The authors have declared that no competing interests exist.
Conceived and designed the experiments: TFG MTS SJS LMN JDK MGP RF. Analyzed the data: TFG MTS SJS LMN JDK MGP RF. Wrote the paper: TFG MTS SJS LMN JDK MGP RF.
To estimate the risk of serious adverse reactions to benzathine penicillin in pregnant women for preventing congenital syphilis.
We searched for clinical trials or cohorts that assessed the incidence of serious adverse reactions to benzathine penicillin in pregnant women and the general population (indirect evidence). MEDLINE, EMBASE, Scopus and other databases were searched up to December 2012. The GRADE approach was used to assess quality of evidence. Absolute risks of each study were calculated along with their 95% confidence intervals (95% CI). We employed the DerSimonian and Laird random effects model in the meta-analyses.
From 2,765 retrieved studies we included 13, representing 3,466,780 patients. The studies that included pregnant women were conducted to demonstrate the effectiveness of benzathine penicillin: no serious adverse reactions were reported among the 1,244 pregnant women included. In the general population, among 2,028,982 patients treated, 4 died from an adverse reaction. The pooled risk of death was virtually zero. Fifty-four cases of anaphylaxis were reported (pooled absolute risk = 0.002%; 95% CI: 0%–0.003% I2 = 12%). From that estimate, penicillin treatment would be expected to result in an incidence of 0 to 3 cases of anaphylaxis per 100,000 treated. Any adverse reactions were reported in 6,377 patients among 3,465,322 treated with penicillin (pooled absolute risk = 0.169%; 95% CI: 0.073%–0.265% I2 = 97%). The quality of evidence was very low.
Studies that assessed the risk of serious adverse events due to benzathine penicillin treatment in pregnant women were scarce, but no reports of adverse reactions were found. The incidence of severe adverse outcomes was very low in the general population. The risk of treating pregnant women with benzathine penicillin to prevent congenital syphilis appears very low and does not outweigh its benefits. Further research is needed to improve the quality of evidence.
Over half of syphilis infections in pregnancy will result in congenital syphilis, which can manifest as early fetal loss, stillbirth, prematurity, low birth weight, neonatal death, or infection in the newborn
Despite the widespread availability, low cost, and effectiveness of penicillin in controlling congenital syphilis, the worldwide incidence is still high
In many settings, prior to penicillin benzathine administration, a subcutaneous or subdermal injection of benzathine penicillin is used as a screening method for an allergic reaction
While speculations about penicillin hazards are frequent, systematic reviews about the incidence of serious adverse reactions in pregnancy are absent. Such evidence is likely to bring more objectivity to the clinical and policy decisions. Our aim was to review the risk of serious adverse reaction to benzathine penicillin in pregnant women with syphilis.
The current review was registered on International Prospective Register of Systematic Reviews (PROSPERO), registration number: CRD42012002103.
We included randomized controlled trials (RCT) or cohort studies that assessed the incidence of serious adverse reactions to benzathine penicillin in pregnant women for preventing congenital syphilis. As indirect evidence, we also included studies that assessed the incidence of adverse reactions to benzathine penicillin in the general population. There were no restrictions for language, length of follow-up, publication date or status.
We used the following adverse reaction definition “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product”
We only included studies that fulfilled all inclusion criteria. If the study did not provide a clear definition of adverse reactions, we reviewed the primary data and assessed which studies contained data that could be categorized using our criteria. Once a study was accepted for inclusion, no patients were reassigned into or out of adverse reaction groups. Results were taken as a group from each study, as individual patient-level reporting was not available.
We searched the following databases from inception up to January 2013: MEDLINE, EMBASE, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Reactions Pharmacovigilance Insight (via OVID), Cochrane Central Register of Controlled Trials (CENTRAL), metaRegister of Current Clinical Trials (mRCT), Latin American and Caribbean Center on Health Sciences Information (LILACS) and Scientific Electronic Library Online (SciELO). References of relevant studies were also screened for eligibility. The search strategy for MEDLINE (via PubMed) is presented on
Two researchers independently reviewed the retrieved studies based on the analysis of the titles and abstracts (MCM and MCRS). Disagreements were resolved by authors’ consensus or by a third reviewer (TFG).
We created a data extraction form to assemble previously defined relevant information from the studies: country, study design, dates of enrollment, population, penicillin regimen, sample size and adverse reactions. One author extracted the data (TFG) and another (MTS) confirmed the extracted information. We contacted studies’ corresponding authors to obtain any additional data not stated in the reports. We labeled the study as “confirmed multiple exposure” if all the patients of the study received more than one dose of penicillin.
To assess the risk of bias in the randomized clinical trials, we considered the Cochrane Collaboration’s tool
We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of the evidence
The primary outcome measured was the incidence of serious adverse reactions in pregnant women due to treatment with benzathine penicillin for preventing congenital syphilis. As serious adverse reactions we considered anaphylaxis and death, but we did not summarize them as a composite outcome.
Absolute risks from individual studies were recalculated and presented along with 95% confidence intervals (95% CI) by the Mid-P test
Our literature search identified 2,765 articles (
We could not identify any studies whose primary objective was to measure the incidence of adverse reactions in pregnant women with syphilis treated with benzathine penicillin. Studies that included pregnant women aimed to assess the effectiveness of benzathine penicillin for preventing congenital syphilis, and the incidence of adverse reactions was recorded as a secondary endpoint. All studies included in our review had a cohort design, either prospective or retrospective. The benzathine penicillin regimen varied from 1 to 4 doses of 1.2 million international units (MIU) and its use was compared to no treatment or erythromycin, or no comparison was done.
Study | Studydesign | Dates of enrolment | Country | Population(diagnosis method if available) | Benzathinepenicillin regimen | Control group |
Shafer 1954 |
prospective cohort | 1950–1952 | USA | adults with sexually transmitted diseases | 1 or 2 doses of 2.4 MIU, IM |
no control group |
Smith 1956 |
prospective cohort | 1946–1950 | USA | adults with syphilis or gonorrhea | 1, 2 or 3 doses of 2.4 MIU, IM | no control group |
Willcox 1957 |
prospective cohort | 1946–1956 | USA | adults with syphilis or gonorrhea | 1 to 4 doses of 2.4 MIU, IM | no control group |
Hsu 1958 |
prospective cohort | several years | USA | adults with rheumatic fever | 1.2 MIU, IM every fourweeks for several years | no control group |
Phaosavasdi 1989 |
prospective cohort | 1984–1985 | Thailand | pregnant women with positive treponemal serological test (RPR, VDRL, TPHA) | 1, 2 or 3 doses of 2.4 MIU, IM | erythromycin 2 g dailyper 30 days, orally |
International rheumatic fever group 1991 |
prospective cohort | 1988–1990 | 11 countries |
adults and children with rheumatic fever | 1.2 MIU, IM every 4weeks for three years | no control group |
Jenniskens 1995 |
prospective cohort | 1992–1993 | Kenya | pregnant women with positivetreponemal serological test (RPR) | 2.4 MIU, IM | no treatment |
Napoli 2000 |
prospective cohort | 1999–2000 | USA | adults with streptococcal pharyngitisprophylaxis | 1.2 MIU, IM | no control group |
Apter 2004 |
prospective cohort | 1987–2001 | UK | adults and children who received penicillin prescription | 1 or 2 prescriptions of penicillin |
no control group |
Watson-Jones 2005 |
retrospective cohort | 2000–2001 | Tanzania | pregnant women with positive treponemalserological test (RPR, TPHA, FTA-ABS) | 1 dose of 2.4 MIU, IM | no treatment |
Bronzan 2007 |
prospective cohort | 2001–2002 | South Africa | pregnant women with primary, secondary,or early latent syphilis (RPR, TPHA) | 1, 2 or 3 doses of 2.4 MIU, IM | no treatment |
Carles 2008 |
retrospective cohort | 1992–2004 | French Guiana | pregnant women with positive treponemalserological test (VDRL, TPHA) | 1, 2 or 3 doses of 2.4 MIU, IM | no treatment |
Li 2012 |
retrospective cohort | 2001–2008 | China | adults with sexually transmitted diseases | 3 doses of 2.4 MIU, IM | erythromycin 2 g daily per14 days, orally ordoxycycline 200 mg orallyfor 15 days |
Notes:
It may have been included also patients treated with other types of penicillin.
Argentina, Chile, China, India, Jamaica, Korea, Kuwait, New Zealand, Taiwan, Thailand, Venezuela.
Abbreviations:
MIU: mega internacional units.
IM: intramuscular.
RPR: Rapid Plasma Reagin.
VDRL: Veneral Disease Research Laboratory.
TPHA: Treponema Pallidum Hemagglutination.
MHA-TP: microhemagglutination
FTA-ABS: test or fluorescent treponemal antibody–absorption.
The quality of evidence of all outcomes was considered very low (
Outcome (population) | Quality assessment | Quality | Importance | ||||
N. studies | Limitation | Inconsistency | Indirectness | Imprecision | |||
death (pregnant women) | five |
serious |
− | − | very low | Critical | |
death (general population) | eight |
serious |
no important inconsistency | very serious |
no important imprecision | very low | Critical |
anaphylaxis (pregnant women) | five |
serious |
− | − | very low | Critical | |
anaphylaxis(general population) | eight |
serious |
no important inconsistency | very serious |
no important imprecision | very low | Critical |
incidence of adverse reactions(pregnant women) | five |
serious |
− | − | very low | Important | |
incidence of adverse reactions(general population) | eight |
serious |
very serious |
very serious |
no important imprecision | very low | Important |
Notes:
All studies had observational design.
Publication bias could not be objectively assessed due to the small numbers of studies.
Imprecision could not be assessed since adequate meta-analysis calculation could not be performed.
RR: relative risk.
NE: Non-estimable.
−We could not access the item for this outcome.
Flawed measurement of outcome, as the study did not aimed to report the incidence of adverse reaction in pregnant women.
Some studies did not report the incidence of adverse reaction; the data was obtained with the authors.
Heterogeneous results across studies were observed.
Different population (patients were not pregnant women and did not have syphilis) and intervention. In one study
Studies did not report any case of anaphylaxis or death in pregnant women treated with benzathine penicillin. The incidence of adverse reactions in this population is presented on
Study | Penicillin treatment group | No penicillin treatment group | ||
No. of patients | Events | No. of patients | Events | |
Phaosavasdi 1989 |
191 | 1 |
6 | 0 |
Jenniskens 1995 |
751 | 0 |
109 | 0 |
Watson-Jones 2005 |
88 | 0 |
56 | 0 |
Bronzan 2007 |
141 | 0 |
31 | 0 |
Carles 2008 |
73 | 0 |
12 | 0 |
Notes:
Skin rash.
Data obtained from contact with corresponding author.
All patients received dexamethasone injection.
In studies whose primary objective was to evaluate the incidence of adverse reactions from benzathine penicillin treatment, no pregnant women were included. From 2,028,982 patients treated with benzathine penicillin, 4 died from an adverse reaction (
Individual studies orpooled results | No. ofpatients | Death | Anaphylaxis | ||
Events | Absolute risk (95% CI) | Events | Absolute risk % (95% CI) | ||
Shafer 1954 |
70,037 | 2 | 0.003 (0.001–0.009) | 0 | 0 (0–0.004) |
Smith 1956 |
7,109 | 0 | 0 (0–0.042) | 0 | 0 (0–0.042) |
Willcox 1957 |
895 | 0 | 0 (0–0.334) | 0 | 0 (0–0.334) |
Hsu 1958 |
32 | 1 | 3.125 (0.156–14.460) | 1 | 3.125 (0.156–14.460) |
International rheumatic fevergroup 1991 |
1,790 | 1 | 0.126 (0.006–0.623) | 4 | 0.223 (0.071–0.538) |
Napoli 2000 |
9,203 | 0 | 0 (0–0,032) | 2 | 0.022 (0.004–0.072) |
Apter 2004 |
2,017,957 | 0 | 0 (0–0,001) | 47 |
0.001 (0,002–0,003) |
Li 2012 |
1,094 | 0 |
0 (0–0.274) | 0 |
0 (0–0.274) |
Pooled result | 2,108,117 | 4 | 0 (0–0); I2 = 0% | 54 | 0.002 (0–0.003); I2 = 12% |
Notes:
16 patients had anaphylaxis after the first prescription of penicillin and 32 had anaphylaxis after the second prescription of penicillin. One patient had anaphylaxis in both prescriptions. Total patients that experienced anaphylaxis in this study = 47.
There were reported 16 events of Jarisch-Herxheimer reaction, which were not considered adverse drug reaction in present review.
Fifty four patients of 2,028,982 treated with penicillin suffered anaphylaxis. Across studies, the absolute risk ranged from 0% (95% CI: 0%–0.004%) to 3.125% (95% CI: 0.156%–14.460%). Studies that included patients with multiple exposures to penicillin had a higher incidence of anaphylaxis
For any adverse reaction 6,377 cases were observed among 3,465,322 treated patients (
Individual studies orpooled results | No. ofpatients | Events | Absolute risk % (95% CI) | Type of adverse reaction(n of patients, if available) |
Shafer 1954 |
70,037 | 56 |
0.080 (0.061–0.103) |
only severe adverse events reported; type not available |
Smith 1956 |
7,109 | 18 | 0.253 (0.155–0.392) | urticaria, nausea and vomiting |
Willcox 1957 |
895 | 26 |
2.905 (1.947–4.168) | urticaria, urticaria, edema, asthma, rash, dyspnea, tetany, faintness, dizziness, diarrhea, urticaria, vomiting |
Hsu 1958 |
32 | 6 | 18.750 (7.968–34.980) | anaphylaxis (1), edema of lips, pruritic eruption (3), serum sickness (2) |
International rheumatic fever group 1991 |
1,790 | 57 | 3.184 (2.443–4.077) | pruritus or urticaria (33), macopapular rashes (11), arthralgia (8), anaphylaxis (4), wheeze (1) |
Napoli 2000 |
9,203 | 2 |
0.022 (0.004–0.072) |
anaphylaxis (2) |
Apter 2004 |
3,375,162 | 6,212 | 0.184 (0.179–0.189) | allergic-like event: adverse drug reaction, anaphylaxis, angioedema, erythema multiforme, toxic epidermal necrolysis, urticaria |
Apter 2004 |
2,017,957 |
3,509 |
0.174 (0.168–0.180) | |
Li 2012 |
1094 | 0 |
0 (0–0.274) | None |
Pooled result |
3,465,322 | 6,377 | 0.169 (0.073–0.265); I2 = 97% | − |
Notes:
Only severe adverse reaction was reported.
Probable cases.
These cases are included in the previous data (one penicillin prescription).
Data obtained from contact with corresponding author.
The study reported 16 events of Jarisch-Herxheimer reaction, but we did not consider them as adverse events.
For the polled result only the incidence of adverse reaction with one prescription of penicillin was considered for Apter 2004
The pooled risk for any adverse reaction was 0.169% (0.073%–0.265%; I2 = 97%). The statistical heterogeneity was very high. In the sensitivity analysis we investigated the effect of older studies, the level of country economic development where the studies were conducted, the stage of disease, and the dosing regimens. It is clear that studies were performed in different decades and settings, and this may be the main causes of the heterogeneity we found, but we could not identify the statistical sources of heterogeneity, nor could we derive more homogeneous results from the sensitivity analysis.
Our findings show that the incidence of serious adverse reactions to benzathine penicillin in pregnant women was very low: no severe or fatal cases were reported. In the general population, a study population with a much larger sample size, the risk of serious adverse reactions was also small, and the pooled risk of death due to penicillin treatment was virtually zero. We rated the quality of the evidence as very low, resulting in a classification of the final evidence as inconclusive. Studies that assessed benzathine penicillin effectiveness in pregnant women did not plan the sample size to measure adverse reactions, therefore the statistical power to detect low frequency adverse reactions was suboptimal
Patients with multiple exposures to benzathine penicillin had a higher incidence of adverse reactions. That finding correlates with clinical data in which patients with more frequent exposure to penicillin have a higher chance of experiencing adverse reactions
Most of the studies had no events of serious adverse reactions, which hampered the summarization of the risk. To conduct a meta-analysis, we tried different approaches, like replacing the zero events with 0.5
The included studies were performed in different decades, and disparate benzathine penicillin regimens and stages of disease were assessed. It is possible that the diagnosis of adverse reaction varied across studies, as well as the benzathine penicillin preparation and adjunct components, with greater variation in the older studies. A possible measurement bias may derive from study design, but this factor could not be investigated due to the low number of retrospective as compared with prospective studies. Such clinical and methodological diversity might explain the heterogeneity observed on the outcome of any adverse reaction and raises concerns about the external validity of the data
Given the widely documented effectiveness of benzathine penicillin in preventing adverse pregnancy outcomes in mothers with syphilis such as stillbirth, preterm delivery, perinatal death and congenital syphilis
Even though the risk of death and serious adverse reactions due to benzathine penicillin seem to be very low, research is needed to specifically determine and monitor the incidence of adverse reactions in pregnant women, including a more clear understanding of the rates of mild, moderate and severe adverse reactions. Large medical databases, for example, could provide a better estimate of the incidence of adverse reactions in the population
It is also reasonable that researchers include the incidence and type of adverse reaction as one of the outcomes when designing prospective studies of benzathine penicillin use in pregnancy. In our literature search we found many studies that could have added more information to the present evidence base if the incidence and type of adverse reaction had been systematically recorded
No case of serious adverse reactions to benzathine penicillin in pregnant women was reported and in the general population the incidence was very low. For clinical practice and public health policy our findings suggest that the risk of adverse reactions does not outweigh the benefits of benzathine penicillin use for maternal syphilis treatment and congenital syphilis prevention. Health authorities should eliminate any policy barriers to the administration of benzathine penicillin. Future studies about penicillin use should record the incidence and type of adverse reactions during pregnancy. Such research efforts are likely to strengthen the available evidence.
Search strategy for MEDLINE (via PubMed).
(DOCX)
We would like to thank our collaborators from the University of Brasilia, Marcia Cristina de Sousa Reis and Mariana Correia Marques, for helping in the study-selection process.