Antibiotic
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
The animal reproduction data suggest high risk, but the available human pregnancy experience suggests that the risk, if it exists, is low. The antibiotic has not been associated with an increased risk of pyloric stenosis.
FETAL RISK SUMMARY
Clarithromycin, a semisynthetic antibiotic structurally related to erythromycin, belongs to the same macrolide class of anti-infectives as azithromycin, dirithromycin, erythromycin, and troleandomycin.
The effects of clarithromycin on fertility and reproduction in rats, mice, rabbits, and monkeys have been reported by the manufacturer. Doses up to 1.3 times the recommended maximum human dose based on BSA (MRHD) (serum levels approximately 2 times the levels in humans) in male and female rats produced no adverse effects on the estrous cycle, fertility, parturition, or fetal outcome. No teratogenic effects were observed in four studies involving one rat strain using oral and IV doses up to 1.3 times the MRHD, but a low incidence of cardiovascular anomalies was seen in two studies, with a second rat strain at an oral dose about 1.2 times the MRHD. A variable incidence of cleft palate occurred in mice given oral doses about 2–4 times the MRHD (1).
In rabbits, IV doses 17 times less than the MRHD resulted in fetal death, but teratogenic effects were not observed with various oral or IV doses (1). Embryonic loss attributed to maternal toxicity occurred in monkeys administered oral doses 2.4 times the MRHD (serum levels three times the levels in humans). In monkeys, an oral dose approximately equal to the MRHD (serum levels about twice those obtained in humans) caused fetal growth restriction.
Clarithromycin crosses the human placenta (2). In an in vitro experiment using perfused term placentas, the mean transplacental transfer of clarithromycin was 6.1%.
At a 1996 meeting, a teratogen information service (TIS) reported the outcomes of 34 exposures to clarithromycin during pregnancy (3). All of the exposures occurred during the 1st and early 2nd trimesters for the treatment of upper respiratory infections. Among the 29 known pregnancy outcomes (5 were pending), there were 8 (28%) abortions (4 spontaneous/4 voluntary), 20 (69%) normal newborns, and 1 (3%) infant with a 0.5-cm brown mark on the temple. One of the normal newborns, delivered at 26 weeks, died from complications of prematurity. Although follow-up of the remaining newborns had not been sufficiently long to exclude completely the presence of congenital malformations, these outcomes do not appear to be different from those expected in a nonexposed population.
Case reports of clarithromycin and congenital anomalies available to the FDA through June 1996 were limited to six diverse birth defects: cystic head, pregnancy terminated; craniofacial anomalies, absent clavicles, bilateral hip deformities, and underdeveloped left heart; spina bifida; cleft lip; pulmonary hypoplasia, anomalous infradiaphragmatic venous return; and CHARGE syndrome (F. Rosa, personal communication, FDA, 1996). By definition, infants having CHARGE association or syndrome must have two or more of the following: coloboma of the eye or eye defects, heart disease, choanal atresia, restricted growth and development with or without CNS anomalies, genital hypoplasia, and ear anomalies with or without deafness (4). The diversity of the malformations lessens the probability of an association with clarithromycin and any or all of these outcomes may have occurred by chance.
A 1998 prospective controlled multicenter study compared the outcomes of 157 pregnancies exposed to clarithromycin with an equal number of matched controls (5). All of the women had called a TIS. The most common indications for use of the antibiotic were respiratory infections. Of the subjects, 122 (78%) were exposed during the 1st trimester. The outcomes of subjects and controls were spontaneous abortions (SABs) (22 vs. 11, p = 0.04), elective abortions (EABs) (11 vs. 3, p = 0.04), live births (123 vs. 143, p = 0.003), stillbirths (1 vs. 0, ns), major malformations (3 vs. 2, ns), and minor malformations (7 vs. 7, ns). The major anomalies (exposure occurred in the 3rd trimester in one case) in the study group were hydrocephalus, Turner’s syndrome, and stenosis uteropelvic junction and cranial synostosis. The minor malformations were a large birth mark, a reflux valve problem, an enlarged right ventricle (brain), a minor ventricular septal defect, undescended testes, a blocked tear ducts defect, and excess breast tissue on the right. The types of malformations in controls were comparable, with no pattern of defects apparent in either group. Although the increased number of SABs in exposed women was within the expected background rate and may have been affected by confounding factors, the investigators concluded that it warranted further study (5).
A prospective, multicenter study published in 2008 compared pregnant women exposed to a new macrolide (azithromycin, clarithromycin, or roxithromycin) with two comparison groups (6). Of the 161 women exposed to a macrolide, 118 were exposed in the 1st trimester. The rate of major malformations in the study group was 4.1% compared with 2.1% of those exposed to other antibiotics (OR = 1.41, 95% confidence interval (CI) 0.47–4.23). The authors concluded that the use of the new macrolides did not represent an increased risk of congenital defects strong enough for an EAB (6).
A 2012 prospective, multicenter observational study was conducted by TISs in Italy, Israel, Czech Republic, the Netherlands, and Germany (7). Of the 608 women exposed to macrolides, 511 were exposed in the 1st trimester. The study group was compared with 773 women exposed to nonteratogens in the 1st trimester. The rate of major congenital defects were similar in the groups (3.4% vs. 2.4%, p = 0.36; OR 1.42, 95% CI 0.70–2.88) or in the rate of cardiovascular defects (1.6% vs. 0.9%). The rates for clarithromycin (N = 218) were 1.8% vs. 2.4%, p = 0.80; OR 0.76, 95% CI 0.25–2.27 and 0.5% vs. 0.9%, p = 0.99; OR 0.54, 95% CI 0.06–4.48 (7).
A register-based, nationwide cohort study conducted in Denmark, covering the period 1997–2007, was published in 2013 (8). The study identified 931,504 pregnancies (705,837 live birth, 77,553 SABs, and 148,114 EABs), 401 of whom were exposed to clarithromycin in the 1st trimester. The hazard ratio (HR) of having an SAB after exposure to clarithromycin was 1.56, 95% CI 1.14–2.13. A significant HR was not found with 1st trimester exposure to three other antibiotics and proton pump inhibitors (PPIs) (HR and 95% CI): amoxicillin (N = 4584, 0.92, 0.82–1.04); erythromycin (N = 6492, 1.03, 0.94–1.13); Penicillin V (N = 33,469, 1.00, 0.96–1.04); and PPIs (N = 3577, 1.03, 0.91–1.18). Among the 253 exposed offspring diagnosed with a major malformation, 9 (3.6%) were exposed to clarithromycin (odds ratio [OR] 1.03, 95% CI 0.53–2.00). The authors concluded that further research was required to examine the possible effects of treatment indications on the above association (8).
Three pregnant women with documented Helicobacter pylori infections, persistent nausea and vomiting, and epigastric pain were treated in the 2nd trimester with a 2-week course of clarithromycin combined with amoxicillin and with famotidine, omeprazole, or ranitidine (9). The therapy was effective in eliminating the conditions. No adverse effects on the pregnancy outcomes were noted.
In a 2005 abstract, 145 pregnant women were exposed to a new macrolide (38 azithromycin, 53 clarithromycin, 54 roxithromycin), of which 103 were exposed in the 1st trimester (10). The rates of congenital anomalies compared with 928 exposed to a nonteratogen were similar (4.0% vs. 3.75%, p = 0.156). In a 2003 Danish study, 188 women received a macrolide (see Breastfeeding Summary) within 30 days of birth and none of their infants had infantile hypertrophic pyloric stenosis (11).
BREASTFEEDING SUMMARY
Clarithromycin is excreted into breast milk. In a 1993 study, 12 mothers were given clarithromycin 250 mg twice daily (12). Both the parent drug and metabolite were excreted into milk, with peaks levels measured at 2.2 and 2.8 hours, respectively, The half-lives of the drug and metabolite were 4.3 and 9 hours, respectively. The combined exposure for an exclusively breastfed infant was about 2% of the mother’s weight-adjusted dose (12).
A 2003 study investigated the association between maternal use of macrolides and infantile hypertrophic pyloric stenosis (11). The Danish population-based cohort study comprised 1166 women who had a prescribed macrolide (azithromycin, clarithromycin, erythromycin, spiramycin, or roxithromycin) from birth to 90 days postnatally compared with up to 41,778 controls. The OR for stenosis was 2.3–3.0, depending on the postnatal period of exposure (42, 56, 70, or 90 days), but none of the ORs was significant. When stratified by gender, the ORs for males were 1.8–3.1 and again were not statistically significant. For females, the ORs at 70 and 90 days postbirth were 10.3 and 7.5, but only the former was significant (95% CI 1.2–92.3) (11).
Investigators from Israel examined the possible association between macrolide (azithromycin, clarithromycin, erythromycin, or roxithromycin) exposure in milk and infantile hypertrophic pyloric stenosis in a 2009 study (13). They compared 55 infants exposed to a macrolide antibiotic to 36 infants exposed to amoxicillin. In the macrolide group, 7 (12.7%) had an adverse reaction (rash, diarrhea, loss of appetite, somnolence), whereas 3 infants (8.3%) in the amoxicillin group had an adverse reaction (rashes, somnolence). The rates of adverse reactions were comparable. No cases of infantile hypertrophic pyloric stenosis were observed (13).
References
1.Product information. Biaxin. Abbott Laboratories, 1996.
2.Witt A, Sommer EM, Cichna M, Postlbauer K, Widhalm A, Gregor H, Reisenberger K. Placental transfer of clarithromycin surpasses other macrolide antibiotics. Am J Obstet Gynecol 2003;188:816–9.
3.Schick B, Hom M, Librizzi R, Donnenfeld A. Pregnancy outcome following exposure to clarithromycin (abstract). Abstracts of the Ninth International Conference of the Organization of Teratology Information Services, May 2–4, 1996, Salt Lake City, Utah. Reprod Toxicol 1996;10:162.
4.Escobar LF, Weaver DD. Charge association. In: Buyse ML, ed. Birth Defects Encyclopedia. Vol. 1. Dover, MA: Center for Birth Defects Information Services, 1990:308–9.
5.Einarson A, Phillips E, Mawji F, D’Alimonte D, Schick B, Addis A, Mastroiacova P, Mazzone T, Matsui D, Koren G. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15:523–5.
6.Bar-Oz B, Diav-Citrin O, Shechtman S, Tellem R, Arnon J, Francetic I, Berkovitch M, Ornoy A. Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study. Eur J Obstet Gynecol Reprod Biol 2008;141:31–4.
7.Bar-Oz B, Weber-Schoendorfer C, Berlin M, Clementi M, Di Gianantonio D, de Vries L, De Saints M, Merlob P, Stahl B, Eleftheriou G, Manakova E, Hubickova-Heringova L, Youngster I, Berkovitch M. The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observations study. Drug Saf 2012;35:589–98.
8.Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C, Keiding N, Poulsen HE. Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register-based nationwide cohort study. PLoS One 2013;8:e53327. doi:10.1371/journal.pone.0053327. Epub 2013 Jan 2.
9.Jacoby EB, Porter KB. Helicobacter pylori infection and persistent hyperemesis gravidarum. Am J Perinatol 1999;16:85–8.
10.Tellem R, Shechtman S, Arnon J, Diav-Citrin O, Bar-Oz B, Berkovitch M, Ornoy A. Pregnancy outcome after gestational exposure to the new macrolides: a prospective controlled cohort study (abstract). Reprod Toxicol 2005;20:484.
11.Sorensen HT, Skriver MV, Pedersen L, Larsen H, Ebbesen F, Schonheyder HC. Risk of infantile hypertrophic pyloric stenosis after maternal postnatal use of macrolides. Scand J Infect Dis 2003;35:104–6.
12.Sedimayr TH, Peters F, Raasch W, Kees F. Clarithromycin, a new macrolide antibiotic: effectiveness in puerperal infections and pharmacokinetics in breast milk. Geburtshilfe Frauenheilkd 1993;53:488–91.
13.Goldstein LH, Berlin M, Tsur L, Bortnik O, Binyamini L, Berkovitch M. The safety of macrolides during lactation. Breastfeed Med 2009;4:157–200.