¶ Membership of EMSCOT is provided in the Acknowledgments.
The authors have declared that no competing interests exist.
An observational study by Ruth Gilbert and colleagues finds that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop serious neurological sequelae.
The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.
Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07–0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2–15) after maternal seroconversion at 10 weeks, and 18 (9–75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21–2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%–38.1%).
The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection.
Toxoplasmosis is a very common parasitic infection. People usually become infected with
Clinicians can find out if a woman has been infected with
The researchers followed 293 children in whom congenital toxoplasmosis had been identified by prenatal screening (in France, Austria, and Italy) or by neonatal screening (in Denmark, Sweden, and Poland) for an average 4 years. Two-thirds of the children received prenatal treatment for toxoplasmosis and 23 fetuses (8% of the fetuses) developed SNSD; nine of these cases of SNSD were terminated during pregnancy. By comparing the number of cases of SNSD among children who received prenatal treatment with the number among children who did not receive prenatal treatment, the researchers estimate that prenatal treatment reduced the risk of SNSD by three-quarters. They also estimate that to prevent one case of SNSD after maternal infection at 10 weeks of pregnancy, it would be necessary to treat three fetuses with confirmed infection. To prevent one case of SNSD after maternal infection at 30 weeks of pregnancy, 18 fetuses would need to be treated. Finally, the researchers report that the effectiveness of pyrimethamine-sulfonamide and spiramycin (which is less toxic) was similar, and that a third of live-born infants with brain damage that was detected after birth subsequently developed SNSD.
These findings suggest that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop SNDS and would be particularly effective in fetuses whose mothers acquired
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Congenital toxoplasmosis occurs when a woman first acquires
We used variation in screening practices across Europe to determine the effect of prenatal treatment on SNSD. Our data derive from two prospective cohort studies in 14 centres in six European countries
We studied infected fetuses that were prospectively identified by universal prenatal screening and newborn screening for congenital toxoplasmosis
Infected fetuses were enrolled into the study after confirmation of a positive prenatal screening test in France, Austria, and Italy, or neonatal screening test in Denmark, Sweden, or Poland. Screening and treatment schedules are summarized in
Prenatal Screening | France | Austria | Italy | All Prenatal Screening |
1996–1999 | 1996–2000 | 1996–2000 | ||
Lyon, Paris, Marseille, Toulouse, Nice, Reims, Grenoble | Vienna | Milan, Naples | ||
Testing regimen | PN monthly retesting | PN + retesting at 12, 20, 32 wk | PN monthly (Milan) or 3-monthly (Naples) retesting | |
First prenatal treatment | Spiramycin | P&S after 15 wk | Spiramycin | |
182 | 24 | 15 | 221 | |
Percent treated prenatally | 85 | 88 | 93 | 86 |
SNSD cases | 2+9 terminations | 1 | 2 | 14 |
Median imputed GASC (IQR) | 29.0 (23.0–33.1) | 18.8 (17.3–25.9) | 18.5 (16.2–20.4) | 27.3 (19.7–32.4) |
Median interval (IQR) | 4.0 (5.0–8.0) | 17.1 (11.9–20.5) | 12.6 (9.1–14.1) | 5.4 (4.1–11.4) |
Total treated | 135 | 21 | 14 | 189 |
Percent spiramycin as first treatment | 88 | 10 | 93 | 79 |
Median imputed GASC to treatment interval, wk (IQR) | 2.9 (2.3–4.0) | 11.0 (7.9–13.0) | 5.9, (4.9–7.0) | 3.1 (2.6–5.7) |
4.0 (3.2–4.8) | 4.3 (4.0–5.1) | 4.0 (1.0–4.1) | 4.0 (3.2–4.7) |
Neonatal Screening | Sweden | Poland | Denmark | Denmark 1992–1996 | All Neonatal Screening |
1997–1998 | 1996–2000 | 1997–2000 | 1992–1996 | ||
Stockholm, South Sweden | Poznan | Copenhagen | National study | ||
Testing regimen | Neo, IgGR and IgM | Neo, IgM and IgA | Neo, IgM and IgA | Neo, IgGR and IgM | |
First prenatal treatment | |||||
3 | 29 | 14 | 26 | 72 | |
Percent treated prenatally | 0 | 0 | 0 | 0 | 0 |
SNSD cases | 1 | 4 | 1 | 3 | 9 |
Median imputed GASC (IQR) | 27.9 (27.3–27.9) | 27.6 (26.9–29.4) | 26.9 (26.9–27.5) | 27.5 (26.8–29.6) | 27.3 (26.9–29.2) |
Median interval (IQR) | 28.1 (26.1–30.6) | 38.4 (36.4–40.6) | 40.0 (40.0–40.0) | 31.1 (29.2–32.4) | 36.4 (31.5–40.0) |
3.9 (3.8–4.6) | 4.1 (3.9–4.3) | 3.5 (3.2–3.9) | 6.3 (4.9–6.4) | 4.2 (3.5–6.1) |
IgGR involves detection of IgG seroconversion by comparing neonatal sample with prenatal booking sample from mother.
Neo, neonatal screening based on detection of specific antibodies in Guthrie card bloodspots; P&S, pyrimethamine and sulphonamide; PN, prenatal screening.
Details recorded during pregnancy included the date of the first abnormal or last normal fetal ultrasound scan, the results of PCR testing of amniotic fluid for toxoplasma DNA, autopsy findings for terminated fetuses, and the start and end dates of any prenatal treatment. Mothers of infants detected in neonatal screening centres were not treated. The variation between centres in the delay before starting prenatal treatment after maternal seroconversion and in the use of spiramycin or pyrimethamine-sulphonamide combinations as first-line treatment is shown in
The primary outcome was serious neurological sequelae or death (SNSD), a composite outcome, comprising a pediatric report at any age of microcephaly, insertion of intraventricular shunt, an abnormal or suspicious neurodevelopmental examination that resulted in referral to a specialist, seizures during infancy or at an older age that required anticonvulsant treatment, severe bilateral visual impairment (visual acuity of Snellen 6/60 or less in both eyes assessed after 3 y), cerebral palsy, or death from any cause before 2 y of age including termination of pregnancy
In order to avoid well-known biases introduced by imputing a covariate as an unadjusted midpoint for interval values of the gestational age at maternal seroconversion (GASC), we imputed values for GASC using all the serological information available to us
For babies identified by neonatal screening, maternal seroconversion was based on an adjusted midpoint between conception, or in Sweden and Denmark 1992–1996, between the first prenatal booking sample and birth, using a previously reported log linear regression model
All live births had at least one pediatric assessment during infancy (up till 12 mo old). Children with a normal pediatric examination during infancy who were subsequently lost to follow-up were assumed to have no SNSD
We used WinBUGS version 1.4.3 to estimate odds ratios for the effect of prenatal exposures on SNSD. All models were adjusted for GASC
Probability of SNSD according to imputed gestational age at seroconversion and 95% Bayesian credible limits: dotted lines denote treated pregnancies; solid lines denote untreated pregnancies.
The posterior probability distributions of SNSD for each level of exposure were calculated using Markov Chain Monte Carlo (MCMC) iterations. We used noninformative priors in two mixing Markov chains with different starting values and allowed 1,000 MCMC burn-in iterations; estimates of all posterior distributions were based on 10,000 realizations of each chain. A linear transformation was applied to the imputed values of gestational age at maternal seroconversion by centering around its mean; this improved the MCMC convergence, assessed by the method proposed by Brooks and Gelman
Sensitivity analyses were used to determine the robustness of the findings to different assumptions. First we explored under-reporting of terminations by excluding data from Austria and Italy, as no terminations were reported for these centres. We also determined whether adding 18 unreported terminated fetuses to the analyses would alter the treatment effect. The 18 unreported fetuses had the same characteristics (GASC and prenatal treatment delay) as the nine terminated fetuses included in the study. Second, we estimated the effect of treatment under the extreme assumption that all terminated fetuses would have been born alive and would have developed normally. We revised this analysis assuming that the three fetuses with normal fetal ultrasound scans and no evidence of disseminated infection would have developed normally, even though two fetuses had their last scan before 21 wk of gestation. Third, we reclassified three live-born, untreated children with SNSD but without intracranial calcification as no SNSD. This reclassification restricted the outcome of SNSD to cases almost certainly attributable to congenital toxoplasmosis. Fourth, we explored potential error in the imputed gestational age at maternal seroconversion for children identified by neonatal screening by assuming seroconversion 1 mo earlier.
We calculated the number of women needed to be treated (NNT) to prevent one case of SNSD as a clinically meaningful measure for counseling women about the absolute difference in the probability of their child developing SNSD with and without treatment. We used the posterior probability distributions and 95% credible interval calculated from the regression model to estimate the NNT for women after a positive prenatal diagnosis (i.e., the number of women with an infected fetus who need to be treated). To estimate the NNT for women without prenatal diagnosis, we multiplied the difference in probability with the estimated risk of mother to child transmission of toxoplasmosis derived from a meta-analysis of all available cohort studies
To inform prognostic counseling for parents of live-born babies, we determined the probability of SNSD according to an exclusive hierarchy of postnatal clinical manifestations (ventricular dilatation and/or intracranial calcification, lymphadenopathy or hepatosplenomegaly, and/or retinochoroiditis) that would be apparent after pediatric examination, ophthalmoscopy, and postnatal cranial ultrasound completed by 6 mo postnatal age
Research ethics approval was granted in countries where screening was offered as part of a research study
The combined cohorts comprised 293 infected fetuses, of whom 284 were born alive. 23 fetuses consisting of nine terminated pregnancies and 14 live-born children died or were classified as having serious neurological sequelae (
Characteristic | Neonatal screened ( |
Prenatal screened ( |
Treated prenatally | 0 | 4 |
Abnormal fetal ultrasound | 2 (4 NR) | 3 |
Gestational age at birth | 26–42 wk | 34–39 |
Intracranial lesions (postnatal cranial ultrasound) | 7 | 4 |
Retinochoroidits | 5 (1 NR) | 4 |
Lymphadenopathy/hepatosplenomegaly | 2 (3 NR) | 3 |
Death before 2 y | 3 | 1 |
Microcephaly, seizures, or shunt required | 5 | 4 |
Cerebral palsy or abnormal neurological development |
5 | 3 |
Ocular complications |
5 | 5 |
Blindness (≤6/60) | 1 (4 NR) | 2 (1 NR) |
Abnormal or suspicious neurological examination leading to referral to a specialist.
Ocular microphthalmia (
NR, not reported.
Characteristic | Abnormal Fetal Ultrasound |
Normal Fetal Ultrasound ( |
Gestational age at maternal seroconversion (wk) | 10–17 | 8–13 |
Gestational age at first abnormal or last normal fetal ultrasound (wk) | 21–30 | 11–23 |
Termination of pregnancy (wk of gestation) | 22–33 | 12–24 |
Autopsy findings ( |
||
Macroscopic examination not reported | 1 | 3 |
Intracranial abnormalities | 1 | — |
Myocarditis, pneumonitis, disseminated disease | 1 | 1 |
Nil abnormal found | 2 | — |
All fetuses had positive PCR detection of
Intracranial calcification or ventricular dilatation on fetal ultrasound scan.
Of the 221 women identified by prenatal screening, 86% (189/221) received prenatal treatment, most (71%, 134/189) within 5 wk of the imputed date of maternal seroconversion (
The characteristics of the 23 fetuses with SNSD are summarized in
Three prenatal factors strongly predicted serious neurological sequelae: the gestational age at maternal seroconversion, prenatal treatment, and an abnormal fetal ultrasound of the brain (
Characteristic | Total Infected Fetuses ( |
Fetuses with SNSD ( |
Odds Ratio for SNSD |
95% BCI | Estimated proportion (%) with SNSD |
95% BCI | |
Terminated | Live Birth | ||||||
293 | 9 | 14 | 7.73 | (5.11–11.21) | |||
Per week of gestation | 0.904 | 0.855–0.953 | |||||
≤20 wk | 57 | 9 | 4 | Ref. | — | 22.81 | 13.00–34.29 |
>20 wk | 236 | 0 | 10 | 0.290 | 0.148–0.520 | 4.12 | 2.03–7.12 |
Neonatal | 72 | 0 | 9 | Ref. | — | 14.95 | 7.42–25.69 |
Prenatal | 221 | 9 | 5 | 0.170 | 0.046–0.534 | 2.90 | 1.04–6.12 |
France | 182 | 9 | 2 | Ref. | — | 3.18 | 1.14–6.75 |
Italy/Austria | 39 | 0 | 3 | 0.444 | 0.083–1.784 | 1.42 | 0.23–5.56 |
Scandinavia | 43 | 0 | 5 | 4.798 | 1.202–19.24 | 13.58 | 5.05–27.29 |
Poland | 29 | 0 | 4 | 5.981 | 1.28–26.94 | 16.40 | 5.21–34.62 |
Term | 246 | 0 | 10 | Ref. | — | 3.82 | 1.91–6.79 |
Preterm | 38 | 9 | 4 | 2.679 | 0.653–9.195 | 9.62 | 2.87–22.08 |
5 unknown | |||||||
Girl | 130 | 2 | 5 | Ref. | — | 3.46 | 1.24–7.66 |
Boy | 154 | 2 | 9 | 1.625 | 0.524–5.381 | 5.51 | 2.64–9.89 |
Normal | 204 | 4 | 2 | Ref. | — | 0.59 | 0.71–2.28 |
Any abnormality | 14 | 5 | 3 | 120 | 7.035–6400 | 42.63 | 6.09–90.16 |
Untreated | 104 | 0 | 10 | Ref. | — | 11.99 | 6.02–20.82 |
Treated | 189 | 9 | 4 | 0.236 | 0.071–0.708 | 3.11 | 1.21–6.47 |
Spiramycin only | 87 | 5 | 2 | Ref. | — | 2.37– | 0.48–7.62 |
Any P&S treatment | 102 | 4 | 2 | 0.777 | 0.204–2.849 | 1.84 | 0.43–5.39 |
≤35 d | 134 | 6 | 1 | Ref. | — | 0.45 | 0.02–2.54 |
>35 d | 55 | 3 | 3 | 0.7581 | 0.190–2.862 | 2.83 | 0.34–11.00 |
Adjusted for gestational age at maternal seroconversion.
Sample restricted to live births.
Sample restricted to mother-child pairs in prenatal centres who had fetal ultrasound (218/221).
Sample restricted to those prescribed prenatal treatment.
P&S, pyrimethamine and sulphonamide treatment.
Prenatal treatment substantially reduced the risk of serious neurological sequelae. The adjusted odds ratio for any prenatal treatment compared with no treatment was 0.236 (95% BCI 0.071–0.708), and the average risk difference between treated and untreated mothers was 8.7% (2.0%–18.1%) (
Rationale for Sensitivity Analysis | Infected Fetuses |
SNSD ( |
Univariable Model | Multivariable Model | ||||
GASC | Adjusted GASC | Prenatal Treatment Versus None | ||||||
OR | 95% BCI | OR | 95% BCI | OR | 95% BCI | |||
Bayesian estimate | 293 | 23 | 0.904 | (0.855–0.953) | 0.866 | (0.806–0.925) | 0.236 | (0.071–0.708) |
Ordinary logistic regression | 293 | 23 | 0.903 | (0.857–0.953) | 0.870 | (0.814–0.930) | 0.248 | (0.081–0.756) |
Excluding Italy and Austria | 254 | 11 | 0.882 | (0.829–0.936) | 0.819 | (0.741–0.889) | 0.123 | (0.025–0.461) |
Addition of 18 fictitious unreported terminations | 311 | 41 | 0.849 | (0.806–0.889) | 0.817 | (0.763–0.867) | 0.294 | (0.096–0.850) |
No terminations have SNSD | 293 | 14 | 0.999 | 0.931–1.082) | 0.948 | (0.870–1.035) | 0.136 | (0.029–0.498) |
Terminations with normal fetal ultrasound and no disseminated disease have no SNSD | 293 | 20 | 0.926 | (0.875–0.980) | 0.890 | (0.829–0.951) | 0.226 | (0.067–0.692) |
Three live births without intracranial lesions reclassified as not SNSD | 293 | 20 | 0.889 | (0.838–0.941) | 0.865 | (0.804–0.923) | 0.367 | (0.104–1.230) |
One live birth without intracranial lesions and no ocular signs reclassified as not SNSD | 293 | 22 | 0.902 | (0.853–0.952) | 0.871 | (0.811–0.927) | 0.287 | (0.085–0.858) |
Imputed GASC placed 1 mo earlier in neonatal screened. | 293 | 23 | 0.883 | 0.830–0.935) | 0.861 | (0.798–0.919) | 0.356 | (0.125–0.992) |
OR, odds ratio.
The nine terminated pregnancies in France made up most of the SNSD cases that seroconverted in the first trimester (
Among treated women, we found no evidence that delayed timing of treatment increased the proportion of fetuses with SNSD. However, the power to detect such an effect was limited. Moreover, most of the early treated fetuses with SNSD were pregnancy terminations (
Fetal ultrasound abnormality was associated with SNSD (adjusted odds ratio 120, 7.04–6400), partly because this was a criterion for pregnancy termination, and hence classification with SNSD. The earliest gestational age at detection of intracranial abnormality on fetal ultrasound was 21 wk in five terminated fetuses and 26 wk in five live-born fetuses (three with SNSD). All five live-born fetuses with intracranial abnormality on fetal ultrasound had intracranial calcification and/or ventricular dilatation on postnatal cranial ultrasound (specificity 178/178, 100%), but few babies with abnormal postnatal scans had intracranial abnormalities reported on fetal ultrasound (5/18, sensitivity 28%).
Postnatal Clinical Manifestations | Postnatal Clinical Manifestations Detected at ≤6 mo Old | |
SNSD | Total Infected | |
All three signs (brain/eye/LHS) | 4 | 4 |
Brain + eye | 3 | 7 |
Brain + LHS | 1 | 4 |
Brain only | 1 | 15 |
Total with brain lesions | 9 | 30 |
Proportion with SNSD (95% BCI) | 30.2% (13.7%–46.6%) | |
Eye + LHS | 0 | 1 |
Eye only | 0 | 13 |
LHS only | 0 | 6 |
None | 2 | 208 |
Total without brain lesions | 2 | 228 |
Proportion with SNSD (95% BCI) | 1.0% (0.0%–2.3%) |
Brain, intracranial calcification or ventricular dilatation detected on postnatal cranial ultrasound examination; eye, retinochoroiditis; LHS, lymphadenopathy or hepatosplenomegaly.
Sample excludes Danish cohort recruited 1992–1996.
Prenatal treatment substantially reduced the proportion of infected fetuses who developed SNSD. We found no evidence that a pyrimethamine-sulphonamide combination was more effective than spiramycin, which is less toxic
This is the first prospective cohort study, to our knowledge, to report the effect of prenatal treatment on serious neurological sequelae in fetuses with congenital toxoplasmosis. We minimized selective inclusion of pregnancies with complications ensuring that universal screening tests preceded prenatal treatment or diagnostic investigations for fetal infection status or abnormalities. Long-term follow-up and repeated pediatric assessments made it possible to ensure that, for the live births at least, SNSD were confirmed. In a retrospective study, Foulon et al. reported a similarly large effect of prenatal treatment on intracranial lesions and/or neurological sequelae detected up to 12 mo of age, but these results could have been explained by referral of untreated women with pregnancy complications to fetal medicine centres
Weaknesses of the study relate to selection biases inherent in observational studies. First, pregnancies terminated for fetal infection may not have been reported to the study
The benefits of prenatal treatment are high for women with a positive prenatal diagnosis for congenital toxoplasmosis. The NNT to prevent one case of SNSD varies from three to 18 depending on the gestational age at maternal seroconversion. As fetal diagnosis carries a risk of fetal loss due to amniocentesis, some women may prefer to trade a lower chance of benefit in order to avoid amniocentesis, provided a treatment such as spiramycin is used, which has no serious side effects
Termination of pregnancy should be limited to fetuses with abnormal intracranial ultrasound findings, otherwise the vast majority of terminations would involve unaffected fetuses; this means deferring termination until 22 wk or later as ultrasound abnormalities do not develop until 21 wk of gestation at the earliest
In terms of the type of treatment, our findings add to previous comparative studies, which have consistently found no evidence that pyrimethamine-sulphonamide combinations are more effective than the less toxic alternative of spiramycin
Whether the benefits of prenatal treatment translate into an effective prenatal screening program remains to be determined by a randomised controlled trial of prenatal screening. In the meantime, cost-effectiveness analyses that take into account regional variation in the prevalence of susceptible women, the incidence of maternal infection, the timing, uptake, and accuracy of repeated screening tests to detect maternal seroconversion, and the timing of prenatal treatment, could provide valuable information for policy makers and for research funders contemplating investment in a large trial.
Finally, our results relate to the relatively benign type II strain of
Interval for gestational age at seroconversion for pregnancies affected by SNSD. The vertical lines show the GASC interval for each pregnancy affected by SNSD (
(0.01 MB PDF)
Interval for gestational age at seroconversion for unaffected pregnancies. The vertical lines show the GASC interval for each unaffected pregnancy (
(0.01 MB PDF)
We are grateful to Rodolphe Thiébaut for contributing data on mother to child transmission from the SYROCOT study.
Writing committee: R.E. Gilbert (chair), M. Cortina-Borja, H.K. Tan, M. Wallon, M. Paul, A. Prusa, W. Buffolano, G. Malm, A. Salt, K. Freeman, E. Petersen.
Centres contributing data (including number of patients contributed to this report): S. Romand, P. Thulliez (68; Institut de Puericulture, Paris), M. Wallon, F. Peyron (47; Hôpital de la Croix Rousse, Lyon), E. Petersen, D. Schmidt (40; Statenseruminstitut, Copenhagen), M. Paul (29; University Medical Sciences, Poznan), A. Prusa, M. Hayde, A. Pollak (24; University Children's Hospital, Vienna), M.-H. Bessieres (23; Hôpital de Rangueil, Toulouse), J. Franck, H. Dumon (21; Hôpital de la Timone, Marseille), W. Buffolano, A. Romano (11; Università di Napoli, Naples), C. Chemla, I. Villena (9; Hôpital Maison Blanche, Reims), N. Ferret, P. Marty (8; Hôpital de l'Archet, Nice), H. Pelloux, H. Fricker-Hidalgo, C. Bost-Bru (6; Centre Hospitalier Universitaire de Grenoble), E. Semprini, V. Savasi (4; Milan), G. Malm, B. Evengard (3; Huddinge Hospital, Stockholm); Study design and coordination: R.E. Gilbert (principal investigator), H.K. Tan, K. Freeman, A. Salt; Statistical analysis: M. Cortina-Borja, H.K. Tan, K. Freeman, A.E. Ades.
Bayesian credible interval
gestational age at maternal seroconversion
immunoglobulin
interquartile range
number needed to treat
serious neurological sequelae or death