Antibiotics for gonorrhoea in pregnancy

  • Protocol
  • Intervention

Authors

  • Gabriella Comunián-Carrasco,

    Corresponding author
    1. Universidad de Carabobo, Departamento de Obstetricia y Ginecología, Valencia, Estado Carabobo, Venezuela
    • Gabriella Comunián-Carrasco, Departamento de Obstetricia y Ginecología, Universidad de Carabobo, Urbanización Fundación Mendoza calle 19, 5ta etapa N° 22-40, Valencia, Estado Carabobo, 2001, Venezuela. comunian@gmail.com.

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  • Guiomar E Peña-Martí,

    1. Universidad de Carabobo, Departamento de Obstetricia y Ginecología, Valencia, Estado Carabobo, Venezuela
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  • Arturo J Martí-Carvajal

    1. Iberoamerican Cochrane Network, Valencia, Venezuela
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the clinical effectiveness and harm of antibiotics for treating gonorrhoea in pregnant women.

Background

Description of the condition

Gonorrhoea is a bacterial infection caused by Neisseria gonorrhoeae, and is a major public health challenge today, which is due to its high incidence (WHO 2012). These infections represent 106 millions of the estimated 498 million new cases of curable sexual transmitted infections that occur globally every year (WHO 2012). Gonorrhea rates among women have been slightly higher than those among men since 2001. During 2011–2012, the gonorrhoea rate among women increased 0.6% to 108.7 cases per 100,000 population (CDC 2013).

Gonorrhoea is most frequently spread during sexual contact; however, it can be also transmitted from the mother's genital tract to the newborn during birth resulting in ophthalmia neonatorum and systemic neonatal infection (CDC 2009). In women, the cervix is the most common site of gonorrhoea, resulting in endocervicitis and urethritis, which can be complicated by pelvic inflammatory disease (Wong 2009). Gonorrhoea can also spread throughout the body to cause localised and disseminated disease (CDC 2010). Gonorrhoea is a major cause of serious reproductive complications in women and can facilitate human immunodeficiency virus (HIV) transmission (CDC 2010).

The clinical pattern of gonorrhoea in pregnant women is similar to non-pregnant women, with up to 45% of cases being asymptomatic (Mullick 2005).

Complications in females

The most frequent complications of gonorrhoea in females are disseminated gonococcal infection (meningitis, pericarditis, endocarditis, and acute perihepatitis also called Fitz-Hugh-Curtis syndrome), pelvic inflammatory disease, and arthritis (CDC 2009; Ison 2011; Stefanelli 2011). Women with disseminated gonococcal infection may present with symptoms of rash, fever, arthralgias (joint pain), migratory polyarthritis, septic arthritis, tendonitis, tenosynovitis, endocarditis, or meningitis (Wong 2009). N. gonorrhoeae organisms spread from a primary site, such as the endocervix, the urethra, the pharynx, or the rectum, and disseminate to the blood to infect other end organs (Wong 2009).

Complications in pregnant women

Gonorrhoea during pregnancy is associated with preterm delivery, prelabour rupture of the membranes, low birthweight, and postpartum endometritis (WHO 2005).

Complications in neonates

Neonates are infected during delivery and occasionally by ascending infection before birth, after prolonged rupture of membranes. Neonatal infection causes purulent bilateral conjunctivitis. Occasionally, infection disseminates causing sepsis, arthritis, or meningitis (Heather 2007). Gonococcal ophthalmia neonatorum is the most common manifestation in infants born to mothers with gonococcal genital tract infections (Woods 2005). Localised gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes (Workowski 2010).

See Appendix 1 for medical glossary.

Description of the intervention

1. Clinical pharmacology and microbiological spectrum

Antimicrobial drugs have been suggested for the treatment of gonorrhoea; recommended regimens include β -lactam antibiotics (third-generation cephalosporin) and macrolides (azithromycin) (CDC 2010; Petri 2006).

1.1 Third-generation cephalosporins

Several cephalosporins are recommended for treating gonorrhoea infection. Classification by generations is based on general features of antimicrobial activity (Andes 2005). Cephalosporins are similar to penicillins, but more stable to many bacterial lactamases and therefore have a broader spectrum of activity, third-generation agents include cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil, cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam (Deck 2012).

1.2 Macrolides

Clarithromycin and azithromycin are semi-synthetic derivatives of erythromycin. Azithromycin is useful in treatment of sexually transmitted diseases, especially during pregnancy when tetracyclines are contraindicated. Azithromycin is derived from erythromycin, and is effective against Gram-negative organisms such as N. gonorrhoeae (Deck 2009).

2. Antibiotic adverse reactions

The major antibiotic adverse reactions associated with the main antimicrobial drugs for treating gonorrhoea have been widely described (Granowitz 2008). Briefly, untoward reactions of these drugs include following.

2.1. β-lactam antibiotics: this group is the most frequent elicitor of drug hypersensitivity reactions (Chambers 2001; Torres 2010). However, beta-lactams are generally safe drugs (Lagace-Wiens 2012; Petri 2010). Serious adverse events are rare and allergy is over diagnosed (Lagace-Wiens 2012). Cephalosporins reactions appear to be identical to those caused by the penicillins, perhaps related to the shared-lactam structure of both groups of antibiotics. Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are observed. More commonly maculopapular rash develops, usually after several days of therapy; this may or may not be accompanied by fever and eosinophilia (Brunton 2010).

2.2. Macrolides are associated with anorexia, nausea, vomiting, and diarrhoea occasionally accompany oral administration. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, other allergic reactions include fever, eosinophilia, and rashes (Deck 2009).

How the intervention might work

The pharmacodynamics of the most frequent antimicrobial drugs used for treating gonorrhoea in pregnant women include the following.

  1. β-lactam antibiotics act by inhibiting the synthesis of the bacterial peptidoglycan cell wall, which is essential for their normal growth and development (Petri 2010).

  2. Macrolides inhibit the protein synthesis which occurs via binding to the 50S ribosomal RNA, which blocks the aminoacyl translocation reaction and formation of initiation complexes (Deck 2009).

Why it is important to do this review

This review will update and replace an earlier Cochrane review on this topic (Brocklehurst 2002). This review will be performed for the following reasons: first, the search will be updated in order to identify new randomised clinical trials on antibiotics for gonorrhoea in pregnancy. Second, potential trials will undergo full assessment of risk of bias as per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Third, potential trials will be subjected to trial sequential analyses in order to assess the risk of random errors and the potential need for further trials. And, fourth, the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system will be used to assess the quality of the body of evidence associated with all main outcomes (Guyatt 2008).

Objectives

To assess the clinical effectiveness and harm of antibiotics for treating gonorrhoea in pregnant women.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials irrespective of their publication status (trials may be unpublished or published as an article, an abstract, or a letter), language and country. No limits will be applied with respect to period of follow-up. We will exclude quasi-randomised trials. Trials using a cluster-randomised or cross-over design will be excluded.

Types of participants

Pregnant women of any age, at any stage of pregnancy diagnosed with gonococcal infection (genital, extragenital or both).

Types of interventions

We will include comparative trials of antibiotics (used either alone or in combination), administered parenterally or orally, or both, and compared with another antibiotic.

Types of outcome measures

Primary outcomes

1. Maternal

  • Cure of gonococcal infection (genital, extragenital or both), according to the definition in included trials

  • Incidence of obstetric complications (miscarriage, premature rupture of membranes, preterm delivery and fetal death

  • Incidence of disseminated gonococcal infection

2. Neonate

  • Incidence of neonatorum ophthalmia

Secondary outcomes
  1. Failure to eradicate gonorrhoea from the genital tract of treated mothers.

  2. Adverse events including treatment-related adverse events (TRAE) (Ioannidis 2004). TRAE will be defined as: “a response to a drug which is noxious and uninitiated and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic functions” (Nebeker 2004). We will extract the number of patients with at least one treatment-related adverse event out of the total randomised in each study arm.

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register. 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of Embase;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

In addition, we will search the following databases using the search terms listed in Appendix 2.

  1. The WHO International Clinical Trials Registry Platform (ICTRP)

  2. The metaRegister of Controlled Trials (mRCT)

  3. ClinicalTrials.gov.

  4. Epistemonikos

Searching other resources

We will handsearch the references of all identified included trials, of relevant review articles and of current treatment guidelines.

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

All three review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult another person.

Data extraction and management

We will design a form to extract data. For eligible studies, all three review authors will extract the data using the agreed form. We will resolve any disagreement through discussion or, if required, we will consult another person. We will enter data into Review Manager software (RevMan 2014) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

All three review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor as specified above.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.  Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings.  We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.  

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2014). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Summary of findings

We will use the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with all main outcomes: (cure of gonococcal infection (genital, extragenital or both); incidence of obstetric complications (miscarriage, preterm rupture of membranes, preterm delivery and fetal death); incidence of disseminated gonococcal infection; and incidence of neonatal ophthalmia neonatorum); and harms. We will construct a 'Summary of findings' table using the GRADE profiler software (GRADEpro 2008). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the quality of a body of evidence considers within-study risk of bias, the directness of the evidence, heterogeneity in the data, precision of effect estimates and risk of publication bias (Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g).

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses.

  • Adolescent pregnant women versus non-adolescent pregnant women

  • Pregnant women with HIV-AIDS infection versus pregnant women without HIV/AIDS

  • Pregnant women with co-sexual transmitted infections versus pregnant women without co-sexual transmitted infections

  • Neonatorum ophthalmia in the babies of women who received prophylaxis versus those who did not receive prophylaxis

Subgroup analysis will be restricted the review's primary outcomes.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2014). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We will perform sensitivity analysis based on trial quality, separating high-quality trials from those of low quality. Furthermore, we plan to conduct a sensitivity analysis to assess attrition bias: trials with low attrition bias (≤ 12% loss of follow-up) versus trials with high attrition bias (> 12% of follow-up).

We will also conduct a trial sequential analysis (TSA), which is a methodology that combines an information size calculation (cumulated sample sizes of included trials) for meta-analysis with the threshold of statistical significance. TSA is a tool for quantifying the statistical reliability of data in a cumulative meta-analysis adjusting P values for repetitive testing on accumulating data. We will conduct a TSA on binary outcomes (Brok 2009; Pogue 1997; Pogue 1998; Thorlund 2009; Wetterslev 2008; Wetterslev 2009). Meta-analysis may result in type I errors due to sparse data or due to repeated significance testing when updating meta-analysis with new trials (Brok 2009; Higgins 2011a; Wetterslev 2008). In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries are applied to decide whether a trial could be terminated early because of a sufficiently small P value, that is, the cumulative Z-curve crosses the monitoring boundaries (Lan 1983). Sequential monitoring boundaries can be applied to meta-analysis as well, called trial sequential monitoring boundaries (Wetterslev 2008; Wetterslev 2009). In TSA, the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to clarify whether additional trials are needed.The idea in TSA is that if the cumulative Z-curve crosses the boundary, a sufficient level of evidence is reached and no further trials may be needed. If the Z-curve does not cross the boundary then there is insufficient evidence to reach a conclusion. To construct the trial sequential monitoring boundaries, the required information size is needed and is calculated as the least number of participants needed in a well-powered single trial (Brok 2009; Pogue 1997; Pogue 1998; Wetterslev 2008). We will apply TSA since it prevents an increase of the risk of type I error (less than 5%) due to potential multiple updating in a cumulative meta-analysis, and provides us with important information in order to estimate the level of evidence of the experimental intervention.

Additionally, TSA provides us with important information regarding the need for additional trials and the required sample size of such trials. We will apply trial sequential monitoring boundaries according to a heterogeneity-adjusted required information size based on an a priori 10% relative risk reduction (RRR) (APHIS) employing α = 0.05 and ß = 0.20.

TAS will be conducted using the TSA software (CTU 2011; Thorlund 2011).

Acknowledgements

As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

Appendices

Appendix 1. Medical glossary

Term Definition Source
Disseminated gonococcal infectionDisseminated gonococcal infection (DGI) results from bacteraemic spread of the sexually transmitted pathogen, Neisseria gonorrhoeae, which can lead to a variety of clinical symptoms and signs, such as tenosynovitis, dermatitis, and multiple skin lesions. http://www.uptodate.com/contents/disseminated-gonococcal-infection
Fetal deathDeath of the developing young in utero. Birth of a dead fetus is stillbirth. http://www.ncbi.nlm.nih.gov/mesh
Fetal membranes, premature ruptureSpontaneous tearing of the membranes surrounding the fetus any time before the onset of obstetric labor. Preterm PROM is membrane rupture before 37 weeks of gestation. http://www.ncbi.nlm.nih.gov/mesh
Fitz-Hugh-Curtis syndromeinflammation of the liver capsule associated with genital tract infection—occurs in up to one-fourth of women with pelvic inflammatory disease (PID). http://ccjm.org/content/71/3/233.full.pdf
Low birth weightAn infant having a birth weight of 2500 g. (5.5 lb.) or less but infant, very low birth weight is available for infants having a birth weight of 1500 g (3.3 lb.) or less. http://www.ncbi.nlm.nih.gov/mesh
MiscarriageExpulsion of the product of fertilisation before completing the term of gestation and without deliberate interference. http://www.ncbi.nlm.nih.gov/mesh
Ophthalmia neonatorumAcute conjunctival inflammation in the newborn, usually caused by maternal gonococcal infection. The causative agent is Neisseria gonorrhoeae. The baby's eyes are contaminated during passage through the birth canal. http://www.ncbi.nlm.nih.gov/mesh
Pelvic inflammatory diseaseA spectrum of inflammation involving the female upper genital tract and the supporting tissues. It is usually caused by an ascending infection of organisms from the endocervix. Infection may be confined to the uterus (endometritis), the fallopian tubes; (salpingitis); the ovaries (oophoritis), the supporting ligaments (parametritis), or may involve several of the above uterine appendages. Such inflammation can lead to functional impairment and infertility. http://www.ncbi.nlm.nih.gov/mesh
Premature rupture of membranesSpontaneous tearing of the membranes surrounding the fetus any time before the onset of obstetric labour. Preterm PROM is membrane rupture before 37 weeks of gestation. http://onlinelibrary.wiley.com/cochranelibrary/search
Preterm deliveryChildbirth before 37 weeks of pregnancy (259 days from the first day of the mother's last menstrual period, or 245 days after fertilisation). http://www.ncbi.nlm.nih.gov/mesh

Appendix 2. Search terms

(gonorrhea or gonorrhoea or gonococcal) and (pregnant or pregnancy)

Contributions of authors

Gabriella Comunian prepared the first draft of the protocol and has overall responsibility for maintaining the review. Arturo Marti-Carvajal and Guiomar E Peña-Martí revised and contributed to the final draft of the protocol.

Declarations of interest

Arturo Martí-Carvajal: in 2004 Arturo Martí-Carvajal  was employed by Eli Lilly to run a four-hour workshop on ’How to critically appraise clinical trials on osteoporosis and how to teach this’. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review. In 2007 Arturo Martí-Carvajal was employed by Merck to run a four-hour workshop ’How to critically appraise clinical trials and how to teach this’. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review

Gabriella Comunián-Carrasco and Guiomar E Peña-Martí: none.

Sources of support

Internal sources

  • Universidad de Carabobo, Venezuela.

External sources

  • Iberoamerican Cochrane Network, Spain.

Ancillary