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:
primary prevention of the spread of sexually transmitted infections;
secondary screening of pregnant women for genital infection;
topical or systemic eye prophylaxis at birth;
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:
the introduction of antibiotics;
the declining prevalence of Neisseria gonorrhoeae in developed countries;
increased rates reported of ophthalmia neonatorum caused by Chlamydia trachomatis;
concomitant questions about the relative effectiveness of silver nitrate; and
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:
There is uncertainty about the evidence of effectiveness of the various prophylactic agents, particularly against Chlamydia trachomatis and emerging resistant strains of Neisseria gonorrhoeae.
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.
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.
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.
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.