RITODRINE

Fetal Risk Summary

Ritodrine is a b-sympathomimetic agent approved for the management of preterm labor. Although congenital malformations caused by ritodrine have not been observed, experience with the drug before the 20th week of gestation is very limited and no reports of 1st trimester use have been located. The manufacturer considers ritodrine to be contraindicated before the 20th week of gestation (1).

Ritodrine rapidly crosses the placenta, appearing in cord blood in amounts ranging from 26% to 117% of the maternal level (2,3,4 and 5). The mean cord:maternal venous blood ratio in eight of nine women delivering at a gestational length of 32 weeks or greater was 0.67 (2). In experiments using an in vitro perfused lobe of human placental tissue, ritodrine was shown to diffuse freely to the fetal side (3). Maternal and fetal plasma concentrations were determined in 28 woman-infant pairs who had been treated with IV ritodrine for preterm labor but who progressed to delivery in spite of the therapy (4). A mean cord:maternal venous ratio of 1.17 (range 0.79–2.24) was measured. In addition, ritodrine levels greater than 10 ng/mL in both maternal and fetal venous samples were present up to 5 hours after cessation of ritodrine therapy with detectable concentrations present up to 16.5 hours. Umbilical cord vein ritodrine levels up to 7 ng/mL were measured at this latter time. Fetal concentrations were closely correlated with maternal dose and the time interval between cessation of IV therapy and delivery (4). In a study of the placental passage of ritodrine using seven healthy women undergoing elective cesarean section at 39–40 weeks' gestation, ritodrine was infused at a rate of 72–149 µg/minute for 161–335 minutes (5). The mean cord:maternal venous blood ratio in this study was only 0.263 (range 0.066–0.544). The mean ritodrine concentrations (approximately 21–24 ng/mL) in umbilical vein, umbilical artery, and amniotic fluid were similar. In an investigation of the effects of ritodrine on fetal and placental blood flow, no significant changes in either intervillous or umbilical vein blood flows were noted at 1 hour in 14 women with premature uterine contractions at 31–36 weeks of gestation given ritodrine at 200 µg/minute (6). A comparison of the pharmacokinetics of orally administered ritodrine in pregnant and nonpregnant women has been published (7).

The effects of ritodrine on the mother, fetus, and the newborn have been the subject of several reviews (8,9,10 and 11). Maternal complications may occur frequently with IV therapy, especially when the dose is rapidly increased. The more serious adverse effects include tachycardia, pulmonary edema, myocardial ischemia, cardiac arrhythmias, hyperglycemia followed by a rise in serum insulin levels, and hypokalemia. Severe maternal hypoglycemia secondary to hyperinsulinemia has been reported in a woman following a cesarean section for triplets (12). The woman had been treated prophylactically with oral ritodrine from 15 to 32 weeks' gestation and then with IV ritodrine or high-dose oral therapy for another 12 days. Delivery occurred at approximately 34 weeks' gestation. Symptoms of hypoglycemia, including unconsciousness, occurred slightly more than 24 hours after delivery with blood glucose levels as low as 20 mg/dL and plasma insulin levels up to 19.4 mU/L. Normal glucose levels finally returned about 5 days later. Other causes of the hyperinsulinemia were excluded, and the investigators concluded that the condition was most likely caused by prolonged ritodrine therapy.

Severe fetal and neonatal complications of ritodrine therapy occur infrequently. Increases in fetal heart rate are the most commonly observed manifestation of toxicity. Fetal heart rates up to 200 beats/minute have been recorded (1,8,9 and 10). Neonatal cardiac arrhythmias have been reported in three newborns exposed in utero to IV ritodrine (13,14 and 15). One infant presented with paroxysmal supraventricular tachycardia involving short bursts up to 300 beats/minute with cyanosis and right cardiac failure occurring 10 minutes, 42 hours, and 60 hours after birth (13). The heart rate converted spontaneously to sinus rhythm a minute after each occurrence. Digitalization, continued until 2 months of age, may have prevented further episodes of the arrhythmia in this infant, but therapy was not required in a second case. In this newborn, the episodes of tachyarrhythmias first presented at 11 hours of age and then decreased in frequency until 24 hours of age, after which no further episodes were observed (14). A third case involved a newborn twin with hydrops fetalis who experienced atrial fibrillation at birth with tachycardia and congestive heart failure most likely caused by maternal treatment with IV ritodrine (15).

Disproportionate septal hypertrophy (DSH), defined as an interventricular septal thickness/posterior left ventricular wall thickness ratio (ST/PW) of greater than 1.3, was observed in infants exposed in utero to ritodrine for 2 weeks or longer (16). Compared with 22 control infants matched for gestational age, the mean ST/PW ratios for all ritodrine-exposed newborns (N=41) and for a subset of infants exposed for 2 weeks or longer (N=22) were significantly (p<0.05) increased. Ritodrine exposure of less than 2 weeks did not cause DSH. However, significant posterior wall thinning was observed in all exposed infants (mean duration of therapy was 16.2 days (range 1–49 days). In those infants exposed for 2 weeks or longer, DSH was caused by an increasing interventricular septal thickness and a thinning posterior wall thickness. Both the ST/PW ratio and the septal thickness were highly correlated with duration of ritodrine exposure (16). The right systolic time interval was also significantly higher in the exposed infants compared with controls. The echocardiographic changes lasted for less than 3 months. Because there were no statistical differences in the mortality rates between the ritodrine and control groups, the clinical significance of these findings is unknown. Possible mechanisms for the defects were thought to include chronic fetal tachycardia, increased glycogen deposition, pulmonary hypertension, or genetic factors (16).

Use of ritodrine may result in transient maternal and fetal hyperglycemia followed by increases in levels of serum insulin. If delivery occurs before these effects have terminated (usually 48–72 hours), hypoglycemia in the newborn may occur (17). Severe maternal ketoacidosis with fetal death has been reported (18). An insulin-dependent diabetic was treated with IV ritodrine up to 0.3 mg/minute for preterm labor at 28 weeks of gestation. Fetal heart rate patterns were normal before therapy. Maternal hyperglycemia with ketoacidosis developed after 26 hours of therapy and 6 hours later fetal heart activity was undetectable. She was subsequently delivered of a stillborn 970-g fetus with cheilognathouranoschisis but with no other abnormalities either in the fetus or the placenta.

A 1989 study compared indomethacin, administered for 48 hours, with IV ritodrine (initiated at 50 µg/minute, then titrated, based on response, to a maximum of 350 µg/minute) in 106 women in preterm labor with intact membranes who were at a gestational age of 32 weeks or less (19). Fifty-four women received ritodrine and 52 received indomethacin. Thirteen (24%) of the ritodrine group developed adverse drug reactions severe enough to require discontinuance of the drug and a change to magnesium sulfate: cardiac arrhythmia (1), chest pain (2), tachycardia (3), and hypotension (7). None of the indomethacin cases developed drug intolerance (p<0.01). For all maternal adverse drug reactions, 39 (72%) of those treated with ritodrine had a side effect vs. 6 (11.5%) of the indomethacin group (p<0.01). The outcomes of the pregnancies were similar, regardless of whether delivery occurred close to or remote from therapy. Of those delivered within 48 hours of initiation of therapy, the mean glucose level in the ritodrine-exposed newborns (N=9) was significantly higher than that in those exposed to indomethacin (N=8), 198 vs. 80 mg/dL (p<0.05), respectively. No cases of premature closure of the ductus arteriosus or pulmonary hypertension were observed. A reduction in amniotic fluid volume was noted in three (5.6%) of the ritodrine group and in six (11.5%) of those treated with indomethacin. On a cost basis, tocolysis with indomethacin was 17 times less costly than tocolysis with ritodrine (19).

Ritodrine-induced neonatal hypoglycemia appears to be related to the route of drug administration. In a double-blind comparison of 17 mothers treated with IV, followed by oral, ritodrine for a mean duration of 9 days vs. 18 control mothers treated with placebo for 10 days, no significant differences between the groups were measured up to 12 hours of age in terms of heart rate, blood pressure, blood volume (measured at 12–24 hours of age), arterial or venous pH, plasma insulin, or blood glucose (20). In contrast, neonatal hypoglycemia (defined as less than 45 mg/dL) was found in 32% (17 of 53) of newborns exposed to IV ritodrine within 12 hours of birth compared with 15% (8 of 54) of controls matched for gestational age and birth weight (p<0.05) (21). The mean onset of hypoglycemia was at 1.0 hour of age. Neither gestational age nor maternal ritodrine dose nor the interval between cessation of therapy and delivery correlated well with the onset. Other parameters not significantly different between the groups were Apgar scores, neonatal pH, plasma bicarbonate, hypotension, respiratory distress syndrome, and neonatal mortality. This lack of neonatal toxicity (other than hypoglycemia) has been confirmed by other studies. In a report involving 82 infants whose mothers had been treated with parenteral ritodrine, with or without oral therapy, for an average of 28.5 days compared with a similar number of matched controls, umbilical pH, Apgar scores, head circumference, and neurologic condition were statistically similar (22). Five study infants had neonatal jaundice compared with none of the controls, but the groups were statistically similar in the number of infants with bilirubin values above 5.2 mg/dL (28 and 23, respectively) (22). The investigators were unable to determine whether ritodrine caused the increased incidence of jaundice.

Neonatal renal function was evaluated in 15 infants exposed in utero to ritodrine for at least 12 of the 24 hours before delivery compared with 15 matched controls (23). On day 1 (12–36 hours of age), exposed infants had significantly decreased glomerular filtration rates (as measured by inulin clearances), higher plasma renin activity, and higher urinary arginine vasopressin excretion than controls. These parameters were not statistically different between the groups on day 6. Both plasma renin activity and urinary arginine vasopressin excretion were statistically associated with plasma ritodrine levels (mean 16.6 ng/mL on day 1) but not inulin clearance. Correlations were not conducted on day 6 because of the low ritodrine levels (mean 1.0 ng/mL in six infants, less than 0.3 ng/mL in nine). The clinical significance of these findings is unknown because clinical signs of renal failure were not observed in any infant. Furthermore, serum and urine electrolyte values, osmolality, fractional sodium excretion, and urine flow rate were similar in treated and control infants.

In a 1988 review of 12 published and 4 unpublished “methodologically acceptable” controlled trials of b-sympatholytic tocolytic therapy, ritodrine was used in 12 (8 published/4 unpublished) (24). The total number of women involved in the ritodrine trials consisted of 412 treated and 329 controls. The outcomes analyzed, not all of which were available in each trial, were (a) delivery within 24 hours of trial entry; (b) delivery within 48 hours of trial entry; (c) delivery before 37 completed weeks; (d) birth weight below 2500 g; (e) respiratory distress syndrome or severe respiratory problems; and (f) perinatal death. The reviewers confirmed that ritodrine was effective in delaying delivery after preterm labor in comparison to placebo or other, nontocolytic therapy. The frequencies of both preterm birth and low birth weight were reduced. However, in contrast to the prevailing view that ritodrine decreases the incidence of neonatal death and respiratory distress syndrome (25,26 and 27), neither perinatal mortality nor severe neonatal respiratory problems were reduced. This raised important questions as to the clinical significance of the positive benefits (24). In attempting to explain their findings, the investigators speculated that the trials may have included too many women in whom tocolytic therapy was unlikely to benefit their fetuses. In addition, they concluded that only a small percentage of perinatal mortality resulted from pregnancies that might benefit from tocolytic therapy. The primary benefit of tocolytic therapy, in their opinion, was the attainment of short-term delay of delivery to allow transfer of the patient to medical centers with obstetric and neonatal intensive care facilities and to allow time for the beneficial effects of glucocorticoids on fetal lung development to appear.

Two-year follow-up studies of infants exposed in utero to ritodrine have failed to detect harmful effects on growth, incidence of disease, development, or functional maturation (28,29). More recent studies have also failed to detect statistical evidence of adverse effects of ritodrine exposure (30,31). In a study of 20 children examined at 7–9 years of age who had been exposed between 24 and 34 weeks' gestation, no significant differences were found compared with controls in physical growth (height and weight), neurologic parameters (motor, sensory, and cerebellar function), and psychometric testing (30). However, scores and measurements were consistently poorer, although not significantly, in the exposed group, even after correction for socioeconomic status. Most of the controls, however, had not experienced preterm labor, which may have affected the findings (30). A group of 78 6-year-old children exposed in utero at a mean gestational age of 32.1 weeks (range 12–37 weeks) for a mean duration of 28.2 days (range 7–163 days) was compared with two control groups composed of 78 children each (31). No significant differences between the three groups were discovered in urinalysis (including no glucosuria in any child), body length and weight, head circumference, neurologic findings, and general behavior as judged by their parents and teachers. The teachers, however, felt the exposed group did worse in school performance (motor and social skills, emotional and cognitive development). As in previous studies, the authors could not determine whether the latter assessment was caused by ritodrine exposure, an unfavorable obstetric situation, or other factors.

Breast Feeding Summary

No data are available.

References

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