a prospective controlled multicentre study of ...

AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 15, NUMBER 9

1998

A PROSPECTIVE CONTROLLED MULTICENTRE STUDY OF CLARITHROMYCIN IN PREGNANCY Adrienne Einarson, R.N.,*Elizabeth Phillips, M.D.,*Fazaleet Mawji, B.Sc.,* Diana DAlimonte, B.Sc.,* Betsy Schick, M.Sc.,f Antonio Addis, PH.M.D.,* Pierpaolo Mastroiacova, M.D.J Teresa Mazzone, M.D.J D. Matsui, W and Gideon Koren, M.D. * ABSTRACT

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Clarithromycin is a relatively new macrolide antibiotic with an action spectrum similar to that of erythromycin. Its main indications for use are for upper and lower respiratory and skin and soft tissue infections. Little is known about its safety in pregnancy, although animal reproductive studies found an increased rate of cardiovascular anomalies, cleft palate, and embryonic loss. Human data, limited to case reports and one small uncontrolled study, cannot allow evidence based counseling of pregnant women who were exposed to the drug before finding out they were pregnant. Pregnant women who had been counseled on the use of clarithromycin by five centers, were matched for age, smoking, and alcohol use with a control group of pregnant women who were exposed to nonteratogenic antibiotics. A total of 157 women were followed up. Of these, 122 were exposed to the drug in the first trimester. There were no significant differences found between the two groups in the rates of major and minor malformations; 2.3 versus 1.4% for major (p = 0.86) and 5.4 versus 4.9% for minor (p = 0.96). Spontaneous abortion rates in the exposed group was significantly different, higher (14%) than in the control group (7%) (p = 0.04). This first prospective controlled study of exposure to clarithromycin in pregnancy suggests that this agent does not increase the rate of major malformations above the baseline risk of 1-3%. The higher rate of reported spontaneous abortions, although still within the expected baseline rate, may warrant further study. Keywords: Clarithromycin; pregnancy; Biaxin®, humans

Clarithromycin (Biaxin®, Abbot, Montreal, Quebec, Canada) is a relatively new macrolide antibiotic introduced in Canada in 1992. Like other macrolide antibiotics, it acts by binding to the 50S ribosomal subunit of bacteria and hence suppresses protein synthesis. It differs from erythromycin only in one methoxy group in the C-6 position instead of a hydroxyl group. Clarithromycin is generally better tolerated than erythromycin with less gastrointestinal side effects. Its main indications for use include bacterial upper and lower respiratory infections and uncomplicated Gram-positive soft tissue infections. The usual dose of clarithromycin is 250-500 mg twice daily. More recent indications include part of triple therapy for Helicobacter pylori associated peptic ulcer disease and combination therapy for pelvic inflammatory disease. It is also commonly used in the long-term treatment for disseminated Mycobacterium avium in patients with the acquired immunodefi-

ciency syndrome.1 Because the primary indications for the prescription of clarithromycin are so common and because 50-75% of pregnancies are unplanned, clarithromycin is likely to be commonly prescribed during early pregnancy.2 There is limited data concerning the safety of this drug in pregnancy. Animal studies found an increased rate of cardiovascular abnormalities, cleftpalate, and embryonic loss at high doses.1 Even though animal studies are not necessarily predictive of human experience, it is stated in the 1998 Compendium of Pharmaceuticals and Specialties (CPS), a

Canadian reference manual for pharmacists and physicians: WARNING: Clarithromycin should not be used in pregnancy except where no alternative therapy is appropriate, especially in the first three months of pregnancy. If pregnancy does occur, the patient should be apprised of the potential hazard to the fetus.3 A warning also exists in the current US-

*The Motherisk Program, Toronto, Canada; tPregnancy Riskline, Philadelphia, PA; +Mario Negri Institute, Milan, Italy; STelefono Rosso, Rome, Italy; and HF.R.A.M.E. Program, London, Canada Reprint requests: Adrienne Einarson, The Motherisk Program, Division of Clinical Pharmacology, The Hospital For Sick Children, 555 University Avenue, Toronto M5G 1X8, Ontario, Canada Copyright ©1998 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1 (212) 760-0888. All rights reserved.

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PDI1998 citing an FDA Category C.4 This was based on a warning label by the United States Food and Drug Administration (FDA) that stated "On the basis of animal data reported by the manufacturer, clarithromycin has been granted a special product warning label that states it should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate."1 Human experience is lacking except for an FDA bulletin in June 1996, which reported six cases of babies born with major malformations whose mothers took clarithromycin in early pregnancy with no specific pattern of defects.5 A small uncontrolled study of 34 cases published as an abstract in 1996 found no increased risk for major malformations above the baseline of 1-3%.6 Because case reports have an inherent bias and because there was no pattern of defects, such data are not sufficient information to counsel women on the safety/risk of this drug in pregnancy. In fact, it may alarm her enough to consider or eventually undergo an abortion of an otherwise wanted pregnancy. Based on this paucity of information, we decided to carry out this study to ascertain the risk or safety of a women consuming this drug during pregnancy.

1998 Table 1 .

Indications for Treatment

Indications

No. Cases

Respiratory infections Influenza/cold Helicobacter pylori Dental infections Urinary tract infections Other

103 23 6 4 5

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sumption during pregnancy. To assess the possibility of a selection bias, women lost to follow-up were compared with those successfully followed up for maternal age, gestational age, parity, previous spontaneous and therapeutic abortions, cigarette, and alcohol consumption. Outcomes of interest were compared between the study and control groups with the Student's t-test, Chi-square, or the Fisher's exact test whenever appropriate. The protocol was approved by our Research Ethics Committee.

RESULTS

PATIENTS AND METHODS

The Motherisk Program at The Hospital for Sick Children in Toronto is a counseling service for pregnant and lactating women and their health professionals. Telefono Rosso in Rome and Mario Negri in Milan, Italy, the Pregnancy Riskline in Philadelphia, PA, and the FRAME program in London, Canada are similar services. We attempted to follow up all women who had called inquiring about the safety of clarithromycin in pregnancy since its introduction on the market in 1992. Upon contacting these women, history of exposure and pregnancy outcome was obtained, as well as other endpoints of interest with the aid of a structured questionnaire. Exposure history included medical indication for drug used, dosage, frequency of administration, and timing of exposure. Outcomes were confirmed whenever possible by the child's primary care physician. The primary outcome of interest was the presence or absence of a major malformation. Major malformations were defined by the presence of any anomaly that has an adverse effect on either the function or the social acceptability of the individual.7 Secondary outcomes included spontaneous or therapeutic abortions, livebirth or stillbirth, minor anomalies, birth weight and gestational age at birth. Exposure was defined as being in the organogenesis period if the drug was consumed between the 4th to 14th week of gestation. Each woman exposed to clarithromycin was matched to a woman who contacted the centers with an exposure to a nonteratogen antibiotic, mostly with the same indication as clarithromycin (i.e., upper and lower respiratory infections). The women were matched by 524 maternal age ±, and cigarette and alcohol con-

We ascertained the outcome of 157 pregnancies exposed to clarithromycin. There were 78 cases from Motherisk; the 34 previously published cases from the Pregnancy Riskline, Philadelphia; 22 from Mario Negri; 21 from Telefono Rosso; and 2 cases from FRAME in London, Canada. Overall 78% of the exposures occurred during organogenesis with 10% occurring in the second trimester and 12% in the third trimester. Indications for use are given in Table 1. In the North American study group, in 94% of the cases, the drug was used for upper and lower respiratory infections. Conversely, in the Italian study group, only 53% were prescribed for these indications. The other 47% were prescribed for a wide spectrum of infections including Mediterranean Spotted Fever, an insect bit, and several cases of urinary tract infection. There was also a substantial number of prescriptions for influenza and colds in the European and North American groups. In the study group there was a total of 123 live births, 22 spontaneous abortions, 11 therapeutic abortions, 1 stillbirth, 3 major malformations (including one case where the woman had a third trimester exposure), and 7 minor malformations. Description of malformations is given in Table 2. In the control group there were 143 live births, 11 spontaneous abortions, 3 therapeutic abortions, 0 stillbirths, 2 major malformations, and 7 minor malformations. Comparison between the study and control group are given in Table 3. There were no significant differences in the rates of major or minor malformations between the groups. However, there were statistically significant differences in the rates of live births, therapeutic abortions and spontaneous abortions, mostly due to a higher of reported spontaneous and therapeutic abortions.


AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 15, NUMBER 9

CLARITHROMYCIN IN PREGNANCY/Einarson et al

Study Group

Control Croup

Major Hydrocephalus, Turner syndrome

Major Dilatation of cerebellummedullary cistern Neural tube defect

Stenosis uteropelvic junction Cranial synostosis Minor Large birth mark Reflux valve problem Enlarged right ventricle (brain) Ventricular septal defect (minor) Undescended testes Blocked tear ducts defect (minor) Excess breast tissue right side

Minor Hammer toe Syndactyly Hydrocele Hypospadia Foot turned Ventricular septal Undescended testes

DISCUSSION

This is the first prospective controlled study of clarithromycin in pregnancy to date. It suggests that first-trimester exposure to clarithromycin does not result in major or minor congenital malformations above the baseline incidence of 1-3% and 10-15%, respectively. Of significance is that the types of major and minor malformations occurring in the clarithromycin and control group were comparable, with no apparent pattern of defects occurring in either group. This is important information in view of animal data suggesting an increased rate of cardiovascular abnormalities and cleft palate with exposure to high doses of clarithromycin during the period of embryogenesis. This is also important in view of the FDA's 1996 report of six cases of babies with sporadic major malformations in women with exposure to clarithromycin in early pregnancy. This again highlights the issue that although case reports can be vital in identifying new drug-related syndromes in human teratology, they should be interpreted with caution. For instance, erythromycin was also initially thought to be teratogenic based on a

Table 3. Pregnancy Outcome

Livebirths Spontaneous abortions Therapeutic abortions Stillbirths Major malformations Minor malformations

Study

Control

P Value

123 22 11 1 3 7

143 11 3 0 2 7

0.003 0.04 0.04 0.93 0.86 0.96

case report until it was identified that the defect in question had been the amniotic band syndrome.8 The rate of spontaneous abortion in the clarithromycin group was statistically higher than the control group (14 vs. 7%). Although of some interest, these results must be interpreted with caution. The control group was comprised of women exposed to nonteratogenic antibiotics during pregnancy and these women were not specifically matched for indication for use of the antibiotic. The design of our study also made it impossible to match patients based on the severity and timing of infection, which may possibly precipitate a spontaneous abortion. There was a higher number of what we would consider "off-label" uses for indications such as urinary tract infections in the Italian group. Hence, the higher observed rate of spontaneous abortions in the clarithromycin group could possibly be due to confounding factors not controlled for in our study. There was also a higher rate of therapeutic abortions in the study group (7%) versus the control group (2%), which is concerning, given that this may have been precipitated by fears regarding the potential teratogenicity of clarithromycin. It may well be that a number of the reported spontaneous abortions could have been in reality therapeutic abortions because women often feel guilty about revealing that they had a therapeutic abortion. In summary, our experience with 157 pregnant women (122 with first-trimester exposure) suggests that clarithromycin can be safely taken at the usual prescribed doses during pregnancy. This is reassuring information for physicians with pregnant patients who may have difficulties tolerating erythromycin or who have a history of serious allergic reactions to beta-lactam antibiotics.


Table 2. Major and Minor Malformations

REFERENCES 1. Product information, Biaxin®, Abbott Laboratories, 1998 2. Skrabanek P. Smoking and statistical overkill. Lancet 1992; 340:1208-1209 3. Compendium of Pharmaceuticals and Specialties: Canadian Pharmaceutical Association, 1998 4. USPDI 1998 5. Briggs Update, volume 9(3), September 1996, FDA (Personal Communication, F. Rosa) 6. Schick B, Horn M, Librizzi R, Donnenfeld A. Pregnancy outcome following exposure to clarithromycin. Reprod Toxicoll996;10:162 7. Marden PM, Smith DW, McDonald MJ. Congenital anomalies in newborn infants, including minor variations. J Pediatr 1964;64:357-371 8. Goldberg JD, Golbus MS. The value of case reports in human teratology. Am J Obstet Gynecol 1986;154(3):479482

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