Systematic screening and treatment of toxoplasmosis during pregnancy: is the glass half full or half empty?

Related article, page 386. Related article, page 386. In this issue of the Journal, Mandelbrot et al1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar report findings of the first randomized clinical trial (RCT) ever performed on the treatment of acute toxoplasma infection during pregnancy. Treatment of acute toxoplasma infection during gestation is aimed at preventing mother-to-child transmission (MTCT) and to minimize clinical sequelae in already infected offspring (CSIo).1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar According to the authors, a placebo-controlled RCT was not possible because most investigators who were surveyed at the time believed that such RCT would be unacceptable, given that spiramycin has been used for this indication in France for >30 years. For this reason, the Toxogest (ClinicalTrials.gov Identifier: NCT01189448) was designed as an RCT to compare the upfront use of spiramycin vs pyrimethamine/sulfadiazine/folinic acid (PS) in women confirmed to have seroconverted during their second trimester of gestation or later. Their hypothesis was that PS would be superior to spiramycin. One hundred fifty-one women were randomly assigned to spiramycin or PS. The time of maternal infection, which is one of the most powerful factors that influences the likelihood of vertical transmission and clinical sequelae in the offspring, was estimated to have occurred between 13 and 25 weeks of gestation (WG) in their participants. The time of maternal infection was determined accurately by choosing the midpoint between the last negative and the first positive Toxoplasma immunoglobulin G finding in the setting of monthly screening. Women could not be enrolled in their first trimester because PS is considered unsafe for the fetus during this period; their study did not have any women enrolled past 25 WG for maternal infection, which may have been a good thing because, in the third trimester, spiramycin is known to be less effective and because the comparison would have been unfair for spiramycin. Unfortunately, Toxogest had to be terminated prematurely because of low enrollment and lack of additional funding. Given the fact that recruitment fell short of the projected sample size, did we learn anything new from Toxogest results? Fortunately, I believe the answer is an unqualified yes. First, we learned that most French investigators who are authorities in the field would consider it unethical to design a study that includes a group in which women who acquire Toxoplasma infection during gestation would be given placebo and left untreated. In their experience, and as it is reflected in >30 published observational studies (including >9000 pregnant women and their offspring), treatment of acute maternal toxoplasmosis decreases MTCT and CSIo.2Maldonado Y.A. Read J.S. Committee on Infectious DiseasesDiagnosis, treatment, and prevention of congenital toxoplasmosis in the United States.Pediatrics. 2017 Feb; 139 (pii: e20163860. https://doi.org/10.1542/peds.2016-3860)Crossref Scopus (114) Google Scholar Among studies with primary data, from early3Desmonts G. Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies.N Engl J Med. 1974; 290: 1110-1116Crossref PubMed Scopus (460) Google Scholar, 4Desmonts G. Couvreur J. Congenital toxoplasmosis: a prospective study of the offspring of 542 women who acquired toxoplasmosis during pregnancy.in: Thalhammer V.O. Pollak A. Baumgarten K. Pathophysiology of congenital disease. Perinatal Medicine, 6th European Congress. Georg Thieme Publishers, Stuttgart, Germany1979: 51-60Google Scholar, 5Couvreur J. Desmonts G. Thulliez P. Prophylaxis of congenital toxoplasmosis: effects of spiramycin on placental infection.J Antimicrob Chemother. 1988; 22: 193-200Crossref PubMed Google Scholar, 6Daffos F. Forestier F. Capella-Pavlovsky M. et al.Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis.N Engl J Med. 1988; 318: 271-275Crossref PubMed Scopus (375) Google Scholar, 7Hohlfeld P. Daffos F. Thulliez P. et al.Fetal toxoplasmosis: outcome of pregnancy and infant follow-up after in utero treatment.J Pediatr. 1989; 115: 765-769Abstract Full Text PDF PubMed Scopus (231) Google Scholar to most recent,8Kieffer F. Wallon M. Garcia P. Thulliez P. Peyron F. Franck J. Risk factors for retinochoroiditis during the first 2 years of life in infants with treated congenital toxoplasmosis.Pediatric Infect Dis J. 2008; 27: 27-32Crossref PubMed Scopus (98) Google Scholar, 9Cortina-Borja M. Tan H.K. Wallon M. et al.Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study.PLoS Med. 2010; 7: e1000351Crossref PubMed Scopus (150) Google Scholar, 10Hotop A. Hlobil H. Gross U. Efficacy of rapid treatment initiation following primary toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2012; 54: 1545-1552Crossref PubMed Scopus (89) Google Scholar, 11Wallon M. Peyron F. Cornu C. et al.Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years.Clin Infect Dis. 2013; 56: 1223-1231Crossref PubMed Scopus (160) Google Scholar, 12Avelino M.M. Amaral W.N. Rodrigues I.M. et al.Congenital toxoplasmosis and prenatal care state programs.BMC Infect Dis. 2014; 14: 33Crossref PubMed Scopus (54) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar trends in MTCT rates and CSIo have always favored treated over untreated. Moreover, findings from these >30 studies have never concluded that the potential harm from treatment outweighs its benefits. Systematic screening and treatment for toxoplasmosis during pregnancy became controversial in the early 2000s because of articles that were published from 1999–200714Foulon 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: 410-415Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 15Gilbert R.E. Gras L. Wallon M. Peyron F. Ades A.E. Dunn D.T. Effect of prenatal treatment on mother to child transmission of Toxoplasma gondii: retrospective cohort study of 554 mother-child pairs in Lyon, France.Int J Epidemiol. 2001; 30: 1303-1308Crossref PubMed Scopus (100) Google Scholar, 16Gras L. Gilbert R.E. Ades A.E. Dunn D.T. Effect of prenatal treatment on the risk of intracranial and ocular lesions in children with congenital toxoplasmosis.Int J Epidemiol. 2001; 30: 1309-1313Crossref PubMed Scopus (80) Google Scholar, 17Gilbert R. Gras L. European Multicentre Study on Congenital Toxoplasmosis. Effect of timing and type of treatment on the risk of mother to child transmission of Toxoplasma gondii.BJOG. 2003; 110: 112-120Crossref PubMed Scopus (146) Google Scholar, 18Gras L. Wallon M. Pollak A. et al.Association between prenatal treatment and clinical manifestations of congenital toxoplasmosis in infancy: a cohort study in 13 European centres.Acta Paediatr. 2005; 94: 1721-1731Crossref PubMed Scopus (134) Google Scholar, 19Thiebaut R. Leproust S. Chene G. Gilbert R. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’ data.Lancet. 2007; 369: 115-122Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar that unfortunately were biased and misleading and misunderstood the biologic impact of spiramycin on MTCT and CSIo. For instance, in these 6 studies, participants were excluded if the fetus was already affected or severely affected (this occurrence would more often fall in the untreated group). In addition, studies before 1985 were also not included in a highly quoted metanalysis because, according to the authors, immunoglobulin M was not widely available before that time.19Thiebaut R. Leproust S. Chene G. Gilbert R. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’ data.Lancet. 2007; 369: 115-122Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Cohorts before 1985 tended to have the largest numbers of untreated women. Moreover, it was assumed erroneously that the efficacy of spiramycin could be established merely by estimating the frequency of infected vs uninfected offspring in the treated vs untreated groups. Under this assumption, an infected offspring would be tallied as a “failure” and an uninfected newborn as a “success.” However, spiramycin is unique in its capacity to concentrate in the placenta, and its effect in MTCT is far more complex.20Bogacz J. [Comparative effect of various synthetic agents and various antibiotics, including spiramycin, on Toxoplasma].Bull Soc Pathol Exot Filiales. 1954; 47: 903-915PubMed Google Scholar, 21Garin J.P. Pellerat J. Maillard M.A. Woehrle-Hezez R. [Bases theoriques de la prevention par la spiramycine de la toxoplasmose congenitale chez la femme enceinte] Theoretical bases of the prevention by spiramycin of congenital toxoplasmosis in pregnant women.Presse Med. 1968; 76: 2266PubMed Google Scholar, 22Forestier F. Daffos F. Rainaut M. Desnottes J.F. Gaschard J.C. [Suivi therapeutique foetomaternel de la spiramycine en cours de grossesse.].Arch Fr Pediatr. 1987; 44: 539-544PubMed Google Scholar Spiramycin partially, but not completely, diminishes MTCT and contributes to ameliorate CSIo. Spiramycin benefit can be summarized in 3 categoric effects: (1) it is successful in preventing fetal infection in some cases; (2) it is not successful in preventing infection but reduces toxoplasma burden, which results in a shift from severe to milder forms of the disease in others; and (3) it is not successful in preventing infection that results in full-blown outcomes of mild/moderate/severe congenital disease in a third group. Thus, spiramycin can avoid transmission in some pregnant women, decrease severity in others, and fail in a third group. Offspring with a lower parasitic burden, who are spared from severe disease and/or death, end up contributing to the number of “infected” children. The net effect of such intervention would be an overall decrease of severe cases and death but less than substantial effects on MTCT because some of the offspring who would have succumbed to the parasite are now born live, with milder forms, and are tallied in the “infected group.” This conceptual framework appears to explain the results that were observed in the SYROCOT (Systematic Review on Congenital Toxoplasmosis) study.19Thiebaut R. Leproust S. Chene G. Gilbert R. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’ data.Lancet. 2007; 369: 115-122Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar In the SYROCOT study, severe cases were excluded to avoid “referral bias.” In addition, in their analysis of clinical manifestations, 4 cohorts from outside Europe (2 in Brazil and 1 in Colombia) that contained significant numbers of severe cases, which were based mainly on neonatal screening, were also excluded. In fact, when a subgroup of SYROCOT investigators analyzed the data that included those with severe neurologic sequelae or death, prenatal treatment (spiramycin±PS) reduced the risk of severe neurologic sequelae or death.9Cortina-Borja M. Tan H.K. Wallon M. et al.Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study.PLoS Med. 2010; 7: e1000351Crossref PubMed Scopus (150) Google Scholar The odds ratio for prenatal treatment was 0.24 (95% confidence interval [CI], 0.07–0.71). Even in the absence of placebo-controlled RTC, there is plenty of evidence that supports the treatment of acute toxoplasmosis during pregnancy, which is the reason that the Mandelbrot et al1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar study could not have a placebo arm. Second, although statistical significance was not achieved because of the limitation in sample size brought by the unintended early termination of the trial,1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar the PS that was initiated as early as 14 WG resulted in a clear trend to lower MTCT in the PS group: 10.4% vs 20.3% as measured by positive amniotic fluid polymerase chain reaction (PCR) test results and 18.5% vs 30% as measured by observing infants up to 1 year of age, which is considered the gold standard for the diagnosis of congenital toxoplasmosis.23Pomares C. Montoya J.G. Laboratory diagnosis of congenital toxoplasmosis.J Clin Microbiol. 2016; 54: 2448-2454Crossref PubMed Scopus (79) Google Scholar Furthermore, ultrasound manifestations of congenital toxoplasmosis were present only in the spiramycin group (8.6%) but not in the PS group (0%). What the study by Mandelbrot et al1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar has taught us is that there is a potential additional benefit in starting PS over spiramycin as the initial treatment for maternal toxoplasmosis, particularly if it is instituted as early as possible. How early during gestation PS is recommended currently for the upfront treatment of acute infection (before work up for fetal infection is undertaken) varies greatly by reference center: 32 WG,24Dunn D. Wallon M. Peyron F. Petersen E. Peckham C. Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling.Lancet. 1999; 353: 1829-1833Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar 30 WG,25Faucher B. Garcia-Meric P. Franck J. et al.Long-term ocular outcome in congenital toxoplasmosis: a prospective cohort of treated children.J Infect. 2012; 64: 104-109Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar 18 WG,26Montoya J.G. Remington J.S. Management of Toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2008; 47: 554-566Crossref PubMed Scopus (475) Google Scholar 16 WG.10Hotop A. Hlobil H. Gross U. Efficacy of rapid treatment initiation following primary toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2012; 54: 1545-1552Crossref PubMed Scopus (89) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar It is interesting to note that the centers with treatment regimens closer (eg, 16 WG)10Hotop A. Hlobil H. Gross U. Efficacy of rapid treatment initiation following primary toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2012; 54: 1545-1552Crossref PubMed Scopus (89) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar in WG to the Mandelbrot et al1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar study (14 WG) have reported lower MTCT rates than other centers that initiate upfront PS later (eg, 32 WG).24Dunn D. Wallon M. Peyron F. Petersen E. Peckham C. Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling.Lancet. 1999; 353: 1829-1833Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar The results of this RTC should lead to centers that recommend PS as an upfront treatment beyond 14 WG24Dunn D. Wallon M. Peyron F. Petersen E. Peckham C. Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling.Lancet. 1999; 353: 1829-1833Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, 25Faucher B. Garcia-Meric P. Franck J. et al.Long-term ocular outcome in congenital toxoplasmosis: a prospective cohort of treated children.J Infect. 2012; 64: 104-109Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 26Montoya J.G. Remington J.S. Management of Toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2008; 47: 554-566Crossref PubMed Scopus (475) Google Scholar to consider initiating PS at 14 WG. Third, timing of the initiation of treatment earlier trended toward further improved outcomes. The effect of prenatal treatment was strengthened by treatment that was initiated (eg, <3 weeks earlier). Treatment benefit varied significantly with an odds ratio for PS vs spiramycin of 1.20 (95% CI, 0.35–4.14) when initiated at >3 weeks and an odds ratio of 0.03 (95% CI, 0.00–1.63) when initiated within 3 weeks of the estimated maternal infection. Other studies have found similar trends with earlier initiation of treatment, which provides further support that prenatal treatment of maternal toxoplasmosis is effective.11Wallon M. Peyron F. Cornu C. et al.Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years.Clin Infect Dis. 2013; 56: 1223-1231Crossref PubMed Scopus (160) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar, 19Thiebaut R. Leproust S. Chene G. Gilbert R. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’ data.Lancet. 2007; 369: 115-122Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Fourth, the fact that a small number of infants were found subsequently to be infected in both arms, despite negative results in amniotic fluid PCR (13.3% in the spiramycin group and 25% in the PS group), supports the recommendation the observation of these babies with serial ultrasound scan results during gestation and continuing drug treatment. One reason spiramycin has been recommended in pregnant women throughout gestation, even after negative PCR and fetal ultrasound results, is the concern that the placenta may be still infected but that the infection has not reached the fetus yet.26Montoya J.G. Remington J.S. Management of Toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2008; 47: 554-566Crossref PubMed Scopus (475) Google Scholar In the study of Mandelbrot et al1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar study, it appears that some of the women in the PS arm had their treatment discontinued upon negative PCR test results. In patients without evidence of fetal infection by PCR and ultrasound scanning, some centers recommend continuation of therapy until the end of gestation, with either spiramycin alone or spiramycin alternated with PS on a monthly basis;10Hotop A. Hlobil H. Gross U. Efficacy of rapid treatment initiation following primary toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2012; 54: 1545-1552Crossref PubMed Scopus (89) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar these infected children, despite prenatal therapy, rarely present with severe disease.10Hotop A. Hlobil H. Gross U. Efficacy of rapid treatment initiation following primary toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2012; 54: 1545-1552Crossref PubMed Scopus (89) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar This fact of infected offspring in the presence of in utero treatment also further emphasizes the need to observe children for at least 1 year and ideally lifelong to evaluate fully the impact of congenital toxoplasmosis in human life. One major benefit of the initiation of treatment in utero is that, even when fetal infection occurs, it has been demonstrated that these treated children achieve a quality of life similar to those not infected.27Peyron F. Garweg J.G. Wallon M. Descloux E. Rolland M. Barth J. Long-term impact of treated congenital toxoplasmosis on quality of life and visual performance.Pediatr Infect Dis J. 2011; 30: 597-600Crossref PubMed Scopus (50) Google Scholar Fifth, the regimens of spiramycin and PS for maternal toxoplasmosis should be viewed as complimentary rather than binary or mutually exclusive. PS is potentially teratogenic, should not be used before 14 WG, has potential hemato-, renal-, and hepatotoxicity that requires at least weekly laboratory testing and, as reported by Mandelbrot et al1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar and others,10Hotop A. Hlobil H. Gross U. Efficacy of rapid treatment initiation following primary toxoplasma gondii infection during pregnancy.Clin Infect Dis. 2012; 54: 1545-1552Crossref PubMed Scopus (89) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar ideally should be used for women with acute toxoplasmosis at ≥14 WG. Spiramycin is not teratogenic, has a well-known and acceptable safety profile, and can be used any time during gestation; however, it should best be used as the initial regimen at <14 WG. In addition, spiramycin should be used throughout gestation when a work up for fetal infection by PCR and ultrasound scanning is negative. Sixth, most of the pregnant women in France who seroconvert during gestation and who benefit from prenatal antitoxoplasma are asymptomatic and do not have identifiable risk factors for toxoplasma infection.28Peyron F. Wallon M. Kieffer F. Garweg J.G. Toxoplasmosis.in: Wilson C.B. Nizet V. Maldonado Y. Remington J.S. Klein J.O. Infectious diseases of the fetus and newborn infant. Saunders, Philadelphia, PA2015: 949-1042Google Scholar, 29Cook A.J. Gilbert R.E. Buffolano W. et al.Sources of toxoplasma infection in pregnant women: European multicentre case-control study.BMJ. 2000; 321: 142-147Crossref PubMed Google Scholar This means that, if the criteria to enter into the study would have been presence of symptoms, most women who seroconverted and were qualified for the trial would have not been enrolled. That women usually do not have symptoms during gestation and/or identifiable risk factors is also a reality in the United States; it has been well-demonstrated by the toxoplasmosis Chicago group.30Boyer K.M. Holfels E. Roizen N. et al.Risk factors for Toxoplasma gondii infection in mothers of infants with congenital toxoplasmosis: implications for prenatal management and screening.Am J Obstet Gynecol. 2005; 192: 564-571Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Thus, the only approach that guarantees the provision of benefit of prenatal treatment to each of the 200,000,000 women who become pregnant each year worldwide is by systematic serologic screening. The global annual incidence of congenital toxoplasmosis has been estimated to be 190,100 cases (95% CI, 179,300–206,300), corresponding to a burden of 1.20 million disability-adjusted life years (95% CI, 0.76–1.90).31Torgerson P.R. Mastroiacovo P. The global burden of congenital toxoplasmosis: a systematic review.Bull World Health Organ. 2013; 91: 501-508Crossref PubMed Scopus (396) Google Scholar Yet, only few countries (eg, France, Austria, Germany, Uruguay, Lithuania, Argentina) protect their fetuses by universal serologic screening during gestation, followed by treatment of women who seroconvert.32Peyron F. Mc Leod R. Ajzenberg D. et al.Congenital toxoplasmosis in France and the United States: one parasite, two diverging approaches.PLoS Negl Trop Dis. 2017; 11: e0005222Crossref PubMed Scopus (64) Google Scholar Surprisingly and unfortunately, this is not the case in the United States (and other countries) where toxoplasmosis screening during pregnancy is not universally recommended.32Peyron F. Mc Leod R. Ajzenberg D. et al.Congenital toxoplasmosis in France and the United States: one parasite, two diverging approaches.PLoS Negl Trop Dis. 2017; 11: e0005222Crossref PubMed Scopus (64) Google Scholar, 33American College of Obstetricians and GynecologistsPractice Bulletin no. 151: Cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy.Obstet Gynecol. 2015; 125: 1510-1525Crossref PubMed Scopus (100) Google Scholar In countries, which includes the United States, where systematic serologic screening is not recommended, severe disease alarmingly is still seen.34Olariu T.R. Remington J.S. McLeod R. Alam A. Montoya J.G. Severe congenital toxoplasmosis in the United States: clinical and serologic findings in untreated infants.Pediatric Infect Dis J. 2011; 30: 1056-1061Crossref PubMed Scopus (112) Google Scholar However, it is common for clinicians in the United States to express their surprise to reports of severe disease because they rarely see congenital toxoplasmosis in their daily practices. Two major reasons may explain the reason that congenital toxoplasmosis is not seen more frequently in clinical practices but only in reference centers such as the Palo Alto Medical Foundation Toxoplasma Serology Laboratory (http://www.pamf.org/Serology/). Toxoplasma seroprevalence (as an indirect evidence of the parasite circulating in a region) has been declining over decades,35Jones J.L. Kruszon-Moran D. Elder S. et al.Toxoplasma gondii Infection in the United States, 2011-2014.Am J Trop Med Hyg. 2018; 98: 551-557Crossref PubMed Scopus (56) Google Scholar which make it more difficult for individual practitioners to see the still existing burden of the disease. Moreover, the placenta does a much better job than we think and better than any medical intervention to safeguard the fetal brain from Toxoplasma gondii36Robert-Gangneux F. Murat J.B. Fricker-Hidalgo H. Brenier-Pinchart M.P. Gangneux J.P. Pelloux H. The placenta: a main role in congenital toxoplasmosis?.Trends Parasitol. 2011; 27: 530-536Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and, for that matter, from any other infection.37Doran K.S. Banerjee A. Disson O. Lecuit M. Concepts and mechanisms: crossing host barriers.Cold Spring Harb Perspect Med. 2013; 3: a010090Crossref PubMed Scopus (66) Google Scholar, 38Robbins J.R. Bakardjiev A.I. Pathogens and the placental fortress.Curr Opin Microbiol. 2012; 15: 36-43Crossref PubMed Scopus (166) Google Scholar Thanks to the placenta “fortress,” even in those women who seroconvert, transmission does not occur in a significant group of them.38Robbins J.R. Bakardjiev A.I. Pathogens and the placental fortress.Curr Opin Microbiol. 2012; 15: 36-43Crossref PubMed Scopus (166) Google Scholar Based on the published literature, starting with the first observations by Desmonts and Couvreur3Desmonts G. Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies.N Engl J Med. 1974; 290: 1110-1116Crossref PubMed Scopus (460) Google Scholar in the 1970s to the most recent ones,1Mandelbrot L. Kieffer F. Sitta R. et al.Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.Am J Obstet Gynecol. 2018; 219: 386-387.e1-9Abstract Full Text Full Text PDF Scopus (50) Google Scholar, 13Prusa A.R. Kasper D.C. Pollak A. Gleiss A. Waldhoer T. Hayde M. The Austrian Toxoplasmosis Register, 1992-2008.Clin Infect Dis. 2015; 60: e4-e10Crossref PubMed Scopus (46) Google Scholar systematic screening for toxoplasmosis, as we do for other rare diseases such as Rubella (https://www.acog.org/Patients/FAQs/Routine-Tests-During-Pregnancy#why), should be performed for every pregnant woman where Toxoplasma infection is known to occur because congenital toxoplasmosis can result in devastating neurologic and ocular consequences and death and because congenital toxoplasmosis is preventable and treatable in utero. The Figure provides a proposed algorithm of such a program. An important additional concern is cost, which will have to be addressed by each country. In the United States, Stillwaggon et al39Stillwaggon E. Carrier C.S. Sautter M. McLeod R. Maternal serologic screening to prevent congenital toxoplasmosis: a decision-analytic economic model.PLoS Negl Trop Dis. 2011; 5: e1333Crossref PubMed Scopus (87) Google Scholar has shown that routine serologic screening during pregnancy, as it is performed monthly in France, is feasible and cost-saving, with the assumption that the cost of serologic screening is contained. Novel developments in serologic testing that include less expensive point-of-care technology40Begeman I.J. Lykins J. Zhou Y. et al.Point-of-care testing for Toxoplasma gondii IgG/IgM using Toxoplasma ICT IgG-IgM test with sera from the United States and implications for developing countries.PLoS Negl Trop Dis. 2017; 11: e0005670Crossref PubMed Scopus (33) Google Scholar and plasmonic-based diagnostic platforms41Pomares C. Zhang B. Arulkumar S. et al.Validation of IgG, IgM multiplex plasmonic gold platform in French clinical cohorts for the serodiagnosis and follow-up of Toxoplasma gondii infection.Diagn Microbiol Infect Dis. 2017; 87: 213-218Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar could meet the technologic and cost challenges that are associated with massive screening. The question should not be anymore, to treat or not to treat, but what to treat with. The glass is sufficiently full in the areas of epidemiology, biology of the parasite and infection, efficacy of drugs, and laboratory science to implement systematic screening for toxoplasmosis, even if the glass will remain half empty because of the lack of placebo-controlled RCTs. Same as for penicillin or ceftriaxone for pneumococcal pneumonia, no ethical clinician or investigator will ever call for a placebo arm in the treatment of pneumococcal pneumonia because placebo-controlled clinical trials were never performed. It is time to not leave anymore pregnant women who silently seroconvert for toxoplasmosis during gestation in the equivalence of a placebo arm. I thank Andrés J. Montoya for technical assistance in creating the Figure and those investigators who have dedicated their lives to the field of toxoplasmosis and whose contributions made possible our better understanding of Toxoplasma infection during pregnancy who include but are not limited to Jack S. Remington, Philippe Thulliez, Jitender P. Dubey, John Boothroyd, Rima Mcleod, David Sibley, Florence Robert-Gangneux, Francois Peyron, Martine Wallon, Herve Pelloux, François Kieffer, Isabelle Villena, Ermanno Candolfi, Lauren Mandelbrot, Pierre Marty, Valeria Meroni, and Christelle Pomares; I honor the memory of those who are not with us any longer: Pierre Ambroise Thomas, Leon Jacobs, George Desmonts, Fausto Araujo, Jacques Couvreur, Francis Derouin, J.K. Addison Beverley, and Jack Frenkel. Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trialAmerican Journal of Obstetrics & GynecologyVol. 219Issue 4PreviewThe efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. Full-Text PDF