Risk Factor: C*
Class: Hormones/ Adrenal agents
Fetal Risk Summary
Hydrocortisone (Cortisol; Compound F) is a corticosteroid secreted by the adrenal cortex. An inactive precursor, cortisone (Compound E), is also secreted by the adrenal cortex and is converted by reduction, primarily by the liver, to hydrocortisone (1). Hydrocortisone is used for a variety of indications. Physiologic doses are used to treat adrenal hormone deficiency, and higher, pharmacologic amounts for the antiinflammatory and immunosuppressant properties and other effects.
A number of studies have described the effects of hydrocortisone or cortisone on the pregnancy outcomes of experimental animals (2,3,4,5,6,7,8,9,10 and 11,13,14 and 15). In five different strains of pregnant mice administered a daily IM dose of cortisone ranging from 0.625 to 10.0 mg for 4 to 5 days, a dose-related and strain-related incidence of cleft palate and resorption were observed (2). Depending on the day of gestation that treatment started, the percentage of young with cleft palate ranged from 2.9% to 79.1%. (Pups with cleft lip and palate similar to the spontaneous defects that sometimes occur in untreated pups were excluded ). In contrast, no cases of cleft palate were observed in the young from control mice injected with an inert cortisone-free vehicle. Other anomalies observed in the offspring of treated groups included marked intrauterine growth retardation (IUGR), shortening of the head and mandible, and spina bifida.
In a continuation of the above work, this same research group studied the effects on pregnant mice of a daily, 2.5-mg IM cortisone dose given for 4 consecutive days beginning on gestational days 7 through 18 (3). The maximum percentage of litters resorbed occurred on day 7 (88%) and declined thereafter as the gestational age increased at the first dose. Depending on the mother’s genotype, the 4-day cortisone treatment beginning on gestational day 11 resulted in an incidence of cleft palate in the offspring varying from 4% to 100%. Much of this and earlier experiments was reviewed by these investigators in a 1957 paper (4).
Hydrocortisone was shown to produce an incidence of cleft palate in mice offspring similar to cortisone (95%) in genetically susceptible pregnant mice treated with 2.5 mg/day IM for 4 days starting on the 10th or 11th gestational day (5). No other gross external malformations were observed in the offspring.
The effect of cortisone treatment in mice on litter size, birth weight, cleft palate, gestation length, and spontaneous cleft lip (with or without palate) has been investigated (6). Litter size was reduced only if treatment was begun before the 12th gestational day, whereas birth weight was primarily reduced (mean reduction 31.2%) by treatment after this time. Cortisone administration had no effect on mean gestation length or on the frequency of spontaneous cleft lip but did induce cleft palate in some offspring. A 1998 correspondence reiterated the negative effect of cortisone on intrauterine growth that was found in this study (7).
The teratogenic potency of three corticosteroids to produce cleft palate in mice was the subject of a study published in 1965 (8). Therapeutically equivalent IM doses of hydrocortisone (4 mg), prednisolone (1 mg), or dexamethasone (0.15 mg) were administered to pregnant mice (weight 20 to 25 g) on gestational days 11 through 14. After exclusion of offspring with spontaneous cleft lip and palate, the frequency of cleft palate with the three agents was 18%, 77%, and 100%, respectively (8). In another study, cleft palate (palatoschisis) and cataract were frequently observed in the offspring of pregnant mice (weight 20 g) administered 1 mg of hydrocortisone SC for 2 to 4 days between gestational days 9 and 16 (9). Resorption of part or all of the litters was common.
One study investigated the effect on reproduction in rabbits of IM cortisone, 1 to 5.7 mg/kg/day administered for 1 to 33 days (10). Gross congenital anomalies were not seen in offspring that survived, but IUGR was evident in some. Further, a marked increase in fetal and neonatal death was observed. In a later study, pregnant rabbits received IM cortisone, 25 or 30 mg (approximately 7 to 8 mg/kg/day), for 4 days beginning on gestational day 14 or 15 (11). (Total gestation time in rabbits is 3134 days ). Seventeen of the 35 embryos had a cleft palate, including 9 of the 12 born dead. Embryos with cleft palate, living or stillborn, usually weighed less than their siblings. In addition, two of the seven exposed litters were completely resorbed. All 36 offspring from nonexposed controls were born alive without cleft palate.
Reduced lung and body weights were observed in rabbit fetuses given a 2-mg IM injection of hydrocortisone on gestational day 24 (13). Treated fetuses also had fewer lung cells as indicated by decreased DNA per lung. The deficiencies in the number of lung cells and the weights of lung and body recovered within 30 days of birth. In a 1979 study, hydrocortisone, 57 mg/kg/day intraperitoneal on day 12 or 15 of gestation, had no effect on the development of brain monoamine cell bodies or the arrival of axon terminals in the regions where the synapses form (14).
A study published in 1991 demonstrated that a single, 250 mg/kg SC dose of hydrocortisone in pregnant mice on gestational days 11 through 17 could induce polycystic kidney disease in the fetus (15). (Total gestation time in mice is 1820 days ). The highest incidence of the defect occurred after exposure on gestational day 12, corresponding to the expected onset of metanephric renal differentiation in the fetal mouse (15).
Hydrocortisone and cortisone cross the human placenta to the fetus (16,17,18 and 19). Six pregnant women, immediately before an elective cesarean section at term, received a continuous IV infusion of a mixture of radioactive-labeled hydrocortisone and cortisone (16). By measurement of the hormones in the mothers and newborns, the investigators demonstrated that most (about 75%) of the hydrocortisone in the fetus was endogenous, whereas most of the cortisone was from the mother. Two other studies described low transfer of hydrocortisone to the fetus because of placental metabolism (17,18). The placenta is a rich source of the enzyme, 11b-ol-dehydrogenase, which can convert hydrocortisone to cortisone, the biologically inactive 11-ketosteroid (17,18). In an in vivo experiment, radioactive-labeled IV hydrocortisone was administered to five women immediately before an elective abortion at 13 to 18 weeks’ gestation (17). The concentrations of hydrocortisone and cortisone in umbilical cord serum and the placenta exhibited similar patterns: about 15% for hydrocortisone and 85% for cortisone, indicating that most of hydrocortisone crossing the placenta had been converted to cortisone (17). Using a perfused human placenta, one investigation discovered that the percentage of hydrocortisone converted to cortisone in three different perfusion mediums was 73% (buffer), 85% (1% human serum albumin), and 78% (washed calf red blood cells) (18).
In a 1982 report, researchers measured the concentration of hydrocortisone in the cord blood of 71 premature infants (mean gestational age 32.5 weeks) after administration of the drug in an attempt to prevent respiratory distress syndrome (RDS) (19). The mothers received an IV dose of 100 mg, followed by 100 mg IM every 8 hours up to a total of 400 mg. The infants were delivered between 6 minutes and 85 hours after the first dose. The peak cord blood concentration (32 g/100 mL) occurred approximately 1 hour after a dose, representing a 3.8-fold increase over endogenous levels (8.5 g/100 mL). Nearly all of the exogenous hydrocortisone was cleared between doses as indicated by the elimination half-life of about 2 hours (19).
Hydrocortisone is frequently prescribed during human pregnancy and case reports and other References have described the use of this agent or its precursor, cortisone, during pregnancies that produced an infant with a congenital malformation. In most cases, however, a relationship between the drug and the outcome cannot be determined.
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 21 and 34 of which were exposed in the 1st trimester to hydrocortisone and cortisone, respectively (20, pp. 388400). Three of the infants exposed in utero to hydrocortisone had a major malformation (relative risk [RR] 2.79), whereas one infant had a defect following exposure to cortisone (RR 0.46) (type of defects not specified). Exposures to hydrocortisone anytime during pregnancy totaled 74 with three malformed infants (RR 1.70, 95% Confidence Interval [CI] 0.354.79) (20, p. 443). Although the number of exposures is limited, no evidence of an association with congenital malformations was found with these data (20, p. 398).
Several case reports have described congenital anomalies in newborns exposed to corticosteroids with and without other drug exposures (21,22,23,24 and 25). Some of these cases are included in the review discussed below (26). A brief 1953 correspondence describes four infants with defects (club foot, coarctation of the aorta, cataract, and hypospadias) who were delivered to mothers treated during the 1st trimester with cortisone for nausea and vomiting (21). Microcephaly was noted in a newborn whose mother was treated with two 100-mg IV doses of hydrocortisone and a single IM dose of procaine penicillin at about the 8th week of gestation (22). A male cyclops with a single orbit containing one eyeball with two corneas and two irides was described in a 1973 publication (23). The mother had been treated with high doses (specifics not given) of cortisone, procaine penicillin, and sodium salicylate at about 4 weeks fetal age for symptoms of diarrhea, fever, and a maculopapular rash. The infant died 5 minutes after birth. In addition to the cyclops, the nose was absent and the ears were low set, and at autopsy, the brain was found to be small and severely malformed. Although the mother had a positive rubella titer, a definite diagnosis of rubella could not be made (23). Moreover, the defects noted in the infant were not consistent with those required for a diagnosis of congenital rubella syndrome (see Vaccine, Rubella). Two malformed infants, one with gastroschisis and the other with hydrocephalus, were briefly noted in a 1965 Reference (24). The mothers had used cortisone (doses not specified) throughout their pregnancies for ulcerative colitis and severe asthma, respectively. Bilateral nuclear cataract was diagnosed in a male infant who had been exposed to prednisone (1560 mg/day) throughout gestation for maternal Crohn’s disease (25). In addition, high dose (amount not specified) cortisone had been given during the 6th month of gestation.
A brief 1995 article reviewed the available literature to assess whether the use of corticosteroids (hydrocortisone, cortisone, prednisone, prednisolone, or dexamethasone) during the first 70 days after human conception was teratogenic (26). The disorders treated were mainly systemic lupus erythematosus, asthma, and infertility. From 18 case reports, the researchers identified 26 exposed pregnancies of which 7 (27%) ended with malformed offspring (26). Four (15%) of the anomalies were cleft palate (three of these cases are described below as References 27,28 and 29) and the other three were bilateral nuclear cataract, gastroschisis, and hydrocephalus. Although the number of infants with congenital defects is much higher than expected, the authors thought it likely that they represented reporting bias (26). In addition, they reviewed 17 reported series of 457 mothers exposed to the corticosteroids during the 1st trimester. In this group, 16 (3.5%) of the offspring, an incidence close to that expected, had malformations. Of these, two had cleft palate (0.2 expected based on population frequency) (26). The other defects were anencephaly (N=2), clubfoot (N=3), dislocated hip (N=1), coarctation of the aorta (N=2; 1 with a positive family history), transposition of the great vessels (N=1; with a positive family history), cataract (N=2; 1 with a positive family history), hypospadias (N=2), and undescended testis (N=1) (26). Other adverse effects including stillbirth, neonatal death, prematurity, and low birth weight accounted for 21% of the outcomes, but the authors were unable to separate the effect of the drug treatment from the disease process itself. They concluded that there was little teratogenic risk, if any, from the use of corticosteroids in human pregnancy (26).
The first reported case of cleft palate in an infant delivered from a woman treated with cortisone was published in 1956 (27). A 30-year-old woman with idiopathic steatorrhea was administered oral cortisone, 100 mg three times daily, beginning on the 38th day of pregnancy. Therapy was gradually tapered and then discontinued about 9 weeks later when pregnancy was diagnosed. The woman eventually delivered a term stillborn male child with a cleft palate. The cause of death was thought to be intrauterine anoxia. A second case was also reported in 1956 (28). A woman with disseminated lupus erythematosus was treated throughout her pregnancy with oral cortisone (100 mg/day) and tolazoline (400 mg/day). She delivered a premature, growth retarded 2 pound 11 ounce (about 1.22 kg) male infant at between 35 and 36 weeks’ gestation. The infant, who died of pneumonia 14 days after birth, had a cleft palate but no other malformations were observed at autopsy. A 1962 paper mentioned an infant with a cleft palate whose mother had taken 62.5 mg/day of cortisone during the first 6 months of pregnancy (29).
A 1960 Reference cited pregnancy outcome data from 31 reports totaling 260 pregnancies exposed to pharmacologic doses of cortisone or its analogues (30). The outcomes included 8 stillborn, 1 abortion, 15 premature infants, and 7 newborns with various disorders, one of which involved transient adrenocortical failure. (Disorders in the other six were not specified.) The authors did not attempt to list the type or frequency of congenital defects, stating only that most . . . showed no malformations. They did, however, mention four cases of cleft palate (two from their series and two from unpublished data) in infants exposed to large doses of corticosteroids during the 1st trimester (30).
Data from the MADRE (an acronym for MAlformation DRug Exposure surveillance) project was published in 1994 (31). This large surveillance study, a part of the International Clearinghouse for Birth Defects Monitoring Systems, compared congenital malformations with 1st trimester drug exposures from six different countries (Australia, France, Israel, Italy, Japan, and South America) during a 2-year period (19901991) (31). A total of 1,448 infants with birth defects were studied. Most of the programs, however, did not report abortions. Moreover, individual drugs were not identified but were grouped into 45 pharmacologic classes. The maternal drug exposure history was determined by interview in the postpartum period. Of interest, seven infants with facial clefts (cleft lip N = 5, cleft lip and palate N=2) were exposed to systemic corticosteroids (odds ratio [OR] 3.16; 95% CI 1.087.91; p=0.04). The authors noted that the association may have occurred by chance (31).
The case-control study Spanish Collaborative Study of Congenital Malformations, surveying more than 1.2 million infants born live from 1976 to 1995, was published in 1995 (32). The study’s purpose was to determine if the occurrence of nonsyndromic cleft lip (with or without cleft palate) was related to 1st trimester exposure to systemic corticosteroids. Three control groups were used: (a) paired controls; (b) controls born at the same hospital 45 days of the case’s birth date; and (c) malformed infants without oral clefts. Statistical analysis was employed to control for four potential confounding factors: (a) maternal smoking; (b) maternal hyperthermia; (c) first-degree malformed relatives with cleft lip with or without cleft palate; and (d) 1st trimester drug exposure to anticonvulsants, benzodiazepines, metronidazole, or sex hormones. A total of 1,184 case infants were identified with nonsyndromic oral clefts, five (0.42%) of whom were exposed during the 1st trimester to corticosteroids. Among the 31,752 control infants, 36 (0.11%) had been exposed to corticosteroids during the 1st trimester. None of the five case infants had been exposed to known teratogens or known risk factors for oral clefts during the 1st trimester. Based on four cases (a case of cleft soft palate was excluded), there was an increased risk of cleft lip (with or without cleft palate) following 1st trimester exposure to systemic corticosteroids (OR 6.55; CI 1.4429.76; p=0.015) (32). Control of the four confounding factors made the association slightly stronger (OR 6.64; CI 1.4630.18; p=0.014). The corticosteroids identified in these four cases were hydrocortisone (N=1; 40 mg/day throughout pregnancy), prednisone (N=2; 1530 mg/day during 1st trimester), and triamcinolone (N=1; 8 mg/day during 2nd month).
Another large case-control study of the teratogenic potential of oral and topical corticosteroids involving 1,923,413 total births from 1980 to 1994 was conducted with the Hungarian Case-Control Surveillance of Congenital Abnormalities and published in 1997 (33). Among the 20,830 malformed case infants, 322 (1.55%) were exposed to systemic corticosteroids (all oral except for four that received parenteral doses) during the 1st trimester compared with 503 (1.41%) (all oral except for three that received parenteral doses) of the 35,727 normal control infants (p=0.19). A corticosteroid ointment was used in 73 (0.35%) of the cases and in 118 (0.33%) of the controls (p=0.69). A corticosteroid spray was used by eight case mothers (0.04%) and 11 controls (0.03%) (p=0.63), but the offspring from those mothers were excluded from the detailed analysis because of the small numbers. The indications for systemic corticosteroids during the 1st trimester were primarily for asthma, hay fever, rheumatoid disorders, and subfertility, whereas the ointments were used for skin diseases. Most of the systemic exposures in both cases and controls were to dexamethasone and prednisolone. None of the patients in either group received systemic hydrocortisone and only 15 cases and 22 controls received systemic cortisone. Hydrocortisone ointment was used by 24 case mothers and 32 controls. No association between the rate of different abnormalities and the use of corticosteroids (oral and ointment) in the 2nd and 3rd months of gestation or during the 1st trimester was found based on the analysis of the case-control pairs (33). In the 1st gestational month, three cases with cleft lip (with or without cleft palate) (OR 5.88, CI 1.7020.32) and multiple defects (OR 4.88, CI 1.4116.88) were observed. However, exposures that occurred only during the 1st gestational month (the 1st half of this month is before conception and the other half involves the processes of pre-implantation and implantation) cannot cause defects because this time is before the critical period for induction of congenital malformations (33).
In a case-control study published in 1999, the California Birth Defects Monitoring Program evaluated the association between selected congenital anomalies and the use of corticosteroids 1 month before to 3 months after conception (periconceptional period) (34). Case infants or fetal deaths diagnosed with orofacial clefts, conotruncal defects, neural tubal defects (NTD), and limb anomalies were identified from a total of 552,601 births that occurred from 1987 through the end of 1989. Controls, without birth defects, were selected from the same database. Following exclusion of known genetic syndromes, mothers of case and control infants were interviewed by telephone, an average of 3.7 years (cases) or 3.8 years (controls) after delivery, to determine various exposures during the periconceptional period. The number of interviews completed were orofacial cleft case mothers (N=662, 85% of eligible), conotruncal case mothers (N=207, 87%), NTD case mothers (N=265, 84%), limb anomaly case mothers (N=165, 82%), and control mothers (N=734, 78%) (34). Orofacial clefts were classified into four phenotypic groups: isolated cleft lip with or without cleft palate (ICLP, N=348), isolated cleft palate (ICP, N=141), multiple cleft lip with or without cleft palate (MCLP, N=99), and multiple cleft palate (MCP, N=74). A total of 13 mothers reported using corticosteroids during the periconceptional period for a wide variety of indications. Six case mothers of ICLP and 3 of ICP used corticosteroids (unspecified corticosteroid N=1, prednisone N=2, cortisone N=3, triamcinolone acetonide N=1, dexamethasone N=1, and cortisone plus prednisone N=1). One case mother of an infant with NTD used cortisone and an injectable unspecified corticosteroid, and three controls used corticosteroids (hydrocortisone N=1 and prednisone N=2). The odds ratio for corticosteroid use and ICLP was 4.3 (95% CI 1.117.2), whereas the odds ratio for ICP and corticosteroid use was 5.3 (95% CI 1.126.5). No increased risks were observed for the other anomaly groups. Commenting on their results, the investigators thought that recall bias was unlikely because they did not observe increased risks for other malformations, and it was also unlikely that the mothers would have known of the suspected association between corticosteroids and orofacial clefts (34).
Hydrocortisone was only partly successful in an attempt to prevent in utero virilization by adrenal suppression of a female fetus with congenital adrenal hyperplasia (21-hydroxylase deficiency) (35). A daily oral dose of 40 mg was started at 9.4 weeks’ gestation and increased to 50 mg/day during midpregnancy. At delivery, low amniotic fluids of estriol indicated only partial suppression of the fetal adrenal glands (35). The infant had moderate virilization as indicated by clitoral hypertrophy and slight posterior fusion (35). In contrast, dexamethasone was used successfully in a second mother (see Dexamethasone). The failure of hydrocortisone to completely prevent virilization was probably a result of the lower placental transfer and adrenal suppression potency compared with dexamethasone.
Hydrocortisone has been used in attempts to enhance fetal lung maturation and, thus, prevent RDS (18,36,37,38,39,40,41,42,43,44 and 45). This therapy is relatively nontoxic to the fetus. However, hydrocortisone is no longer used for this purpose because very large doses are required to overcome placental metabolism and relatively short half-life of the corticosteroid in the fetus. Compared with a corticosteroid frequently used to prevent RDS (betamethasone 24 mg/treatment course), at least a 2000 mg/treatment course of hydrocortisone would have to be administered to achieve therapeutically equivalent results (45).
Both hydrocortisone and cortisone have been used to treat pregnancy-induced severe nausea and vomiting (i.e., hyperemesis gravidarum (21,46,47). Although this therapy appears to be successful, its risks, especially in the 1st trimester (e.g., see Reference 21), indicate that corticosteroids should not be used as primary therapy.
Hydrocortisone and other systemic and inhaled corticosteroids are frequently prescribed to control the symptoms of severe asthma during pregnancy (48,49,50,51,52,53 and 54) . Most authorities believe that these agents are relatively safe in pregnancy and that their benefit to both the mother and her pregnancy clearly outweigh the potential risks to the fetus (48,49,50,51,52 and 53) . One author, however, suggested caution in their use around the time of palate closure and in women with a family history of cleft lip (with or without cleft palate) (48). A recent study of 824 pregnant asthmatic patients matched with 678 controls (all singleton pregnancies in both groups) found no significant relationship between major congenital malformations and 1st trimester exposure to corticosteroids (oral, inhaled, or intranasal) (50). However, significant associations were found between corticosteroid use and preeclampsia (exposed 11.4% vs. controls 7.1%, p=0.014), preterm birth (exposed 6.4% vs. controls 3.8%, p=0.048), and low birth weight (exposed 6.0% vs. controls 3.3%, p=0.032) (50). Other References have reported IUGR as a complication of systemic corticosteroids (51,52 and 53) . The latter Reference quantified the impaired fetal growth as about a 300- to 400-g decrease in birth weight (53).
In summary, hydrocortisone and its inactive precursor, cortisone, appear to present a small risk to the human fetus. These corticosteroids produce dose-related teratogenic and toxic effects in genetically susceptible experimental animals consisting of cleft palate, cataracts, spontaneous abortion, IUGR, and polycystic kidney disease. Although the large number of data do not support these effects in the great majority of human pregnancies, adverse outcomes have been observed and may have been caused by corticosteroids. Moreover, the decrease in birth weight and a small increase in the incidence of cleft lip with or without cleft palate is supported by large epidemiologic studies. In addition, cataracts, resulting from a toxicity observed in humans administered the drug directly, have been reported in human offspring exposed in utero, but a causal relationship to maternal corticosteroid use is less certain. Because the benefits of corticosteroids appear to far outweigh the fetal risks, these agents should not be withheld if the mother’s condition requires their use. The mother, however, should be informed of the risks so that she can actively participate in the decision on whether to use these agents during her pregnancy.
[*Risk Factor D if used in 1st trimester.]
Breast Feeding Summary
Trace amounts of endogenous hydrocortisone (cortisol) are excreted into human breast milk (54,55). The amount of the corticosteroid in milk varies from 0.2 to 32 ng/mL with the highest mean concentrations (25.5 ng/mL) measured in colostrum during late pregnancy (55). The concentration of hydrocortisone in colostrum averages 7.5% of the plasma level (55).
No reports describing the excretion of exogenous hydrocortisone or cortisone into human milk have been located. It is unlikely, however, that these agents pose a risk to a nursing infant. Prednisone, a corticosteroid more potent than hydrocortisone, is excreted in trace amounts into milk and is classified as compatible with breast feeding (see Prednisone). Moreover, a 1997 review stated that corticosteroids have been used safely during lactation (51).
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