Chapter 20. Conjunctivitis in the Neonate

Neonatal conjunctivitis (ophthalmia neonatorum or neonatal blennorrhea) is a conjunctivitis that occurs in the first 4 weeks of life. It is the most common ocular disease of newborns, occurring in 1.6–12% of neonates. Neonatal conjunctivitis has been associated with a wide variety of organisms, which have varied in their relative importance over time and geographic location (Table 20–1). The introduction of neonatal ocular prophylaxis and the introduction of routine screening and treatment of pregnant women for gonorrhea and, more recently, Chlamydia trachomatis infection have altered the epidemiology of ophthalmia neonatorum in the United States.3,4 In the nineteenth century, gonococcal ophthalmia was an important cause of blindness in infants; today, it is relatively uncommon in industrialized nations, although it remains a serious problem in many developing countries.1,5–8 Before the introduction of systematic screening and treatment of C. trachomatis infection in pregnant women in the 1990s, C. trachomatis was the most frequent identifiable infectious cause of neonatal conjunctivitis in the United States.3 Screening and treatment of pregnant women have resulted in a dramatic decrease in perinatal chlamydial infections. However, in countries where pregnant women are not routinely screened, including the Netherlands and many developing countries, C. trachomatis still remains the most frequent cause of neonatal conjunctivitis.2,5

Neisseria Gonorrhoeae

The main population at risk of gonococcal conjunctivitis is neonates born to mothers with vaginal infection. The transmission rate in neonates born to infected mothers who have not received ocular prophylaxis may be as high as 42%.1 Neonatal gonococcal ophthalmia (Figure 20–1) may cause primary disease at other mucous membrane sites or systemic disease. Gonococcal conjunctivitis in the newborn usually produces an acute purulent conjunctivitis that appears from 2 to 7 days after birth, although presentations during the second week of life are commonly described. Presentation may be earlier if there has been premature rupture of membranes, but the initial course may, occasionally, be indolent, with onset occurring later than 5 days after birth. Permanent corneal damage following gonococcal ophthalmia neonatorum was usual in the preantibiotic era.3

C. Trachomatis

C. trachomatis infection is acquired by the infant from his or her mother during parturition. This is based on a number of well-controlled prospective studies of maternal–infant infection conducted in the 1970s and 1980s, where infection occurred only in those infants born to infected mothers.3,9 Infection after cesarean delivery or through intact membranes is rare but may occur. In the former, there has usually been early rupture of the amnionic membranes. The overall risk of acquiring infection in an infant born to a mother with active chlamydial infection at any anatomical site has been approximately 50–75% in various studies.9 Approximately one-half of infants with inclusion conjunctivitis will also be infected in the nasopharynx.9,10 The incubation period of C. trachomatis conjunctivitis is 5–14 days after delivery; infection occurs earlier with premature rupture of membranes and onset as late as 60 days has been described.

Other Causes of Neonatal Conjunctivitis

Practically every known bacterial species has been implicated as a cause of ophthalmia neonatorum. Viruses, such as herpes simplex, may also cause ocular infection in neonates but is relatively uncommon. Infection is thought to occur during passage through the birth canal. A major problem in interpretation of the role of any specific bacteria is that many of these organisms are also frequently isolated from the conjunctivae of infants without conjunctivitis.

Bacteria implicated as causes of ophthalmia neonatorum include those commonly responsible for bacterial conjunctivitis in older children such as Streptococcus pneumoniae and Haemophilus influenzae. The prevalence of S. pneumoniae and H. influenzae in infants with neonatal conjunctivitis has been reported to range from 0% to 10% and 0% to 17%, respectively, compared with only 0% to <1% of infants without conjunctivitis.3 Viridans streptococci, including Streptococcus mitis and Streptococcus sanguis, have been isolated from up to 16% of infants with conjunctivitis, but were also isolated from up to 5% of normal infants.11

Various gram-negative enteric rods, including Escherichia coli,Klebsiella species, and, rarely, Pseudomonas species have also been associated with neonatal conjunctivitis, usually in infants in intensive care. Pseudomonas conjunctivitis may progress to corneal ulceration and perforation and endophthalmitis. It can also disseminate systemically causing bacteremia and meningitis even in the absence of corneal perforation.12–14

The role of Staphylococcus aureus in neonatal conjunctivitis is controversial. Although the organism can be isolated from the conjunctivae of 8–46% of infants with conjunctivitis, it has also been isolated from the conjunctivae of 3–10% of age-matched infants without conjunctivitis.3 Other organisms that are infrequent causes of neonatal conjunctivitis are moranella catarrhalis and Neisseria species including Neisseria cinerea and N. meningitidis. As these organisms are gram-negative diplococci, there is potential for confusion with N. gonorrhoeae if appropriate culture methods are not used.15,16

The conjunctiva is a loose connective tissue that covers the surface of the eye (bulbar conjunctiva) and forms the inner layer of the eyelids (palpebral conjunctiva). It is adherent to the underlying sclera at the limbus (corneal margin). It also contains numerous goblet cells, which secrete the mucinous layer of the tear film. Conjunctivitis is characterized by dilatation of the superficial conjunctival blood vessels, resulting in hyperemia and edema of the conjunctiva, with discharge. Fluid may accumulate beneath the loosely attached bulbar conjunctiva, causing it to swell away from the globe making eye closure difficult (chemosis), which can be seen in neonatal conjunctivitis caused by C. trachomatis and other bacteria.

The age at onset may suggest a specific etiology of conjunctivitis; however, there is substantial overlap among the various causes (Table 20–2).14,17–20

N. Gonorrhoeae

The infant typically develops tense edema of both lids, followed by chemosis and a progressively purulent and profuse conjunctival exudate, which literally pours or squirts out of the lids when they are separated. If treatment is delayed, the infection extends beyond the superficial epithelial layers, reaching the subconjunctival connective tissue of the palpebral conjunctivae and, more significantly, the cornea. Corneal complications include ulcerations, which may leave permanent nebulae or cause perforation and lead to anterior synechiae, panophthalmitis (rarely), and loss of the eye.

C. Trachomatis

The presentation of C. trachomatis conjunctivitis is variable, ranging from mild conjunctivitis with scant mucoid discharge to severe conjunctivitis with copious purulent discharge, chemosis, and pseudomembrane formation. The conjunctiva can be very friable (Figure 20–2) and may bleed when stroked with a swab.21 Eyelid erythema and edema are frequently present. A Gram-stained conjunctival smear may initially reveal a neutrophil predominance. There can be overlap in both incubation periods and presentation. Bilateral infections are present in two-thirds of cases. A follicular reaction is not seen because infants younger than 3 months do not have the requisite lymphoid tissue present in the conjunctiva. Although uncommon, chlamydial neonatal conjunctivitis may result in long-term sequelae, including corneal neovascularization and scarring.

Conjunctivitis Caused by Gram-Negative Enteric Bacteria

Infection from these organisms presents as an acute purulent conjunctivitis in an infant in an intensive care setting. Pseudomonas conjunctivitis may progress to corneal ulceration and perforation and endophthalmitis. Pseudomonas aeruginosa can also disseminate systemically, causing bacteremia and meningitis, even in the absence of corneal perforation.12–14

Chemical Conjunctivitis

While 1% silver nitrate is no longer manufactured or used in the United States, it is still used in many parts of the world and is associated with a mild chemical conjunctivitis, which can be easily distinguished from gonococcal conjunctivitis. Evidence of epithelial desquamation and polymorphonuclear leukocytic exudate appears usually within 6–8 hours and disappears usually within 24–48 hours.

In neonates, conjunctivitis is almost always from infection. Common infecting organisms are summarized in Table 20–1.

It is difficult to make an etiologic diagnosis of neonatal conjunctivitis on clinical grounds alone. There can be significant overlap in both incubation period and clinical findings. Conjunctival exudate can be directly examined by Gram stain for the presence of gram-negative intracellular bean-shaped diplococci suggestive (but not definitive) of N. gonorrhoeae, as other Neisseria spp. have also been associated with purulent ophthalmia neonatorum, as stated above. If infection with N. gonorrhoeae is suspected because of maternal risk factors, the diagnosis should be confirmed by culture and antibiotic susceptibility testing should be performed. Cultures for N. gonorrhoeae should also be obtained from the oropharynx and anal canal, since concomitant infection of these sites has been demonstrated in association with gonococcal ophthalmia neonatorum. None of the currently available nucleic acid amplification tests (NAATs) for N. gonorrhoeae have been evaluated or have FDA approval for use in any specimens from children including the conjunctiva.4 Two assays, polymerase chain reaction (PCR) (Amplicor, Roche Molecular Diagnostics, Nutley, NJ) and strand displacement amplification (ProbeTec, Becton Dickson, Sparks, MD), have been reported to cross-react with other Neisseria species, including N. cinerea, N. lactamica, N. sicca, and N. subflava.22 For this reason, only culture should be used for diagnosis of gonococcal conjunctivitis in infants and children.

The “gold standard” for diagnosis of C. trachomatis infections in infants and children remains isolation by culture of C. trachomatis from the conjunctiva, nasopharynx, vagina, or rectum. C. trachomatis culture has been defined further by the Centers for Disease Control and Prevention (CDC) as isolation of the organism in tissue culture and confirmation by microscopic identification of the characteristic inclusions, preferably by staining with a fluorescein-conjugated species-specific monoclonal antibody.4 Several nonculture tests are approved for diagnosis of chlamydial conjunctivitis in infants, specifically enzyme immunoassays (EIAs), and direct fluorescent-antibody tests (DFAs). The only EIA and DFA assays still available in the United States are Pathfinder® Chlamydia DFA and EIA Microplate (Bio-Rad Laboratories). These tests appear to perform well with conjunctival specimens with sensitivities 90% or more and specificities 95% or more compared with culture.3 There are currently three FDA-approved, commercially available NAATs for diagnosis of C. trachomatis infection: PCR (Amplicor, Roche Molecular Diagnostics, Nutley, NJ), strand displacement amplification (ProbeTec, Becton Dickson, Sparks, MD), and transcription-mediated amplification (GenProbe, San Diego, CA). These assays all have FDA approval for cervical swabs from women, urethral swabs from men, and urine from men and women.4 Data suggest that PCR is equivalent to culture for detection of C. trachomatis in the conjunctiva and nasopharynx of infants with conjunctivitis; however, PCR and other NAATs do not have FDA approval for use with conjunctival specimens.23 The identification of C. trachomatis and/or N. gonorrhoeae in a newborn infant indicates untreated infection in the parents.

The patient should be referred to a subspecialist in certain cases of neonatal conjunctivitis including, but not limited to,

1. gonococcal conjunctivitis because of the potential complications;

2. suspicion or documentation of herpetic keratoconjunctivitis;

3. progression of disease despite adequate treatment;

4. lack of improvement of symptoms despite alteration of therapy;

5. development of complications during treatment, i.e., corneal perforation and endophthalmitis in infants with infections from P. aeruginosa or other gram-negative bacilli.

The currently recommended therapy for neonatal gonococcal conjunctivitis by both the CDC and the WHO is ceftriaxone, 25–50 mg/kg IV or IM in a single dose, not to exceed 125 mg.4 The infant should be hospitalized until the conjunctivitis has resolved, which usually occurs within 24–48 hours after treatment with ceftriaxone. Topical antimicrobial therapy is not beneficial in the presence of systemic treatment. Alternatives for the treatment of gonococcal conjunctivitis when ceftriaxone is not available are cefotaxime 25 mg/kg IM in a single dose or kanamycin 25 mg/kg (maximum 75 mg) IM in a single dose. Infants born to mothers with untreated gonorrhea at the time of delivery are at high risk of infection and should receive ceftriaxone, 25–50 mg/kg IV or IM in a single dose, not to exceed 125 mg.4

Oral erythromycin suspension (ethylsuccinate or stearate) (50 mg/kg/d for 14 days) is the therapy of choice for the treatment of chlamydial conjunctivitis in infants.4 It provides better and faster resolution of the conjunctivitis as well as treats any concurrent nasopharyngeal infection. Additional topical therapy is not needed. The efficacy of this regimen has been reported to range from 80% to 90%; as many as 20% of infants may require another course of therapy.3 Treatment with oral erythromycin has been associated with infantile hypertrophic pyloric stenosis in infants younger than 6 weeks who were given the drug for prophylaxis after nursery exposure to pertussis.24 Data on use of other macrolides, including azithromycin or clarithromycin, for the treatment of neonatal Chlamydia infection are limited. There is one small study that evaluated azithromycin: It found that a short course of azithromycin suspension, 20 mg/kg/day orally, one dose daily for 3 days, was as effective as 2 weeks of erythromycin in eradication of C. trachomatis from the conjunctivae and nasopharynx of infants with conjunctivitis.25 Prophylactic treatment of infants born to women with untreated chlamydial infection is not recommended, as optimum dosing and duration of treatment are not known.

Data on treatment of neonatal conjunctivitis caused by other bacteria are limited. Considering the wide range of organisms, it is difficult to treat presumptively. Once gonococcal and chlamydial infections have been ruled out, one can follow the recommendations proposed for conjunctivitis in older children. Neonatal conjunctivitis caused by Pseudomonas and other gram-negative bacteria should be treated with systemic antibiotics. Choices for presumptive treatment should be based on the susceptibility patterns for these organisms in your institution and should include an aminoglycoside (gentamicin, tobramycin, or amikacin) and an expanded spectrum penicillin (ticarcillin–sulbactam, piperacillin–tazobactam, imipenem, or meropenem). Final choice of antibiotics results should be based on susceptibility testing of the isolate.

Neonatal conjunctivitis from bacteria such as viridans streptococci, H. influenzae, and S. pneumoniae is usually self-limited and will often resolve without specific treatment. Neonatal conjunctivitis from gram-negative bacteria including P. aeruginosa is potentially very serious and needs to be treated aggressively with appropriate systemic antibiotics, as described above.

Untreated neonatal gonococcal ophthalmia can lead to corneal complications including ulcerations that may leave permanent nebulae or cause perforation and lead to anterior synechiae, panophthalmitis (rarely), and loss of the eye. However, single-dose treatment with ceftriaxone is highly effective. Neonatal conjunctivitis caused by C. trachomatis may rarely result in long-term sequelae, including corneal neovascularization and scarring. Treatment with oral antibiotics significantly shortens the duration of symptoms and eradication of concurrent nasopharyngeal infection, which could progress to pneumonia. Herpes simplex virus (HSV) is a very rare cause of neonatal conjunctivitis. Infants with suspected HSV conjunctivitis should be hospitalized, evaluated for systemic HSV infection, and treated with parenteral acyclovir.