Interventions for preventing ophthalmia neonatorum

  • Major change
  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The objectives of this review are:

  1. To determine if any type of ophthalmia neonatorum prophylaxis reduces the incidence of conjunctivitis in neonates.

  2. To determine which ophthalmia neonatorum prophylaxis is most effective at reducing the incidence of conjunctivitis in neonates.

Background

Description of the condition

Ophthalmia neonatorum, also called neonatal conjunctivitis, is an inflammatory disorder of the ocular surface in newborns in the first month of life (WHO 1986). In Europe in the late 1800s, a significant percentage of those who were blind was due to gonococcal ophthalmia neonatorum. Specifically, it was reported that the percentage of those who were blind from ophthalmia neonatorum was 8% in Copenhagen, 20% in Berlin, 30% in Vienna and 45% in Paris (Buller 1900; Haussman 1895; Milot 2008). During the same period, it has been estimated that 20% to 80% of the children in blind institutions in Germany were blind due to ophthalmia neonatorum caused by Neisseria gonorrhoeae (Konigstein 1882). In the United States, among new admissions to schools for the blind between 1906 and 1911, approximately 24% were due to ophthalmia neonatorum caused by Neisseria gonorrhoeae, with a range of 8% to 45% (Barsam 1966). In 1918, a hospital was opened specifically for the treatment of neonates with ophthalmia neonatorum in London, UK; (Annonymous 1918; Annonymous 1919).

Ophthalmia neonatorum remains a significant cause of childhood corneal blindness in developing countries, mainly from Neisseria gonorrhoeae (Whitcher 2001). There are major epidemiological challenges in determining the prevalence and incidence of blindness from ophthalmia neonatorum. In addition, childhood blindness is related to mortality in the under the age of five age range, thereby underestimating rates of childhood blindness (Gilbert 2012). Notwithstanding these limitations, cross-sectional surveys have estimated the percentage of blindness or severe visual impairment due to ophthalmia neonatorum to be 3% in Ethiopia (Kello 2003), 0.7% in Bangladesh (Muhit 2007), 0.4% in Malaysia (Koay 2015), 5% in East Africa (Foster 1991), 0.8% in India (Rahi 1995), and 2% in Tanzania (Foster 1987).

Ophthalmia neonatorum caused by Neisseria gonorrhoeae, also called gonococcal ophthalmia neonatorum, is mainly contracted from the mother's infected birth canal during delivery, but can also be contracted in-utero by ascending infections. Neonates born to gonorrhoea-infected mothers have a 30% to 50% risk of developing gonococcal conjunctivitis (Laga 1989). Untreated or inappropriately treated gonococcal conjunctivitis can result in corneal perforation and vision loss within 24 hours (Donham 2008; Duke-Elder 1965). In one case series, the mean duration of corneal perforation from untreated gonococcal conjunctivitis was 11 days (Kawashima 2009). In areas with low incidence of gonococcal ophthalmia neonatorum or limited access to appropriate health care, appropriate clinical diagnosis and appropriate therapy may be delayed, which can lead to loss of vision (Bastion 2006; McElnea 2015; Schwab 1985; Wan 1986).

After historical declines in rates of gonorrhoea, it is now making a resurgence in some developed countries. In 2012, among adults aged 15 to 49 years, it was estimated that there were 27 million cases of gonorrhoea globally (Newman 2015). Further, there is increasing incidence of drug-resistant strains of Neisseria gonorrhoeae globally (Martin 2015; Van de Laar 2012; WHO 2012). In addition to Neisseria gonorrhoeae, Chlamydia trachomatis is another significant sexually transmitted pathogen that can be transmitted from the mother to the neonate during delivery. While ophthalmia neonatorum caused by Neisseria gonorrhoeae has a high risk of blindness, ophthalmia neonatorum caused by Chlamydia trachomatis has a low risk of blindness (Whitcher 2001). Still, chlamydial conjunctivitis may lead to corneal and conjunctival scarring and rarely, loss of vision, if left untreated (Darville 2015). Chlamydia trachomatis can also cause a hemorrhagic conjunctivitis (Chang 2006). Studies of the risks of an infant acquiring Chlamydia trachomatis conjunctivitis from an infected mother range from 8% to 44%, with a point estimate of 15% (Rosenman 2003).

Chlamydial ophthalmia neonatorum is much more prevalent than gonococcal ophthalmia neonatorum, and has historically been underdiagnosed, first, due to a lack of appropriate diagnostic techniques, and second, due to a lack of diagnostic techniques with appropriate sensitivity and specificity (Darville 2015; Yip 2008). In some developed countries, there is an increasing rate of chlamydial infection, and in some jurisdictions, a commensurate rise in the rate of chlamydial conjunctivitis (Quirke 2008). In 2012, among adults aged 15 to 49 years, it was estimated that there were 128 million cases of chlamydia globally (Newman 2015). In addition to the sexually transmitted pathogens of Neisseria gonorrhoeae, and Chlamydia trachomatis, ophthalmia neonatorum can be caused by other bacteria, less often by viruses such as herpes simplex, and adenovirus, and finally, it can be caused by chemical agents (Albert 1994).

The relative frequencies of bacterial causes of ophthalmia neonatorum varies by study and jurisdiction (Amini 2008; Chhabra 2008; Di Bartolomeo 2001; Di Bartolomeo 2005; Hammerschlag 1993; Mohile 2002; Sandstrom 1984). In a high percentage of ophthalmia neonatorum cases, no causative pathogen is found. This could be due to the method of obtaining the sample, the culture medium, an inability to culture for viruses or other microorganisms, or the cause is not a pathogen, but rather chemical conjunctivitis or nasolacrimal duct obstruction (Sandstrom 1987).

Even though certain bacteria are frequently cultured from neonates with conjunctivitis, their role as the causative agent of conjunctivitis is uncertain, as the same bacteria may be frequently cultured from the eyes of asymptomatic neonates. An example of this is Staphylococcus aureus, which is frequently found in both asymptomatic neonates and neonates with conjunctivitis (Amini 2008; Fransen 1987; Krohn 1993).

Many of the agents that cause ophthalmia neonatorum are not acquired from the birth process or the mother’s birth canal, but are acquired postnatally from caregivers or the nasopharyngeal passages of the neonate (Krohn 1993). The proportion acquired from the birth process compared to postnatal acquisition, likely varies by jurisdiction (Isenberg 1995; Vedantham 2004; Verma 1994).

Description of the intervention

There are four strategies to prevent ophthalmia neonatorum:

  1. primary prevention of the spread of sexually transmitted infections;

  2. secondary screening of pregnant women for genital infection;

  3. topical or systemic eye prophylaxis at birth;

  4. tertiary prevention via early diagnosis and treatment of eye infections in neonates (Foster 1995; Laga 1989).

German born obstetrician and gynaecologist Carl Siegmund Franz Credé (1819 to 1892) introduced the third strategy, ophthalmia neonatorum prophylaxis, to the world in his seminal publication in 1881 (Crede 1881; Dunn 2000). In his seminal study, Dr. Credé showed that he reduced the incidence of ophthalmia neonatorum in his maternity hospital in Leipzig, Germany, from 13.6% to 0.05% with the introduction of silver nitrate prophylaxis (Crede 1884).

The procedure of ophthalmia neonatorum prophylaxis was simple. After mechanical cleansing of the eyelids, he instilled a drop of silver nitrate solution into each of the open eyes of all neonates, immediately after birth. This same procedure has continued into the current day with different prophylactic agents (Crede 1881). Since the introduction of silver nitrate prophylaxis, consideration of other prophylactic agents, or even the complete abandonment of ophthalmia neonatorum prophylaxis, have been caused by the following factors:

  1. the introduction of antibiotics;

  2. the declining prevalence of Neisseria gonorrhoeae in developed countries;

  3. increased rates reported of ophthalmia neonatorum caused by Chlamydia trachomatis;

  4. concomitant questions about the relative effectiveness of silver nitrate; and

  5. concerns about side effects of silver nitrate, such as chemical conjunctivitis and their concomitant effects on maternal-infant bonding (Napchan 2005; Wahlberg 1982).

Initially, studies looking for alternatives to silver nitrate mainly examined penicillin as a prophylaxis for ophthalmia neonatorum. Later, erythromycin and tetracycline were studied in comparison to silver nitrate, and more recently, povidone-iodine. There have been studies of other prophylactic agents, but the majority of jurisdictions in the world today appear to use either erythromycin or povidone-iodine as a prophylaxis. However, there remains a high degree of variability in the prophylactic agents used for ophthalmia neonatorum prophylaxis, with some jurisdictions using prophylactic medications that are uncommon or not well-studied (Guala 2005; Zloto 2016).

Erythromycin and tetracycline gained acceptance as prophylactic agents in the 1980s because of their allegedly superior activity against Chlamydia trachomatis, and because they lacked some of the side effects of silver nitrate, such as chemical conjunctivitis (Isenberg 1994). However, it remains unresolved whether these antibiotic agents are in fact, any more effective than silver nitrate in preventing chlamydial conjunctivitis. Further, the emergence of beta-lactamase-producing Neisseria gonorrhoeae has reduced the prophylactic effectiveness of erythromycin and tetracycline (Ison 1998; Martin 2015; Van de Laar 2012; WHO 2012). Povidone-iodine is a more recently used prophylactic agent, which is alleged to have many advantages over silver nitrate, erythromycin, and tetracycline, including a broader antibacterial spectrum and lack of development of bacterial resistance (Isenberg 1994b).

How the intervention might work

Ophthalmia neonatorum prophylactic agents used around the world are antimicrobial or antiseptic agents, which, when administered topically, or systemically (only rarely), destroy or inhibit microorganisms in the eye to prevent conjunctivitis and keratitis (Kramer 2000). The microorganisms may be acquired from the mother’s infected birth canal, in-utero by ascending infections, or from the hospital or home environment.

Why it is important to do this review

Launched in 1999, Vision 2020 is a global initiative of the World Health Organization and the International Agency for the Prevention of Blindness, with the goal to eliminate avoidable blindness by 2020 (WHO 1999). Vision 2020 was updated by the World Health Organization in 2013 to develop a Global Action Plan for 2014 to 2019, “to reduce the prevalence of avoidable visual impairment by 25% by 2019” (WHO 2013).

Controlling childhood blindness is a high priority of this plan, as it has been estimated that 4% of all global blindness is due to childhood blindness, and 45% of all childhood blindness is avoidable. Corneal scarring is one of five childhood blindness conditions prioritised for control. While Vitamin A and measles are responsible for the majority of corneal scarring, ophthalmia neonatorum is a significant cause of corneal blindness, mainly in developing countries such as those in sub-Saharan Africa (Gilbert 2012; Robaei 2014; Whitcher 2001; WHO 2013).

There is considerable global variability in the requirement for ophthalmia neonatorum prophylaxis, and the prophylactic agents used around the world. Certain jurisdictions still carry out ophthalmia neonatorum prophylaxis, including Brazil (Caligaris 2010), the US (USPSTF 2011), Italy (Guala 2005), Spain (Luna 2009), Canada (Moore 2015), Slovenia (Dosier 2015), France (Dageville 2015), Turkey (Eser 2009), certain areas of Central America, some countries of Africa, parts of the Far East, areas of the Middle East, and sections of Central Asia (Zloto 2016). Norway, Great Britain, Sweden, The Netherlands (Geneeskundige 1980; Rours 2008), Australia (Shaw 1977), Belgium (Tribolet 2016), and Denmark (Pande 2006) discontinued ophthalmia neonatorum prophylaxis years ago (Kramer 2000). As recently as 2010, England and Wales removed ophthalmia neonatorum from the list of reportable diseases, even though, there is some evidence of significant underreporting of ophthalmia neonatorum (Dharmasena 2015; UK Department of Health 2010).

In Canada, there have been recent recommendations that prophylaxis for ophthalmia neonatorum be discontinued, although no legislative changes have yet been made (Moore 2015). Some groups in Canada oppose this recommendation (Mulholland 2015); others question whether the alternative strategy of prenatal screening is an optimal substitute (Poliquin 2015). The Canadian recommendation to discontinue prophylaxis has been made in spite of the fact that between 2003 and 2012, the rate of chlamydia in Canada has increased by 57.6% (Totten 2015a), and the rate of gonorrhoea has increased by 38.9%, mainly in women (Totten 2015b). In France, ophthalmia neonatorum prophylaxis is no longer universally recommended. Ocular prophylaxis is only recommended for neonates when there is a risk of sexually transmitted infections in the mother, and when the mother has had poor prenatal care (AFSSAPS 2010). Still, other jurisdictions are considering implementation of ophthalmia neonatorum prophylaxis (Alexandre 2015).

This global variability in practice and adoption of ophthalmia neonatorum prophylaxis can be explained by the following reasons:

  1. There is uncertainty about the evidence of effectiveness of the various prophylactic agents, particularly against Chlamydia trachomatis and emerging resistant strains of Neisseria gonorrhoeae.

  2. There are questions about the risk-benefit ratio of ophthalmia neonatorum prophylaxis, considering the side effects of the prophylactic agents, such as chemical conjunctivitis, and their effect on maternal-infant bonding.

  3. There is controversy about whether there is a difference in rates of ophthalmia neonatorum in jurisdictions where ophthalmia neonatorum prophylaxis continues and those in which it has been discontinued.

  4. There is debate about whether rates of ophthalmia neonatorum caused by Neisseria gonorrhoeae have sufficiently declined in the developed world to warrant discontinuing ophthalmia neonatorum prophylaxis.

  5. There are differences of opinion about whether alternative strategies, such as screening of pregnant women for genital infections, and early diagnosis and treatment of neonatal conjunctivitis, are adequate to prevent ophthalmia neonatorum.

This systematic review aims to synthesize the best available evidence to determine if ophthalmia neonatorum prophylaxis is effective, and to determine which prophylactic agent is most effective.

Objectives

The objectives of this review are:

  1. To determine if any type of ophthalmia neonatorum prophylaxis reduces the incidence of conjunctivitis in neonates.

  2. To determine which ophthalmia neonatorum prophylaxis is most effective at reducing the incidence of conjunctivitis in neonates.

Methods

Criteria for considering studies for this review

Types of studies

We will consider randomised and quasi-randomised trials.

Types of participants

We will consider trials that enrolled neonates born either vaginally or by cesarean section for inclusion in this review.

Types of interventions

We will consider trials that compare any medication with placebo, or with each other, whether administered topically, systemically, or in a combination. Medications can include antibiotics or antiseptics. Examples of antibiotics include tetracycline and erythromycin. Examples of antiseptics include povidone-iodine and silver nitrate. An example of systemic medication is intramuscular penicillin.

Types of outcome measures

Primary outcomes
  1. Proportion of infants developing blindness, defined as a visual acuity of 20/200 or worse, measured, for example, with a Teller visual acuity card at 12 months.

  2. Proportion of infants developing any adverse visual outcome measured, for example, with a Teller visual acuity card at 12 months.

  3. Proportion of neonates developing gonococcal conjunctivitis (GC) within 28 days of birth, where diagnosis was made with a laboratory-based method to identify the infecting organism. We anticipate that most studies would not have studied blindness as an outcome. Because severe GC can result in loss of vision, we will consider this outcome as a substitute for the more important measure of blindness.

Secondary outcomes
  1. Proportion of neonates developing chlamydial conjunctivitis (CC) within 28 days of birth.

  2. Proportion of neonates developing bacterial conjunctivitis (BC) within 28 days of birth; this includes cases of conjunctivitis confirmed to be of bacterial origin by culture, gram stain, or both. In addition to conjunctivitis cases of other bacterial etiology, this category includes GC and CC.

  3. Proportion of neonates developing any clinical conjunctivitis within 28 days of birth, referred to as any conjunctivitis cases of any etiology (ACAE): includes all cases of conjunctivitis clinically diagnosed, irrespective of etiology. This would include infectious and non-infectious conjunctivitis. Infectious conjunctivitis includes bacterial conjunctivitis, mycoplasma conjunctivitis, chlamydial or viral conjunctivitis. Non-infectious conjunctivitis includes chemical, toxic or mechanical conjunctivitis. In cases where there was selective outcome reporting, and all cases of clinical conjunctivitis were not reported, this outcome will not be included in comparisons.

  4. Proportion of neonates developing conjunctivitis of unknown etiology (CUE) within 28 days of birth: this includes cases of conjunctivitis which are culture-negative, where the etiology is unknown. These may be infectious, but showing no growth of pathogenic agents on culture media, or on other methods to identify microbiologic etiology. This may include non-infectious conjunctivitis, such as chemical conjunctivitis. Finally, it may be a mix of the aforementioned causes of conjunctivitis. In many cases, it is calculated by subtracting the total conjunctivitis cases of any etiology from the conjunctivitis cases proven to be bacterial origin.

  5. Proportion of neonates developing the following adverse effects of ophthalmia neonatorum prophylaxis:

    1. Proportion of neonates developing keratitis from ophthalmia neonatorum prophylaxis within 28 days of birth:

    2. Proportion of neonates developing nasolacrimal duct obstruction from ophthalmia neonatorum prophylaxis within 60 days of birth

Search methods for identification of studies

Electronic searches

We will search CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; latest issue), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to present), Embase (January 1980 to present), Latin American and Caribbean Health Sciences Literature Database (LILACS; 1982 to present), the ISRCTN registry (isrctn.com/editAdvancedSearch), ClinicalTrials.gov (clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP; who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic search for trials.

See appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), ISRCTN (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).

Searching other resources

We will check the reference lists of identified trial reports and existing review articles to identify additional trials. We will contact the authors of identified trials, pharmaceutical companies, and experts in the area to locate further trials.

Data collection and analysis

Selection of studies

Two review authors will independently screen titles and abstracts of records retrieved from the searches, and categorize each record as either include, exclude, or unclear. We will retrieve full-text articles of records that any of the review authors mark as include or unclear. Two review authors will independently assess the full-text articles and mark them as include or exclude. We will report reasons for full-text articles excluded in this process. The authors will resolve disagreements through discussion and consensus. In cases where additional information is needed before a decision on eligibility of the full-text articles, we will attempt to obtain this information from the study investigator.

Data extraction and management

For each eligible study (using all reports from the study), two review authors will independently extract information on methods, participants, interventions, outcomes, and funding sources using data forms developed for this review. We will contact the study authors for information missing from available reports.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias in each included study according to methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess risk of bias for generation and concealment of the allocation sequence, masking of participants, caregivers or study personnel, and outcome assessors, completeness of follow-up, reporting biases (selective outcome reporting), and other sources of potential bias, such as funding.

The review authors will mark the risk of bias for each item as high, low, or unclear. We will contact study authors if available reports do not contain information necessary for our assessment. We will use available information if study authors do not respond within four to six weeks.

Measures of treatment effect

We will compute the risk ratio for dichotomous outcomes.

Unit of analysis issues

We will consider the individual as the unit of analysis. The interventions are typically administered to both eyes, and we will consider infants to be infected if at least one eye is affected. We anticipate that trials will have randomised infants and not eyes. We will exclude studies in which both eyes within infants are randomised to different interventions.

Dealing with missing data

We will contact authors of included trials where we identify missing data on risk of bias or outcomes. If authors provide information on risk of bias that is not described in the trial reports, we will mark it as such in the review. If missing data on outcome are not available from authors of included trials, we will assess whether a meta-analysis is possible, using an intention-to-treat or an available case approach.

Assessment of heterogeneity

We will assess heterogeneity in effect estimates from included trials through a visual examination of the forest plot and based on the I² value. We will consider I² values of 60% or greater to indicate substantial heterogeneity. If we find substantial heterogeneity and the effect estimates in the included trials are in the same direction of the null value, then we will consider performing a meta-analysis; we will discuss the observed heterogeneity in such an instance. If we find estimates on both sides of the null value and substantial heterogeneity, we will not do a meta-analysis and instead provide a narrative summary. We will also consider the nature of interventions and the patient population to evaluate clinical heterogeneity in the included trials.

Assessment of reporting biases

For meta-analyses where we include more than 10 trials, we will evaluate the risk of publication bias using a funnel plot. For trials where the protocol is available, we will assess whether all the outcomes relevant to this review that were specified in the protocol have been described in the published reports.

Data synthesis

We will conduct a meta-analysis for comparisons where we determine minimal or no clinical heterogeneity and no substantial statistical heterogeneity. We will use a random-effects model. We will use a fixed-effect model for comparisons with two eligible studies. For trials with more than one comparison group, we will include the trial in relevant non-overlapping comparisons.

We will not explicitly include risk of bias as a factor in determining whether to include eligible trials in meta-analyses. We will discuss the findings from meta-analyses considering the risk of bias in included studies, and perform sensitivity analyses as described below.

Subgroup analysis and investigation of heterogeneity

We will consider subgroups by the cause of infection where data allow such analyses. If data permit, we will assess the effect of interventions within studies conducted in high income versus low income countries, using classification specified by the United Nations (WESP 2014).

Sensitivity analysis

We will conduct sensitivity analyses to assess the impact of studies with high risk of bias for sequence generation, allocation concealment, or completeness of follow-up.

Summary of findings

We will prepare Summary of Findings tables using the GRADE approach (Langendam 2013) for the following seven outcomes:

  1. Blindness

  2. Any adverse visual outcome

  3. Gonococcal conjunctivitis (GC)

  4. Chlamydial conjunctivitis (CC)

  5. Bacterial conjunctivitis (BC)

  6. Conjuncitivitis of any etiology (ACAE)

  7. Conjunctivitis of unknown etiology (CUE)

Summary of Findings tables will be done for the following comparisons, each with the above seven outcomes. This selection has been determined based on the clinical questions of the review, current global use of ophthalmia neonatorum prophylaxis, and consultation with CEVG:

  1. Any versus no prophylaxis

  2. Erythromycin versus no prophylaxis

  3. Povidone-Iodine versus no prophylaxis

  4. Tetracycline versus no prophylaxis

  5. Erythromycin versus Tetracycline

  6. Povidone-Iodine versus Erythromycin

  7. Povidone-Iodine verus Tetracycline

  8. Povidone-Iodine versus Chloramphenicol

Acknowledgements

  • We wish to thank Karen Neves at the Kellogg Health Sciences Library, Chris Emeneau at Medical Computing for their assistance with previous versions of this protocol.

  • We are very thankful to Cochrane Eyes and Vision, specifically, Mr. Richard Wormald and Anupa Shah for their assistance for current and past versions of this protocol; and Jennifer Evans and Kristina Lindsley for their assistance for the current version of this protocol.

  • We are grateful to Haroon Saloojee for peer review comments on a previous version of this protocol.

  • We would like thank Dr. Roger F. Soll, M.D., H. Wallace Professor of Neonatology, University of Vermont College of Medicine Coordinating Editor, Cochrane Neonatal Review Group, and Dr. Dr Kamiar Mireskandari MBChB, FRCSEd, FRCOphth, PhD, Staff Ophthalmologist and Associate Professor, Dept. of Ophthalmology and Visual Sciences, Hospital for Sick Children and University of Toronto for assistance with defining visual outcomes.

  • We would like to express our gratitude to Dr G. Robert LaRoche MD FRCSC, Professor of Ophthalmology, Dalhousie University, Head, Division of Pediatric Ophthalmology and Oculomotility for providing the idea for this review, and assisting with the past version of the protocol.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Gonorrhea] explode all trees
#2 MeSH descriptor: [Neisseria gonorrhoeae] explode all trees
#3 gonorr*
#4 MeSH descriptor: [Chlamydia] explode all trees
#5 MeSH descriptor: [Chlamydia Infections] explode all trees
#6 chlamyd*
#7 MeSH descriptor: [Streptococcus] this term only
#8 MeSH descriptor: [Staphylococcus aureus] this term only
#9 MeSH descriptor: [Staphylococcal Infections] this term only
#10 MeSH descriptor: [Haemophilus] this term only
#11 MeSH descriptor: [Vaginal Diseases] this term only
#12 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13 MeSH descriptor: [Conjunctivitis] explode all trees
#14 conjunctiv*
#15 MeSH descriptor: [Eye Infections] explode all trees
#16 (eye* or ocular) near/3 infection*
#17 #13 or #14 or #15 or #16
#18 MeSH descriptor: [Infant, Newborn] explode all trees
#19 infan* or newborn or new-born* or neonat* or neo-nat*
#20 #18 or #19
#21 #12 and #17 and #20
#22 MeSH descriptor: [Ophthalmia Neonatorum] explode all trees
#23 ophthalmia near/2 neonat*
#24 ophthalmia near/2 newborn*
#25(neonatal or ophthalmia or gonococcal or Chlamydia) near/4 conjunctivit*
#26 #22 or #23 or #24 or #25
#27 #21 or #26

Appendix 2. MEDLINE (Ovid) search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp gonorrhea/
14. exp neisseria gonorrhoeae/
15. gonorr$.tw.
16. exp chlamydia/
17. exp chlamydia infections/
18. chlamyd$.tw.
19. Streptococcus/
20. Staphylococcus aureus/
21. Staphylococcal Infections/
22. Haemophilus/
23. Vaginal Diseases/
24. or/13-23
25. exp conjunctivitis/
26. conjunctiv$.tw.
27. exp Eye Infections/
28. ((eye or ocular) adj3 infection$).tw.
29. or/25-28
30. exp infant newborn/
31. (infan$ or newborn or neonat$).tw.
32. (new adj1 born$).tw.
33. (neo adj1 nat$).tw.
34. or/30-33
35. exp ophthalmia neonatorum/
36. (ophthalmia adj2 neonat$).tw.
37. (ophthalmia adj2 newborn$).tw.
38. ((neonatal or ophthalmia or gonococcal or Chlamydia) adj4 conjunctivit$).tw.
39. or/35-38
40. 24 and 29 and 34
41. 39 or 40
42. 12 and 41

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by (Glanville 2006).

Appendix 3. EMBASE (Ovid) search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp gonorrhea/
34. exp neisseria gonorrhoeae/
35. gonorr$.tw.
36. exp chlamydia/
37. exp chlamydia trachomatis/
38. chlamyd$.tw.
39. Streptococcus/
40. Staphylococcus aureus/
41. Staphylococcus infection/
42. Haemophilus/
43. vagina disease/
44. or/33-43
45. exp conjunctivitis/
46. conjunctiv$.tw.
47. eye infection/
48. ((eye or ocular) adj3 infection$).tw.
49. or/45-48
50. exp infant newborn/
51. (infan$ or newborn or neonat$).tw.
52. (new adj1 born$).tw.
53. (neo adj1 nat$).tw.
54. or/50-53
55. exp newborn ophthalmia/
56. (ophthalmia adj2 neonat$).tw.
57. (ophthalmia adj2 newborn$).tw.
58. ((neonatal or ophthalmia or gonococcal or Chlamydia) adj4 conjunctivit$).tw.
59. or/55-58
60. 44 and 49 and 54
61. 59 or 60
62. 32 and 61

Appendix 4. LILACS search strategy

ophthalmia or conjunctivitis and neonatorum or newborn or neonatal or gonococcal or Chlamydia

Appendix 5. ISRCTN search strategy

(ophthalmia OR conjunctivitis) AND (neonatorum OR newborn OR neonatal OR gonococcal OR Chlamydia)

Appendix 6. ClinicalTrials.gov search strategy

(ophthalmia OR conjunctivitis) AND (neonatorum OR newborn OR neonatal OR gonococcal OR Chlamydia)

Appendix 7. ICTRP search strategy

(ophthalmia OR conjunctivitis) AND (neonatorum OR newborn OR neonatal OR gonococcal OR Chlamydia)

What's new

DateEventDescription
21 September 2016New citation required and major changesThis protocol replaces the withdrawn protocol on the same topic (first published online: 25 Oct 1999 | DOI: 10.1002/14651858.CD001862). It has a broader remit.

History

Protocol first published: Issue 3, 1999
Review first published: Issue 2, 2007

DateEventDescription
14 October 2008AmendedConverted to new review format.

Contributions of authors

Vimal Kapoor and S. Swaroop Vedula wrote and edited the protocol. All authors edited and approved of the final version.

Declarations of interest

Vimal Kapoor was funded by a Pharmaceutical Manufacturers' Association of Canada/IWK-Grace Studentship for this systematic review in the past. However, no one involved with this review has any financial links with Pharmaceutical Manufacturers' Association of Canada.

Sources of support

Internal sources

  • Pharmaceutical Manufacturers' Association of Canada / IWK-Grace Studentship, Canada.

External sources

  • No sources of support supplied

Ancillary