How Do I Treat a Pregnant Woman With a Macula-Threatening Toxoplasmosis Lesion?
Rajiv
Shah,
MD
Toxoplasma gondii is the leading cause of infectious posterior uveitis worldwide. Macula- or vision-threatening retinochoroiditis or optic nerve involvement represents indication for treatment. However, unique to pregnancy is the urgency of preserving a mother’s vision in addition to limiting, if not preventing, vertical transmission of the parasite, which may lead to severe comorbid effects or even termination of the pregnancy. Reactivation of congenital lesions is the classic teaching as to the etiology behind retinochoroiditis, but as more cases of acquired toxoplasmosis are recognized, this notion may change. Acquired toxoplasmosis commonly occurs from the consumption and handling of raw or undercooked meat (especially pork) or from the cleaning of cat litter boxes by pregnant women.
The approach to treatment in a pregnant patient is often intimidating because concerns arise with respect to which medication is safe for the fetus. Unfortunately, randomized controlled trials are simply not present for all classes of medications with respect to treating ocular toxoplasmosis. The standard scheme for summarizing the clinical evidence with respect to safety in pregnancy is as follow: “A” for safe as shown in human trials, “B” for presumed safe based on animal models, “C” for uncertain safety based on no human or animal trials, “D” for unsafe based on animal models, and “X” unsafe based on human trials. Currently, the only agents that carry a “D” rating are the tetracycline class. Thus, for pregnant woman and children, this class should not be considered unless all other options are exhausted or after an extensive risk/benefit discussion has been conducted with the patient and/or family. There are no known medications that are the “X” distinction. The only “A”-rated medication is folinic acid, which is used as an adjuvant to limit bone marrow toxicity when pyrimethamine therapy is used. The “B” category (macrolides, clindamycin, and atovoquone) or the “C” category (pyrimethamine/sulfadizine, Bactrim, and prednisone) will be discussed in more detail.
The macrolide class, in particular spiramycin, has the most human trial experience for the treatment of toxoplasmosis in pregnancy. Spiramycin is used 1 g every 8 hours for a period of 3 weeks. It has been a longstanding belief since the work of Desmonts and Couvreur that spiramycin decreased the rate of transmission by 60%. Recent multicenter European trials have challenged the notion that spiramycin prevents maternal fetal transmission, and recent work suggests that spiramycin does not cross the placenta to treat an infected fetus. This medication is not commercially available in the United States, but it can be obtained at no cost from Sanofi-Aventis after consultation with Food and Drug Administration (FDA), National Collaborative Treatment Trial Study, or Palo Alto Medical Foundation Toxoplasma Serology Laboratory. Azithromycin has not been as well studied in the setting of pregnancy, but there are limited data validating its safety. Azithromycin is used 500 mg daily. As will be discussed, pyrimethamine/sulfadiazine/folinic acid is considered the gold standard for treatment in the nonpregnant woman. A study evaluated the combination of pyrimethamine and azithromycin against the gold standard and found the end result to be equivalent between the 2 treatments with the notable exception that the azithromycin regimen was better tolerated. There is not enough evidence for azithromycin as monotherapy for the treatment of ocular toxoplasmosis.
The most classic treatment for toxoplasmosis centers on inhibition of the folic acid metabolism pathway of the parasite. Given the importance of folic acid metabolism for fetal neurologic development, this class of agents is contraindicated for usage in the first trimester. Pyrimethamine is the most effective anti-Toxoplasma agent. Pyrimethamine is given as a 100-mg loading dose with 25 to 50 mg daily for 30 to 60 days. It is coupled with sulfadiazine 1 g 4 times daily for synergistic antagonism of the folate acid metabolic pathway. Folinic 5 to 20 mg daily must be given with pyrimethamine to prevent bone marrow toxicity. Pyrimethamine/sulfadiazine/folinic acid is known as triple therapy and is considered the gold standard for treating Toxoplasma. One study compared it to other regimens (triple versus clindamycin versus Bactrim) and found that visual loss and recurrence rates were not different between regimens. The true benefit of triple therapy was that 49% of patients on triple therapy achieved smaller retinal lesion size and subsequently smaller retinal scars. Intolerance to medication, particularly to pyrimethamine, is the most common difficulty encountered with triple therapy. Bactrim DS, 1 tablet twice daily, inhibits folic acid in a similar fashion to triple therapy but is less toxic to the bone marrow and is better tolerated. Although clinical experience is more limited compared to triple therapy, a recent trial of Bactrim versus triple therapy demonstrated no difference in visual outcomes and/or retinal lesion size, contrary to the early comparison study.
Clindamycin used 300 mg 4 times a day for 30 to 40 days is another option. It has been coupled with the pyrimethamine/sulfadiazine/folinic acid as quadruple therapy. From animal models, clindamycin may reduce the number of Toxoplasma cysts, and it has been found to concentrate at the level of the retinal pigment epithelium, which is why lower doses are sufficient for treatment of retinochoroiditis. Furthermore, as a treatment for an obligate intracellular parasite such as toxoplasmosis, clindamycin has the advantage of increased intracellular concentration of nearly 3 times when compared to erythromycin. Pseudomembranous colitis remains the dreaded complication of systemic clindamycin therapy, which occurs approximately 1/50,000 or 1/100,000 cases. Because chronic diarrhea may follow with many systemic antibiotic regimens, the recognition of pseudomembranous colitis requires vigilance and constant surveillance on the part of the practitioner. Despite these concerns with systemic usage, I am a strong supporter of this medication especially when used intravitreally for macula-threatening toxoplasmosis in pregnancy or otherwise. Clindamycin given intravitreally 1.0 mg/0.1 cc can be obtained locally or nationally through compounding pharmacies (such as Leiters). Intravitreal clindamycin has been shown to be highly effective as monotherapy in cases of medication intolerance in nonpregnant patients. The side effects and systemic delivery (and risk to the fetus) from intraocular injection are negligible if any. The typical dose has been found to be nontoxic to the retina with a half-life of 40 hours, sustaining levels above the 50% inhibitory concentration for toxoplasmosis. Some have advocated the co-injection with dexamethasone 400 mcg concomitantly with intravitreal clindamycin. A recent masked prospective trial evaluated intravitreal clindamycin with dexamethasone versus classic triple therapy with oral corticosteroids; the results demonstrated no difference in visual outcome and lesion size between the 2 regimens. Interestingly, there was a subgroup analysis that suggested that acquired toxoplasmosis, as indentified by positive immunoglobulin M (IgM) titers, may have reduced lesion size with systemic rather than intravitreal therapy. Although there is certainly a theoretical concern of creating a toxoplasmosis acute retinal necrosis with use of intravitreal corticosteroids, this trial and previous reports have not demonstrated this when antibiotics and steroids are injected together. As with any procedure, the risk of endophthalmitis, hemorrhage, damage to the crystalline lens, etc, must be discussed with the patient, but with proper technique and needles 30-ga or smaller, I find the benefits to outweigh the risks.
Atovoquone, an anti-malarial agent, is another option that may be better tolerated than the sulfa-based therapies. It is typically dosed 750 mg 4 times daily for 4 to 6 weeks. Although the experience for treatment of toxoplasma is also limited, this agent is widely used in treating malaria, especially in pregnancy with no known adverse effects to the fetus. There is a suspension form that increases the bioavailability, and in animal models, there has been a suggestion that Atovoquone may have activity against the cyst forms, which is poorly targeted by the more widely used agents for toxoplasma.
Corticosteroids are an adjunct to consider in addition to antimicrobial therapy. In retinochoroiditis, the use of steroids is thought to reduce the damage from the inflammation caused by toxoplasma. During pregnancy, the prolonged use of steroids may cause increases in cleft lips or palate, in addition to exacerbation of pregnancy-induced hypertension, gestational diabetes, osteoporosis, and infection. Close follow-up with a patient’s obstetrician is necessary when systemic steroids are considered. One could consider periocular or intraocular steroids if the risks to the fetus are deemed unacceptable.
An additional consideration that bears mention in the pregnant patient revolves around maternal-fetal transmission. Recent longitudinal studies from Europe demonstrate an increase in vertical transmission with gestational age. The peak risk of transmission of 72% occurs around 36 weeks. These findings underscore some important nuisances. First, in an ideal scenario, close screening for toxoplasmosis antibodies titers through most prenatal visits would aid in early detection of a reactivation of latent maternal disease or newly acquired toxoplasmosis. Such screening is not routine in the United States but is mandated in some other countries. If there is a high concern for transmission to the fetus after 18 weeks of age, amniotic fluid sampling can be performed (although consideration must be given to the risk that such procedures pose to the fetus) and sent for PCR analysis. In one study, the PCR analysis had a sensitivity of 64% and a positive predicative value of 100% (a positive test means infection in the fetus). Ultrasound evaluations are also valuable to detect the possible fetal abnormalities such as hydrocephalus, calcification, or hepatosplenomegaly, which would be suggestive of toxoplasmosis. Current recommendations advocate Spiramycin for maternal infections prior to 18 weeks of gestation with a switch to pyrimethamine, sulfadiazine, and folinic acid after 18 weeks. The latter should also be used in cases where fetal infection has been confirmed.
Summary
Although there is no clear gold standard approach to the treatment of sight-threatening toxoplasmosis retinochoroiditis in pregnancy, I will suggest the following recommendations. Given the evolving evidence, I recommend intravitreal clindamycin for vision-threatening disease. One could consider reinjection after 3 days if necessary. The addition of concomitant intravitreal steroid is a matter of debate, but from the data available, I feel comfortable recommending it. With respect to the issue of concern for the fetus, I would recommend the macrolide class as first-line therapy, and this should be started as soon as possible, especially in the first trimester to protect the fetus from the severe consequences of vertical transmission. Although the bulk of the experience would indicate that Spiramycin should be the agent of choice, it is reasonable to use azithromycin or clarithromycin instead. As the patient approaches the 18-week gestation mark, a careful discussion of risk and benefit should be made regarding the amniotic fluid sampling and/or the switch to classic triple therapy. Certainly, other agents (such as atovoquone or combinations of pyrimethamine/azithromycin or pyrimethamine/atovoquone) can be considered given intolerance to medication or resistance to treatment, but there are fewer data and experience to guide outcomes and risk.
Suggested Readings
Foulon W, Villena I, Stray-Pedersen B, et al. Treatment of toxoplasmosis during pregnancy: a multicenter study of impact on fetal transmission and children’s sequelae at age 1 year. Am J Obstet Gynecol. 1999;180(2 Pt 1):410-415.
Kump LI, Androudi SN, Foster CS. Ocular toxoplasmosis in pregnancy. Clin Experiment Ophthalmol. 2005;33:455-460.
Montoya J, Remington J. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2008;47:554-566.
Sobrin L, Kump LI, Foster CS. Intravitreal clindamycin for toxoplasmic retinochoroiditis. Retina. 2007;27:952-957.
Soheilian M, Ramezani A, Azimzadeh A, et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology. 2011;118:134-141. Epub 2010 Aug 12.