Phenoxymethylpenicillin potassium

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Study type:

case control study (retrospective)

Endpoint addressed:

developmental toxicity / teratogenicity

Test guideline

Qualifier:

no guideline followed

Test material

Test material information

1

Reference substance name:

Phenoxymethylpenicillin potassium

EC Number:

205-086-5

EC Name:

Phenoxymethylpenicillin potassium

Cas Number:

132-98-9

Molecular formula:

C16H17KN2O5S

IUPAC Name:

potassium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

Test material form:

solid

Method

Type of population:

other: pregnant women

Ethical approval:

not applicable

Details on study design:

The large population-based dataset of the Hungarian Case–Control Surveillance of congenital Abnormalities (HCCSCA) makes it possible to check the teratogenic potential of antibiotics by comparison of 38.151 healthy infants with 23 677 cases with congenital abnormality born between 1980 and 1996. The aims of the international EU Biomed programme are
(1) to determine the occurrence and distribution of different antibiotic treatments during pregnancy,
(2) to evaluate their indications,
(3) to study the effects of antibiotics for intrauterine.

The first step of the procedure in the HCCSCA was the identification of cases referred to the Hungarian Congenital Abnormality Registry within the first quarter of postnatal life. The Hungarian Congenital Abnormality Registry is a national registry of malformed liveborn infants, malformed stillborn fetuses and selectively terminated malformed fetuses.
The second step was to acquire appropriate healthy controls for each case. Two newborn infants without congenital abnormalities were matched to every case according to gender, birth week, and district of parents’ residence from the national birth registry of the Central Statistical Office. The third step was to obtain exposure data. A reply-paid questionnaire, an explanatory letter and a list of drugs and diseases were mailed immediately after notification to the diseases were mailed immediately after notification to the requested information on drugs taken, maternal diseases, pregnancy complications during pregnancy according to gestational weeks. To standardize the answers, mothers were asked to read the enclosed lists of drugs and diseases before they replied. Furthermore, mothers were requested to send us their prenatal care logbook and every medical document concerning the pregnancy or child studied. In the group of cases, regional district nurses were asked to visit and question nonrespondent families. Thus, information was available for 81% (69% from reply, 12% from visit) of the cases. The response rate for controls was 65%. District nurses did not participate in the evaluation of nonrespondent healthy controls for ethical reason. The fourth step was to evaluate drug intake in seven different respects. (1) The source of information was divided into three groups: (a) only data from the prenatal care logbook (prenatal care obstetricians are obliged to record all prescribed drugs for women concerning pregnancy related complications and diseases in the logbook) or other medical documents, (b) only data for questionnaires (for drugs used for treatment of diseases unrelated to pregnancy are prescribed by general practitioners or other physicians, in addition drugs taken by personal choice of pregnant women) and (c) data concordant from both medical documents and questionnaire. (2) The use of the antibiotic studied alone and with other drugs were differentiated. For multiple use of different drugs, each drug was coded independently according to the internationally accepted ATC classification. (3) The route of administration, i.e., oral, parenteral and topical treatments were separated. (4) Gestational time was calculated from the first day of the last menstrual period and three time periods were considered. (a) The earliest was the first month of pregnancy, often as a continuation of preconception treatment. (b) The second and third months of gestation involve the most sensitive, critical period for major congenital abnormalities. (c) The third category was the fourth–ninth months of gestation. However, there were some pregnant women with unknown gestational time of drug use. Sometimes the same antibiotic was used two or more times in different periods of the study pregnancy, it explains that the number of pregnant women and treatments may be different. (5) The dose of drugs, the recommended dose of antibiotics was used in most pregnant women. (6) Potential confounding factors, such as maternal age, birth order, pregnancy complications, acute and chronic maternal fetuses. (7) Birth weight and gestation age were evaluated mainly in the group of controls for each case. Two newborn infants without controls: the data of infants born to mothers with or without antibiotic treatment were compared. The fifth step was statistical analysis of the data. First, the time trend of different antibiotic uses was analysed. Second, among potential confounders, mean maternal age and birth order, were evaluated using Student’s t-test, while the most frequent maternal infectious diseases as the main indications of treatments were compared in untreated and treated groups by X2 test. Finally mean birth weight and gestation age of newborn infants with or without the use of antibiotic studied were compared using Student t-tests.

Results and discussion

Results:

The mean birth weight was higher in the treated than in the untreated group. This can be explained mainly by the higher mean birth weight after the maternal treatment of other macrolides, other cephalosporins, other aminopenicillins, oxytetracycline, penamecillin, erythromycin, doxycycline and ampicillin. However, the mean birth weight was lower in the group of aminoglycosides and cefalexin. The mean gestation age was similar in the untreated and treated subgroups. However, it was higher in the group of doxycycline and other cephalosporins while lower in the group of phenoxymethylpenicillin, other penicillins and chloramphenicol.

The mean gestation age was similar in the untreated and treated subgroups. However, it was higher in the group of doxycycline and other cephalosporins while lower in the group of phenoxymethylpenicillin, other penicillins and chloramphenicol. Many pregnant women were treated in parallel or successively by two or more antibiotics and their interaction may be important in the evaluation of their teratogenic potential.

Applicant's summary and conclusion

Conclusions:

The evaluation of antibiotic use during pregnancy allows some conclusions to be drawn.

(1) Different antibiotics, including penicillins have different chemical structures and different indications for treatment, therefore it is not appropriate to study their teratogenic potential in general, i.e., in combined group, e.g., penicillins.

(2) The underlying maternal disorders which make the antibiotic treatments necessary (i.e., the specific indications) and other drugs may have an important interaction with drug studied, thus it is necessary to use appropriate controls and adjusted odds–risk ratios.

(3) The frequency and distribution of antibiotic treatments show significant differences in European and North-American countries. Antibiotics use and indications have different priorities in different countries and it is necessary to consider this in the evaluation of their teratogenic potential in different interactions of macrolides. Obviously, this may also apply to their use [10] Reese RE, Betts RF, Douglas RG. The tetracyclines. A practical during pregnancy, it would be useful to organize interna- approach to infectious diseases. Boston: Little Brown, 3rd ed. tional comparative studies.

(4) Recently, intrauterine in fections have been increasingly important in the origin of fetal and neonatal diseases, therefore the possible prophylactic antibiotic treatments may reduce these.

(5) Antibiotics are used frequently in Hungary, but so far their teratogenic hazards have not been detected.

Antibiotics provide a case in point where recommendations to avoid all drugs during pregnancy including the second–third months of gestation is unrealistic and may be dangerous.
About 8% of pregnant women need permanent drug treatment because of chronic disorders such as asthma, epilepsy, diabetes mellitus, hypertension, reduction of infant morbidity after preterm premature rupture of the etc.
In addition many more pregnant women have acute infectious diseases of respiratory system (e.g., flu), urinary tract (e.g., pyelocystitis) and genital organs (STDs) and these may cause serious hazards for the fetus due to high fever, endotoxins of Gram negative bacteria and amnionitis–intrauterine infections.
Thus, the anxiety and fear created by the notion that nearly all drugs cause congenital abnormalities may be more harmful than some proven human teratogenic drugs themselves. A better risk–benefit estimation of drug use, including antibiotics, during pregnancy is therefore an urgent and important task.

Executive summary:

Of 38 151 control pregnant women who delivered later newborn infants without congenital abnormality, 6554 (17.2%) were treated by antibiotics. Most women (14.5%) had penicillin, while 1.2% and 0.7% of pregnant women were treated by cephalosporins and tetracyclines, respectively. More than 100 pregnant women used the following antibiotics: ampicillin (6.9%), penamecillin (5.9%), cefalexin (1.0%), phenoxymethylpenicillin (0.6%), oxytetracycline (0.5%), erythromycin (0.45%), benzylpenicillin-procain (0.4%) and benzylpenicillin1benzylpenicillin-procain (0.3%). Different antibiotics had different indications for treatment. The mean birth weight was significantly lower in the treated group compared to the untreated group. Practical implications: Different antibiotics have different chemical structures and indications for treatment. Therefore it is not appropriate to evaluate their teratogenic potential of combined antibiotic groups. There may be many interactions between underlying maternal diseases, other drug uses, further confounding factors and
antibiotics studied, thus adequate controls are needed to estimate the adjusted teratogenic odds–risk ratios. European countries have different spectrum of antibiotic use. It would be necessary to know these baseline data of different populations. The anxiety and fear created by the notion that nearly all drugs cause congenital abnormalities may be more harmful than some proven human teratogenic
drugs themselves. Thus a better risk–benefit estimation for antibiotic uses during pregnancy is an urgent and important task.