blood flow or uterine vascular resistance; norepinephrine increased blood pressure without chenging heart rate, decreased uterine blood flow, and increased uterine vascular resistance. The changes produced by angiotensin and norepinephrine were the same after dexamethasone treatment. These studies indicate that dexamethasone does not influence systemic and uterine vascular reactivity during normal sheep pregnancy.

A sensitive and specific assay for ritodrine in serum was developed using high-performance liquid chromatography (HPLC) with electrochemical detection. Serum samples were alkalinized to pH 9.4 by the addition of a sodium carbonate buffer and extracted with ethyl acetate. The extracts were evaporated to dryness and the residues were reconstituted in the HPLC mobile phase and chromatographed on a octadecylsilane reverse-phase column. The detection of ritodrine was achieved by an electrochemical detector with a glassy carbon electrode. The sensitivity was 0.2 ng for on-column injection. The extraction efficiency was 80%.

In nine chronically catheterized fetal lambs (120 to 135 days; term 147 days), umbilical venous blood flow and its distribution were measured by the radionuclide-labeled microsphere technique before and during autonomic blockade with atropine (0.20 to 0.25 mg/kg; seven studies) or phentolamine (0.10 to 0.12 mg/kg; six studies). Atropine significantly increased mean fetal heart rate (182 to 207 beats/min), descending aortic blood pressure (49 to 55 mm Hg), and umbilical venous blood flow (210 to 239 ml/min/kg fetus), without changing umbilical venous blood pressure. Phentolamine decreased mean descending aortic pressure (48 to 45 mm Hg), but did not affect heart rate, umbilical venous blood pressure, or umbilical venous blood flow. Neither atropine nor phentolamine altered the distribution of umbilical venous blood flow to the ductus venousus, the liver, or the other fetal organs. These data indicate that the cholinergic nervous system only indirectly affects the basal umbilical venous blood flow in the near-term fetal lamb. This effect is small and is secondary to associated changes in heart rate and arterial blood pressure. Neither the cholinergic nor the α-adrenergic systems influence the basal distribution of umbilical venous blood flow.

Cells from term human placentas were maintained in culture, and progesterone production was monitored over 24 h. The beta 1-adrenergic receptor agonist dobutamine (10(-5) M) and the beta 2-adrenergic receptor agonist terbutaline (10(-5) M) increased progesterone production by 36 +/- 19% and 49 +/- 8% (+/- SE), respectively, compared with that in controls (P less than 0.001). Propranolol (10(-5) M) completely blocked the stimulatory effects of both drugs. The cAMP analog 8-bromo-cAMP (0.5 mM) also significantly altered (increased) progesterone production compared with controls (P less than 0.001), but this effect was not blocked to a significant degree by propranolol. The alpha-adrenergic receptor agonist methoxamine (10(-4) - 10(-6) M) did not significantly alter placental progesterone production compared with controls, and the stimulatory effect of terbutaline on progesterone production was not significantly affected by blockade of the alpha-adrenergic receptor with phentolamine. These data indicate that placental progesterone production can be significantly modulated by stimulation of beta-adrenergic, but not by alpha-adrenergic, receptors. This response may be mediated by increased intracellular cAMP. These findings may be important in considering other metabolic functions of the placenta as well as the treatment of preterm labor.

In adult nonpregnant animals and human beings, glucocorticosteroids increase circulating leukocytes (predominantly neutrophils) and decrease lymphocytes, monocytes, and eosinophils. We were interested in studying effects of glucocorticoids on leukocyte counts during pregnancy to determine any differences between responses in the nonpregnant and pregnant states. After general anesthesia was administered, we placed catheters in a carotid artery and a jugular vein in pregnant sheep and in fetal lambs. Six days after surgery, we administered dexamethasone intravenously to the mother (0.2 mg. per kilogram) or to the fetus (0.06 mg. per kilogram) and obtained maternal and fetal jugular venous blood samples immediately before (control) and 3, 6, 12, 24, 48, and 72 hours after steroid injection. administration of dexamethasone to the mother significantly increased total leukocyte and neutrophil counts (leukocytes per cubic millimeter blood) and decreased lymphocyte and eosinophil counts, but it did not change monocyte counts. Leukocyte counts returmed to control values within 48 hours. Administration of dexamsthasone to the fetus rapidly increased total leukocyte and neutrophil counts, decreased monocyte and eosinophil counts, and had no effect on lymphocyte counts. Fetal leukocyte counts returned to control values by 24 hours after dexamethasone injection. Our results suggest that maternal and fetal leukocytes can respond to glucocorticoids as they do in the adult nonpregnant state.

Preterm delivery accounts for a major proportion of perinatal deaths. The cause of preterm labour is usually not known, but in most instances, maintaining the fetus in utero appears to be preferred to allowing preterm delivery. Numerous pharmacological agents have been utilised to inhibit preterm labour, but none has proven to be ideal. Currently, the beta-adrenoceptor stimulants such as ritodrine, terbutaline, isoxsuprine, salbutamol and fenoterol provide the best combination of safety and efficacy. However, because of their potential adverse effects, adequate maternal and fetal surveillance needs to be maintained throughout their administration. Magnesium sulphate, although probably not as effective as other labour-inhibiting drugs, is an appropriate choice when the beta-adrenoceptor stimulants are either contraindicated or poorly tolerated. Other drugs such as the prostaglandin inhibitors, diazoxide or the calcium antagonists are also potent labour-inhibitors, but further controlled studies are required to evaluate the risks associated with their use. Ethanol has been supplanted by the beta-adrenoceptor stimulants and is unlikely to be used in the future.

Dosing regimens for ritodrine are based in large part on pharmacokinetic studies performed with nonpregnant subjects. Pregnancy is characterized by changes in renal blood flow, plasma volume, protein concentration, and hepatic function. These physiologic changes frequently alter drug pharmacokinetics. To define the effect of pregnancy on ritodrine kinetics, we compared ritodrine pharmacokinetics in four pregnant and four nonpregnant rhesus monkeys. Significant differences were demonstrated in the distribution phase half-life (0.40 +/- 0.08 hours in the pregnant monkeys and 0.21 +/- 0.03 hours in the nonpregnant animals), volume of distribution (1.99 +/- 0.94 L/kg in the pregnant monkeys and 4.75 +/- 0.90 L/kg in the nonpregnant animals), plasma clearance (18.8 +/- 7.1 ml/min/kg in the pregnant monkeys and 27.2 +/- 5.0 ml/min/kg in the nonpregnant animals), and disposition half-life (1.8 +/- 0.4 hours in the pregnant monkeys and 3.3 +/- 0.4 hours in the nonpregnant animals). Pregnant animals receiving ritodrine had higher steady-state plasma concentrations than nonpregnant animals (104 versus 53 ng/ml at an infusion rate of 2 micrograms/kg/min). These data indicate that dosing regimens for ritodrine based on studies of nonpregnant subjects may be subject to considerable error.

We evaluated the relationship of ritodrine concentration to several maternal variables and to fetal heart rate in 17 women who received the drug for inhibition of preterm labor. Ritodrine was measured by high-performance liquid chromatography with electrochemical detection. Ritodrine increased maternal and fetal heart rate and decreased serum potassium in a dose-related manner, but wide variability was noted between patients and within individual patients. Tachyphylaxis of the maternal heart rate response to continuing treatment with ritodrine was seen in at least seven women. Maternal blood pressure, serum glucose concentration, and frequency of uterine contractions were changed by ritodrine treatment, but the changes in these variables were not closely correlated to the concentration of ritodrine (r less than or equal to 0.30 in all cases). The maximal infusion rate and the concentration of ritodrine in maternal serum after 4 hours of treatment were significantly (p less than 0.001) correlated with the frequency of uterine contractions prior to treatment. Successful inhibition of labor was achieved with serum concentrations of 15 to 31 ng/ml in 10 of 17 women; in six of the other seven women, labor could not be inhibited in spite of serum concentrations of 90 to 146 ng/ml. Side effects, such as hypotension, vomiting, chest discomfort, and shortness of breath, were most commonly observed when the infusion rate and concentration of ritodrine were increasing.

Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2–4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Doxylamine succinate–pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy. Clinical Trial Registration No: NCT00614445 .

Ninety-two women in preterm labor were randomly assigned to receive either terbutaline or ethanol. In women with intact membranes, terbutaline was significantly more effective than ethanol in preventing progressive cervical dilation during the first 36 hours of treatment while betamethasone was given to the mother. Additionally, pregnancy was maintained significantly longer in women with intact membranes who were treated with terbutaline (15 ± 4 days) rather than with ethanol (10 ± 3 days). However, only 18% of women in each treatment group maintained their pregnancy beyond 36 weeks’ gestation. In women with ruptured membranes and cervical dilation less than 4 cm, terbutaline was significantly better than ethanol in maintaining pregnancy for a minimum of 36 hours. Serious maternal side effects were not observed with terbutaline or ethanol, although a majority of women also received betamethasone. Neither drug caused serious adverse neonatal effects.