Purpose
To investigate whether recurrence rates of ocular toxoplasmosis are higher during pregnancy in women of childbearing age.
Design
Retrospective longitudinal cohort study.
Methods
We reviewed medical records of all women seen at a university eye clinic (Utrecht, Netherlands) during episodes of active toxoplasmic retinochoroiditis that occurred while the women were of childbearing age (16–42 years). Each woman was sent a questionnaire requesting information regarding all pregnancies and episodes of ocular toxoplasmosis, whether or not episodes were observed at the eye clinic. Conditional fixed-effects Poisson regression was used to model incidence rate ratios of recurrence during pregnant versus nonpregnant intervals, adjusted for potential confounders, including age at time of active toxoplasmic retinochoroiditis and interval since last episode of active disease, which are known to influence risk for recurrence.
Results
Questionnaires were returned by 50 (58%) of 86 women, 34 of whom had had 69 pregnancies during 584 person-years of study. There were 128 episodes of ocular toxoplasmosis during the study period (6 during pregnancy). First episodes of ocular toxoplasmosis occurred between ages 9.6 and 38.5 years. The youngest age at pregnancy was 16.1 years; the oldest age at childbirth was 40.9 years. The incidence-rate ratios for pregnant versus nonpregnant intervals were in the direction of lower recurrence rates during pregnancy, with point estimates of 0.54 and 0.75 under 2 different approaches, but the ratios were not significantly different from the null value ( P values of 0.16 and 0.55).
Conclusions
Recurrence rates of ocular toxoplasmosis are probably not higher during pregnancy, in contrast to traditional beliefs.
Ocular toxoplasmosis is characterized by periodic recurrences of active disease. It is commonly believed that women with histories of ocular toxoplasmosis are at increased risk for recurrent ocular disease during pregnancy, although there has been little objective evidence to support that belief. The reasons toxoplasmic retinochoroiditis lesions reactivate are unknown. It has been suggested that hormonal changes play a role in disease recurrences, which might explain an association with pregnancy. Pregnancy is believed to affect other forms of uveitis as well.
Most episodes of recurrent disease occur in people between the ages of 20 and 40 years; for women, this time interval represents the childbearing years. Risk for recurrent ocular toxoplasmosis during pregnancy is an especially important issue because active toxoplasmic retinochoroiditis during pregnancy poses unique therapeutic challenges. We sought to clarify the risk for ocular toxoplasmosis during pregnancy by investigating whether recurrence rates are greater during pregnancy than during nonpregnant periods in women of childbearing age.
Methods
We performed a retrospective review of medical records for all female patients with active toxoplasmic retinochoroiditis examined at the Department of Ophthalmology of the University Medical Centre in Utrecht, the Netherlands, from 1995 through 2005. Each eligible patient was sent a questionnaire asking for the dates of all childbirths, miscarriages, and known episodes of active toxoplasmic retinochoroiditis. They were specifically asked whether any episodes of active toxoplasmic retinochoroiditis occurred during pregnancy. An attempt was made to locate nonresponders by telephone or through their general practitioners. Reported data were confirmed with hospital records, if available. This retrospective study was approved by institutional review boards at the University Medical Center, Utrecht, Netherlands, and at UCLA prior to commencement of the study. The requirement of informed patient consent was waived for all aspects of the study. For authors in the United States, the study was in accordance with Health Insurance Portability and Accountability Act regulations.
Women with retinochoroidal scars alone were not considered if no episodes of active retinochoroiditis were observed during the study period, even if the scars were consistent with past episodes of toxoplasmic retinochoroiditis, because such scars are nonspecific, and we could not rule out other potential causes. Excluded from further analysis were patients who were not examined during their potential childbearing years, as defined below. Extensive demographic, medical and ophthalmic information was available about each patient from a pre-existing database maintained at the study institution.
Study Definitions
Active toxoplasmic retinochoroiditis was diagnosed on the basis of a discrete focus of retinal inflammation and necrosis, as described previously for clinical studies. The presence of inflammatory cells in the anterior chamber or vitreous humor without an active retinal lesion was not considered to be an episode for study purposes. Sites of active retinal inflammation did not have to arise from pre-existing retinochoroidal scars for inclusion in the study; such primary lesions , if seen at the first observed episode, may be associated with a newly acquired infection but are believed to result more commonly from reactivation of clinically inapparent tissue cysts already present in the retina following a remote infection. For simplicity, we refer to all episodes as recurrences in this article.
For study purposes, we arbitrarily defined the childbearing years to extend from 16 years of age through 42 years of age. We defined the duration of a pregnancy that ended in a live birth to be 266 days, based on a mean gestational age for singletons of 38.7 weeks (available at http://www.cdc.gov/Features/dsAvgPregnancyDuration ), and we adjusted it downward slightly for multiple births. We defined the duration of a pregnancy that ended in a miscarriage to be 70 days, based on the fact that most miscarriages occur during the first trimester.
A study period was established for each patient in a way that captured the time interval during childbearing years when the patient was at risk for active toxoplasmic retinochoroiditis. Patients were considered to be at risk for recurrence after serologic confirmation of Toxoplasma gondii infection or documentation of active retinochoroiditis or retinal scars consistent with past episodes of active retinochoroiditis. For the primary analysis (approach 1; see description below), we defined the start of the study period as the earliest date on which the patient was known to be at risk for recurrence or 16 years of age, whichever was later. For patients with congenital disease, the study period was defined as starting at 16 years of age. We defined the end date of the study period as the latest date for which information about both ocular disease and pregnancies was available or 42 years of age, whichever was earlier. In our sensitivity analysis (approach 2; see description below), we used an alternative start date for the study period, which was defined as beginning after the resolution of an episode, if the study period started with an episode of active retinochoroiditis.
Data Collection and Study Analyses
The following information was collected from the pre-existing database for each included patient: age at first observed episode of toxoplasmic retinochoroiditis (and date of that episode so as to establish temporal relationships with all subsequent events); whether retinochoroidal scars were already present at the first observed episode; the mode of initial T. gondii infection (congenital vs postnatally acquired), if known; and the presence or absence of anti- T. gondii IgG and IgM antibodies, if known. We recorded whether additional tests were performed on intraocular fluids to confirm intraocular T. gondii infection. Based on the questionnaires, we determined for each included patient the total number of pregnancies (and dates for each); whether each pregnancy resulted in a live birth or miscarriage; and the total number of known episodes of active toxoplasmic retinochoroiditis (and dates for each), whether or not the episode had previously been observed and entered into our existing database.
In our primary analysis (approach 1), each patient’s study period was divided into pregnant and nonpregnant at-risk intervals, and the unadjusted rate of recurrence during pregnancy was calculated as number of recurrences that started during a pregnancy divided by total duration of pregnant at-risk intervals; the unadjusted rate of recurrence during nonpregnant at-risk intervals was calculated in a similar manner. We removed the durations of episodes of active retinochoroiditis from study intervals based on the assumption that patients are not at risk for a recurrence during an active episode.
As a sensitivity analysis (approach 2), we repeated the calculations using the alternative start date for the study period, as defined above. The motivation for this alternative was to avoid inflating the rate of recurrence during nonpregnant at-risk intervals. Most first episodes occurred while patients were not pregnant and of younger age, by definition, but the period of risk before these attacks was unknown and was not included; thus, the rate of recurrence during nonpregnancy periods could be inflated by starting the study interval at the time of first episode. Confounding by younger age was also possible.
Multivariate analysis was conducted in order to compare rates of recurrence during pregnant and nonpregnant at-risk intervals, adjusting for potential confounders, including patient age at the time of recurrence and interval since last episode of active retinochoroiditis. As additional determinations of sensitivity, we repeated the analyses while omitting each patient so as to assess for undue influence and while omitting patients known to have congenital disease.
Statistical Techniques
The Wilcoxon matched-pair signed rank test, a nonparametric analogue of the paired t test, was used to test the hypothesis that the unadjusted rate of recurrence was the same during pregnant and nonpregnant at-risk intervals.
Because the dependent variable was a rate (number of episodes per unit time during pregnant and nonpregnant at-risk intervals), Poisson regression was used to conduct adjusted analysis. Effects of predictors were expressed as incidence rate ratios, which provide the estimated multiplicative change in the event rate when the predictor is increased by 1 unit. To conduct these analyses, the study period for each patient was broken into subintervals associated with different values of predictor variables, creating multiple observations per patient, and a conditional fixed-effects Poisson regression was used. This technique utilizes within-individual differences to estimate effects; each patient was used as her own control, and all time-stable characteristics (age at onset of infection and mode of acquisition) were automatically controlled for and thus did not need to be entered into the model. This feature is a major advantage of the technique because it controls for both measured and unmeasured time-stable variables that could be confounding factors. These models are appropriate for estimating the effect of time-varying characteristics, including pregnant/nonpregnant status, which was the main characteristic of our interest. As control variables, we included average age during the subinterval and years since last episode of active retinochoroiditis, calculated with reference to average age during the subinterval. We also repeated the analyses using random effects Poisson regression and negative binomial regression.
A P value of <0.05 was considered to be statistically significant.
Results
A total of 86 women with 1 or more episodes of active toxoplasmic retinochoroiditis during childbearing years had been seen at our institution during the years covered by our dataset. Of these 86 women, 50 (58%) responded to the questionnaire and were included in this study. The earliest pregnancy among study participants occurred at age 16.1 years; the oldest age at which childbirth occurred was 40.9 years.
Characteristics of the study participants are shown in Table 1 . The mean age at first documented episode of active retinochoroiditis (25.4 ± 7.3 years) was early in the childbearing period. The first documented episodes occurred before the age of 16 years in 7 patients (14%). In a large proportion of patients (n = 39; 78%), the first observed episode of active retinochoroiditis arose from a pre-existing retinochoroidal scar, indicating an earlier infection. None of the study participants had been treated with long-term antiparasitic drug therapy as secondary prophylaxis to prevent future recurrences.
| Characteristic | Value |
|---|---|
| Age at first observed episode (years) | |
| Mean ± SD | 25.4 ± 7.3 |
| Range | 9.6–38.5 |
| Laterality of toxoplasmic retinochoroiditis (n, percentage) | |
| Unilateral | 48 (96%) |
| Bilateral | 2 (4%) |
| Mode of infection (n, percentage) | |
| Congenital | 4 (8%) |
| Acquired | 2 (4%) |
| Unknown | 44 (88%) |
| Retinal scars at initial examination (n, percentage) | |
| Yes | 39 (78%) |
| No | 2 (4%) |
| Unknown | 9 (18%) |
| IgM anti- T. gondii antibodies (n, percentage) | |
| Positive | 1 (2%) |
| Negative | 26 (52%) |
| Unknown | 23 (46%) |
| IgG anti- T. gondii antibodies (n, percentage) | |
| Positive | 33 (66%) |
| Unknown | 17 (34%) |
| Study periods a (years) | |
| Median | 11.7 |
| Range | 0.3–26 |
| Total number of episodes of active toxoplasmic retinochoroiditis during study periods | 128 |
| Total number of episodes of active toxoplasmic retinochoroiditis that began during pregnancy | 6 |
| Any pregnancies (including miscarriages) during study periods (n, percentage) | 34 (78%) |
| Pregnancies resulting in childbirth during study periods, per patient (n, percentage) | |
| 0 | 17 (34%) |
| 1 | 13 (26%) |
| 2 | 15 (30%) |
| 3 | 5 (10%) |
| Pregnancies resulting in miscarriage during study periods, per patient (n, percentage) | |
| 0 | 41 (82%) |
| 1 | 7 (14%) |
| 2 | 2 (4%) |
| Episodes of active toxoplasmic retinochoroiditis during study periods, per patient (n, percentage) | |
| 0 | 2 (4%) |
| 1 | 20 (40%) |
| 2 | 9 (18%) |
| 3 | 8 (16%) |
| 4 or more | 10 (20%) |
a The study period was defined as the interval during childbearing years (16–42 years of age) during which patients were at risk for active toxoplasmic retinochoroiditis. The start date was the age of 16 years for patients known to have had congenital infections; for all others, the start date was defined by the first observation of active retinochoroiditis (or retinochoroidal scars consistent with past episodes of toxoplasmosis) or the age of 16 years, whichever was later; the end date was the age of 42 years or at last contact with patient if younger than 42 years.
The median time over which histories of toxoplasmic retinochoroiditis and pregnancies was collected was 15 years (range, 2.5–40.8 years). When these times were confined to the known pregnant/nonpregnant at-risk intervals, the median study period was 11.7 years (range, 0.3–26 years). The total study period for all patients was 584 person-years; 44.8 of these person-years occurred during pregnant states.
The number of recurrences during study periods ranged from 0 for 2 patients to 11 for 2 patients. The total number of recurrences during study periods over all patients was 128; 6 of these recurrences began during pregnancies. In all episodes of recurrent toxoplasmic retinochoroiditis reported by study participants, the patients had been seen by an ophthalmologist, and the visits were documented in medical records. In 6 cases, the diagnoses were confirmed by study of the aqueous humor (5 showed evidence of intraocular anti- T. gondii antibody production and 1 showed evidence of parasitic DNA using the polymerase chain reaction technique). There were no documented recurrences during pregnancies that resulted in miscarriages.
The unadjusted recurrence rates during pregnant and nonpregnant at-risk intervals are shown in Table 2 . A total of 34 included patients had at least 1 pregnancy ending in either live birth or miscarriage during their study periods. In unadjusted analysis, recurrence rates were significantly lower during the pregnant at-risk intervals. Mean recurrence rates during pregnant at-risk intervals were 0.22 ± 0.67 and 0.14 ± 0.54 episodes per year under approaches 1 and 2, respectively, whereas mean recurrence rates during nonpregnant at-risk intervals were 0.47 ± 0.96 and 0.17 ± 0.17 episodes per year, respectively ( P values were <0.05 for both approaches).
| Approach | Recurrence Rate During Pregnant at-risk Periods a (episodes/year) | Recurrence Rate During Non-pregnant at-risk Periods (episodes/year) | P Value b | ||||
|---|---|---|---|---|---|---|---|
| Mean ± SD | Median | Range | Mean ± SD | Median | Range | ||
| 1 c | 0.22 ± 0.67 | 0.00 | 0–2.99 | 0.47 ± 0.96 | 0.23 | 0–6.67 | .03 |
| 2 d | 0.14 ± 0.54 | 0.00 | 0–2.99 | 0.17 ± 0.24 | 0.10 | 0–1.26 | .007 |
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