Betamethasone Risk Summary

Risk Factor: C*
Class: Hormones / Adrenal agents

Fetal Risk Summary

Betamethasone is often used in patients with premature labor at about 26 - 34 weeks' gestation to stimulate fetal lung maturation (1,2,3,4,5,6,7,8,9,10,11,12,13,14 and 15). The benefits of this therapy are: Reduction in incidence of respiratory distress syndrome (RDS) Decreased severity of RDS if it occurs Decreased incidence of, and mortality from, intracranial hemorrhage Increased survival of premature infants Betamethasone crosses the placenta to the fetus (16). The drug is partially metabolized (47%) by the perfused placenta to its inactive 11-ketosteroid derivative, but less so than other corticosteroids, although the differences are not statistically significant (17).

In patients with premature rupture of the membranes (PROM), administration of betamethasone to the mother does not always reduce the frequency of RDS or perinatal mortality (18,19,20,21 and 22). An increased risk of maternal infection has also been observed in patients with PROM treated with corticosteroids (19,20). In a study comparing betamethasone therapy with nonsteroid management of women with PROM, neonatal sepsis was observed in 23% (5 of 22) of steroid-exposed newborns vs. only 2% (1 of 46) of the non-steroid-exposed group (21). A 1985 study also found increased neonatal sepsis in exposed newborns who were delivered more than 48 hours after PROM, 18.6% (14 of 75) vs. 7.4% (4 of 54) of nonexposed controls (22). In addition, moderate to severe respiratory morbidity was increased over that in controls, 21.3% vs. 11.1%, as well as overall mortality, 8% vs. 1.8% (22). Other reports, however, have noted beneficial effects of betamethasone administration to patients with PROM with no increase in infectious morbidity (15,23,24,). In women colonized with group B streptococci, the combined use of betamethasone and ampicillin improved the outcome of preterm pregnancies with PROM (25).

Betamethasone therapy is less effective in decreasing the incidence of RDS in male infants than in female infants (23,26,27). The reasons for this difference have not been discovered. Slower lung maturation in male fetuses has been cited as a major contributing factor to the sex differential noted in neonatal mortality (28). Therapy is also less effective in multiple pregnancies (27,29), even when doses have been doubled (27). In twins, only the first-born seems to benefit from antenatal steroid therapy (27).

An increased incidence of hypoglycemia in newborns exposed in utero to betamethasone has been reported (30). Other investigators have not observed this effect.

In the initial study examining the effect of betamethasone on RDS, investigators reported an increased risk of fetal death in patients with severe preeclampsia (1). They proposed that the corticosteroid had an adverse effect on placentas already damaged by vascular disease. A second study did not confirm these findings (7).

A case of suspected betamethasone-induced leukemoid reaction was observed in an 880-g, 30-weeks'-gestation female infant whose mother received 12 mg of betamethasone 4 hours prior to delivery (31). A second case, in a female infant born at 25-26 weeks' 71 hours after betamethasone, was published in 1997 (32). Within about 710 days, the white blood cell count had returned to normal in both infants. A 1984 study examined the effect of betamethasone on leukocyte counts in mothers with PROM or premature labor (33). No effect, as compared to untreated controls, was found in either group.

A case of acute, life-threatening exacerbation of muscular weakness requiring intubation and mechanical ventilation was reported in a 24-year-old woman who was treated with betamethasone, 12 mg IM, to enhance fetal lung maturity at 32 weeks' gestation (34). The onset of symptoms occurred 30 minutes after the corticosteroid dose. The authors attributed the crisis to betamethasone (adrenocorticosteroids are known to aggravate myasthenia) after other potential causes were ruled out. The infant was delivered by emergency cesarean section and, except for the typical problems related to prematurity, he had a normal hospital course.

Hypertensive crisis associated with the use of ritodrine and betamethasone has been reported (35). Systolic blood pressure was above 300 mm Hg with a diastolic pressure of 120 mm Hg. Although the hypertension was probably caused by ritodrine, it is not known whether the corticosteroid was a contributing factor.

The effect of betamethasone administration on patent ductus arteriosus (PDA) was investigated in premature infants with a birth weight of less than 2,000 g (36). Infants of nontreated mothers had a PDA incidence of 44% vs. 6.5% for infants of treated mothers (p<0.01). This reduction in the incidence of PDA after betamethasone therapy has also been observed in other studies (25). A study published in 1989 indicated that betamethasone caused transient, mild constriction of the ductus arteriosus (37). Eleven women with placenta previa with a mean gestational age of 31.7 weeks (range 27.3-37.3 weeks) were given two 12-mg IM doses of the drug, 24 hours apart, to promote fetal lung maturation. Fetal Doppler echocardiography of the ductus arteriosus was conducted just before the first dose then at 5 and 30 hours after the dose. Two of the fetuses showed mild constriction of the ductus 45 hours after the first injection, but the tests were normal when performed at 30 hours. No evidence of tricuspid regurgitation was observed (37). The authors concluded that the changes were probably not clinically significant.

A 1984 article discussed the potential benefits of combining thyroid hormones with corticosteroids to produce an additive or synergistic effect on fetal lung phosphatidylcholine synthesis (38). The therapy may offer advantages over corticosteroid therapy alone, but it is presently not possible because of the lack of commercially available thyroid stimulators that cross the placenta. The thyroid hormones, T4 and T3, are poorly transported across the placenta and thus would not be effective.

Five premature infants (three males and two females), exposed in utero to two 8-mg IM doses of betamethasone administered to the mother 48 and 24 hours before birth, were evaluated to determine the effect of the drug on endogenous progesterone, mineralocorticoid, and glucocorticoid activity (39). Plasma levels of the mineralocorticoids, aldosterone and 11-deoxycorticosterone, were not significantly decreased in the newborns at birth or during the next few days. Glucocorticoid activity in the newborns, as measured by levels of corticosterone, cortisol, cortisone, and 11-deoxycortisol, was significantly depressed at birth but rebounded above normal values when the subjects were 2 hours of age, then returned to normal ranges shortly after this time. Progesterone and 17-hydroxyprogesterone levels in the fetuses and neonates were not affected by betamethasone.

A 1994 case report described a pregnancy in which seven weekly courses (two 12.5 mg IM doses every 12 hours) of betamethasone were given between 24 weeks' gestation and delivery at 34.5 weeks' (40). The 2625-g male infant had a moon facies appearance and a buffalo hump of apparent excess adipose deposition in the upper back. Tests in the mother and infant shortly after delivery were consistent with hypothalamic-pituitary-adrenal axis suppression with low basal serum cortisol levels (40). At 10 months of age, the infant's motor development and cognitive function were normal for age, length and head circumference were at the 20th percentile, and weight was slightly less than the 5th percentile. The cushingoid features had completely resolved (40). Two more recent reports have also described adrenal suppression in women secondary to multiple antenatal betamethasone courses (41,42), and in newborns exposed to (3 courses (43). A 1999 study, however, did not observe adrenal suppression in nine infants whose mothers had received a mean of 4.8 treatment courses of betamethasone (44).

Although human studies have usually shown a benefit, the use of corticosteroids in animals has been associated with several toxic effects (45,46): Reduced fetal head circumference Reduced fetal adrenal weight Increased fetal liver weight Reduced fetal thymus weight Reduced placental weight None of these effects has been observed in human investigations with single courses of betamethasone. However, multiple courses of betamethasone have been associated with lower birth weights and reduced head circumference at birth (43,47,48).

In children born of mothers treated with betamethasone for premature labor, studies conducted at 4 and 6 years of age have found no differences from controls in cognitive and psychosocial development (49,50). Two studies published in 1990 evaluated children at 1012 years of age who had been exposed in utero to betamethasone in a randomized, double-blind, placebo-controlled trial of the effects of the corticosteroid on fetal lung maturity (51,52). No differences were found between the exposed and placebo groups in terms of intellectual and motor development, school achievement, and social-emotional functioning (51). Concerning physical development, no differences between the groups were measured in terms of physical growth, neurologic and ophthalmologic development, and lung function (52). However, during the first few years of life the corticoid-exposed group had significantly more hospital admissions relating to infections than did those in the placebo group (52).

Studies conducted on very-low-birth-weight infants (5001500 g) at 2 years of age indicated that, compared to nonexposed controls, exposed infants received antenatal betamethasone therapy that was associated with a significant improvement in survival, improved growth, and a decrease in early respiratory morbidity (53). Further study of the children at 5 years of age, but limited to those with birth weights of 500-999 g, found significantly improved survival but without significantly improved growth or decrease in early respiratory morbidity (54).

A study published in 1999 (55), with an accompanying editorial (54), reported a decrease in the incidence of cystic periventricular leukomalacia (PL) with prenatal betamethasone, but not with dexamethasone. Among 883 live-born infants, with gestational ages ranging from 24 to 31 weeks,' the rates of cystic PL in infants of mothers given betamethasone (N=361), dexamethasone (N=165), or no prenatal corticosteroids (N=357), were 4.4%, 11.0%, and 8.4%, respectively. Cystic PL (necrosis of the white matter adjacent to the lateral ventricles resulting in the formation of cysts [56]), is the most frequent cause of cerebral palsy in premature infants (55).

A 1999 study reported a modest reduction in the risk of cerebral white matter damage (echolucency) and intraventricular hemorrhage (IVH), but a significant reduction in ventriculomegaly in premature infants weighing 500 to 1500 g (57). Significant reductions in the risk for echolucency and ventriculomegaly were seen in the gestationally youngest infants and in those with IVH, hypothyroxinemia, or vasculitis of the umbilical cord or chorionic plate of the placenta (57). In addition to this study, three other reports have also shown that the risk of IVH is reduced in preterm infants by the administration of antenatal betamethasone (58,59 and 60).

Another study on the reduction of PL with betamethasone appeared in 2001 (61). In 1,161 neonates born at gestational ages of 24-34 weeks', 400 were exposed to antenatal betamethasone and 761 were not exposed (controls). The effects of antenatal betamethasone compared to controls were: PL or IVH 23% vs.31%, p=0.005, PL with IVH 5% vs. 11%, p=0.001, and isolated PL 3% vs. 7% p=0.009. The investigators concluded that antenatal betamethasone therapy was associated with a greater than 50% decrease in PL in preterm infants (61).

Among miscellaneous effects of antenatal betamethasone, decreased fetal heart rate variability has been demonstrated (62,63). In addition, a 1999 report described three newborns who developed various degrees of transient hypertrophic cardiomyopathy after multiple courses of antenatal betamethasone (64).

Although no reports linking the use of betamethasone with birth defects have been located, four large epidemiologic studies have associated the use of corticosteroids during the 1st trimester with orofacial clefts. Betamethasone was not specifically identified in these studies, but only one study listed the corticosteroids used (see Hydrocortisone for details).

[*Risk Factor D if used in 1st trimester.]

Breast Feeding Summary

No reports describing the use of betamethasone during human lactation have been located. The molecular weight (about 435 for the acetate salt and about 517 for the sodium phosphate salt) are low enough, however, that excretion into milk should be expected.

References

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