Toxoplasmosis Infection in Newborn: A Systematic Review and Meta-analysis

Abstract

Background:

Toxoplasmosis is a disease caused by Toxoplasma gondii, and one-third of the world's population has T. gondii antibodies. Due to this issue, the aim of this study was to assess the mean prevalence and odds ratios of T. gondii infection and epidemiological features of neonatal infection worldwide.

Materials and Methods:

We performed a meta-analysis and systematic review of published studies reporting T. gondii infection using the PubMed, MEDLINE, Web of Science, EMBASE, and Scopus electronic databases through January 1999 to December 2020, regarding diagnostic tests, and prevalence data of infection among the newborn population. The pooled prevalence of T. gondii with a 95% confidence interval (CI) was calculated using the random-effects models.

Results:

A total of thirty eligible articles were included. The estimated global prevalence rate was 44% (95% CI: 29%–0.58%); the highest prevalence rate was in America 47% (95% CI: 30%–64%), followed by Europe 41% (95% CI: 26%–57%) and Asia 33% (95% CI: 4%–61%). In this study, despite our careful analysis of possible modifiers, the heterogeneity was significant (P = 0.000). The publication bias was not significant based on the results of Egger's (P = 0.918) and Begg's tests (P = 0.230).

Conclusion:

Based on the results of this study, T. gondii infection can be a serious concern in newborns around the world. Therefore, further research is needed to provide better strategies to screen and diagnose T. gondii infection in neonates and determine the risk factors associated with the prevalence of infection in neonates worldwide.

INTRODUCTION

Toxoplasmosis is an infection caused by Toxoplasma gondii, a parasite infecting almost all homeothermic animals, such as humans. Toxoplasmosis is considered the most prevalent parasitic zoonotic disease worldwide.[1] Approximately 35% of the world's population has been estimated to be infected with T. gondii in their lifetime.[2] In the parasite life cycle, humans can play the role of intermediate hosts. In humans, the infection usually occurs through eating raw or undercooked meat containing viable tissue cysts and drinking the water and food contaminated with feces of infected cats, moreover it can also be transmitted from the mother to the embryo.[3,4,5] All felids can be the final hosts of T. gondii; infected cats excrete T. gondii oocytes through their feces.[6] T. gondii infection is traditionally asymptomatic and self-limiting in immunocompetent people; however, it can cause a variety of life-threatening clinical complications in immunocompromised individuals.[7]

In pregnant women, the parasite can cross the placental barrier and infect the developing fetus, often causing miscarriage or severe abnormalities such as low birth weight, hydrocephaly, microcephaly, and retinochoroiditis, if it happens during the first and second trimesters of pregnancy.[8,9] Infection in the third trimester of pregnancy is usually asymptomatic at birth, though intracranial calcification, hearing loss, and visual disturbances may occur in the later stages of life.[10] Factors influencing the transmission of toxoplasmosis infection from mother to infant during pregnancy include the time of transmission during pregnancy, immunological status of mother, fetal age, and the pathogenicity level of parasites transmitted to the fetus.[11] Therefore, the chance of exposure of fetus to Toxoplasma parasites depends on the socioeconomic, cultural, and health conditions.[12] Toxoplasmosis infection in fetus can be classified into acute and chronic forms. The parasite during the first and second trimesters of pregnancy can lead to severe symptoms, such as intracranial calcifications, abortion, low birth weight, hydrocephaly, and retinochoroiditis, which are recognizable at birth. In contrast, fetus infected in the third trimester of pregnancy does not show any symptoms of the disease at birth, however, they may develop intracranial calcifications, visual disorders, hearing impairments, and developmental delays later in life.[13,14,15,16]

The seroprevalence rates of T. gondii infection in general population and pregnant women worldwide have been reported to be 39.3% and 41.0%, respectively.[16,17] Precise estimations of the seroprevalence rate of toxoplasmosis in specific populations can help health-care organizations to control this infection and its consequences. With regard to mentioned information, the aim of the present study is to accurately estimate the prevalence of toxoplasmosis in the neonatal population worldwide.

MATERIALS AND METHODS

Search strategies and selection criteria

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to conduct the current study.[17] Five databases were searched (PubMed, MEDLINE, Web of Science, EMBASE, and Scopus) for all studies that probably contained data for T. gondii prevalence in neonates during January 1999 to December 2020. There was no language limitation. The databases were searched utilizing the keywords including “Toxoplasma gondii,” “Toxoplasma,” “toxoplasmosis,” “epidemiology,” “prevalence,” “newborn,” “neonate,” and “incidence.”

Inclusion and exclusion criteria

Initially, repetitious articles were removed and then original studies and brief reports were evaluated according to the following inclusion criteria: (1) investigation of T. gondii incidence in neonates worldwide, (2) evaluation of mothers and their infants, (3) diagnosis of toxoplasmosis by applying serological and molecular methods on the serum and cord blood, and (4) adoption of a cross-sectional design. The exclusion criteria were as follows: (1) publication in languages other than English or Persian, (2) inclusion of aborted fetuses, (3) irrelevancies, (4) lack of suitable data, and (5) review articles.

Study selection and data extraction

The review was authored by three independent authors. It includes studies which have been listed in the EndNote software (EndNote X9, Thomson Reuters, Boston, Massachusetts, USA) and screened based on the title, abstract, and full text. Finally, the search strategy results and the screening section briefly are shown in Figure 1.

Figure 1.

Flow diagram of the literature search and study selection

Data extraction

The data from thirty selected articles were imported to Excel software. The extracted variables included the name of the first author, the publication date, the country where the investigation has been done, the study design, sample type, number of samples, prevalence rate, and the conducted study methods.

Assessment of study quality

We evaluated the quality of included observational studies with the Newcastle–Ottawa Quality Assessment Scale.[18] The quality of each study was graded either low (0–3) or high (7–9) level based on three subscales: (1) selection, (2) comparability, and (3) outcome (for cohort studies) or exposure (for casecontrol studies). Studies that scored ≥7 were defined as high quality.[19] The inter-rater agreement for each subscale was reasonably good (infraclass correlation coefficient valued between 0.75 and 0.93).[20]

Meta-analysis approach

Meta-analysis was carried out using Stata software version 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX, USA). Substantial heterogeneity was expected and considered the nature of the study. Heterogeneity was assessed by the Cochrane Q-test and I² index among studies. When the heterogeneity was not significant (I² < 50%), a fixed-effects model was applied in all of the analyses; otherwise, a random-effects model was used. Publication bias was evaluated by Egger's and Begg's tests at a significance level of 0.05. Forest plot showed the prevalence in each study and the pooled prevalence with a confidence interval (CI) of 95%. The size of each box indicated the weight of the study, and each horizontal line defined the reported 95% CI. The subgroup analysis and meta-regression test were conducted according to continent, sample size, and the year in which the study has been carried out.

RESULTS

Search results

A total of 1290 articles were collected. The duplicates were removed prior to examination of article titles and abstracts. Finally, after review of the titles and abstracts, 30 (606,648 cases) articles were selected to be included in this systematic review and meta-analysis study [Figure 1]. The main characteristics in the results of literature searches are revealed in Table 1.

Table 1.

The included studies for the prevalence of neonatal toxoplasmosis

First author name	Country	Year	Sample size	Sample	Study design	Prevalence (%)	Methods	Reference
Paul	Denmark	2000	27,516	Serum	C	61.8	ELISA	[21]
Neto	Brazil	2000	47	Serum	C	17	EIA-FEIA	[22]
Kwofie	Ghana	2016	106	Serum	C	57.5	PCR/ELISA	[23]
Pinon	France	2001	50	Serum	C	70	PCR	[24]
Paul	Denmark	2001	19	Serum	C	43.7	ELISA	[25]
Rilling	German	2003	175	Serum	C	52	PCR	[26]
Sáfadi	Brazil	2003	43	Serum	C	88	ELISA	[27]
Carvalheiro	Brazil	2005	15,162	Serum	C	38.5	PCR	[28]
Gallego-Marín	Colombia	2005	200	Serum	C	45.4	PCR/ELISA	[29]
Mehbod	Iran	2005	210	Serum	C	5.6	ELISA	[30]
Schmidt	Denmark	2006	262,912	Serum	C	14.9	PCR	[31]
Gilbert	London	2006	10,000	Serum	C	25	PCR	[32]
Gras	London	2007	225	Serum	C	41	ELISA	[33]
Guerina	England	1994	100	Serum	C	40	ELISA	[34]
Pinon	France	1996	103	Serum	C	80	ELISA	[35]
Bessières	France	2009	57	Serum	C	24	PCR	[36]
Vasconcelos-Santos	Brazil	2009	146,307	Serum	C	50	ELISA	[37]
Röser	Denmark	2010	100	Serum	C	41	PCR	[38]
Gómez-Marin	Colombia	2011	15,333	Serum	C	51.7	ELISA	[39]
Faucher	France	2012	127	Amniotic fluid	C	18.9	PCR	[40]
Lopes-Mori	Brazil	2013	31	Serum	C	58.3	ELISA	[41]
Noorbakhsh	Iran	2013	270	Serum	C	50	ELISA	[42]
Marangoni	Italy	2014	18	Serum	C	26.8	PCR	[43]
Gontijo da Silva	Brazil	2015	487	Serum	C	63	PCR/ELISA	[44]
Rasti	Iran	2015	798	Serum	C	42.7	PCR-ELISA	[45]
Contopoulos-Ioannidis	California	2015	233	Serum	C	36	ELISA	[46]
Paraguassú-Chaves	Brazil	2019	114,793	Serum	C	90	PCR/ELISA	[47]
Bischoff	Brazil	2016	10,000	Serum	C	14.3	ELISA	[48]
Carral	Argentina	2018	67	Serum	C	18.3	PCR	[49]
Storchilo	Brazil	2019	1159	Serum	C	43.9	PCR/ELISA	[50]

C: Cohort, PCR: Polymerase chain reaction, ELISA: Enzyme-linked immunosorbent assay, FEIA: Fluorometric enzyme immunoassay, EIA: Indirect enzyme immunoassay

The total sample size was 606,648. The largest sample size belonged to Schmidt et al. (262,912),[31] Vasconcelos-Santos et al. (146,307),[37] and Paraguassú-Chaves et al. (114,793).[47] The smallest sample size belonged to Marangoni (n = 18), Paul (n = 19), and Capobiango (n = 31). In addition, the highest and lowest prevalence rates of T. gondii were observed in studies conducted by Paraguassú-Chaves et al. as 90% (95% CI: 90%–90%)[47] and Mehbod et al. as 6% (95% CI: 2%–9%).[30]

Prevalence of neonatal toxoplasmosis

The result of the Q-test (Chi-squared = 4.6e+ 0.5, df = 29, P = 0.0001) and I² index (I² = 100%) presented that the prevalence of neonatal toxoplasmosis is strongly heterogeneous among thirty studies. Therefore, the random-effects models were used to estimate the prevalence. The total prevalence of toxoplasmosis in neonates was 44% (95% CI: 29%–0.58%) [Figure 2]. Furthermore, the results of the subgroups revealed that the pooled prevalence is different among the continents [Figure 3], and the highest prevalence rates are in America with the prevalence of 47% (95% CI: 30%–64%), followed by Europe with the prevalence of 41% (95% CI: 26%–57%) and Asia with the prevalence of 33% (95% CI: 4%–61%). The meta-analysis revealed that the prevalence of neonatal toxoplasmosis decreases in coordination with sample size and the publication year of articles, but they were not significant [Table 2].

Figure 2.

Forest plot of the prevalence of neonatal toxoplasmosis

Figure 3.

Forest plot of the prevalence of neonatal toxoplasmosis according to the continent

Table 2.

Result of meta-regression, the effect of sample size, and year on the prevalence of neonatal toxoplasmosis

	Coefficient	SE	t	P>t	Lower	Upper
Year	−0.0030501	0.0060553	−0.50	0.619	−0.0154745	0.0093743
Sample size	−1.20e-07	7.31e-07	−0.16	0.871	−1.62e-06	1.38e-06
Cons	6.565077	12.16182	0.54	0.594	−18.38891	31.51906

SE: Standard error

Publication bias

Publication bias was assessed using Egger's (P = 0.918) and Begg's tests (P = 0.230). No publication bias was observed.

DISCUSSION

T. gondii is one of the most common infectious agents worldwide that can be transmitted from mothers to their newborn and cause congenital toxoplasmosis. Therefore, adequate knowledge about epidemiology and incidence of toxoplasmosis in neonates in different parts of the world is essential for effective control and prevention of this infection and its related complications in an infected mother and her child.[50] Due to this issue, we designed this systematic review and meta-analysis to assess the pooled prevalence of this infection in newborns across the world.

The prevalence of toxoplasmosis in different parts of the world relies on different climatic conditions, cats’ population, and local lifestyles.[50] In this study, a meta-analysis was performed including 30 articles (606,648 cases) which were found as a result of searching from 5 databases. According to the results of the search, the prevalence of toxoplasmosis ranged from 5.6% to 88%.

We explain the prevalence of toxoplasmosis infection due to continental segregation below:

America

The lowest and highest prevalence rates of toxoplasmosis were observed in the United States and Brazil, respectively. Neto et al., in 2000, reported the lowest prevalence of newborn toxoplasmosis in Brazil over a 3-year period. They found that out of every 3000 live births, one infant has the parasitic infection; in this investigation, out of 140,914 samples, 66,320 (47%) had come from the state of Rio Grande do Sul, and 74,684 (53%) had come from the rest of the country.[22] The clinical symptoms of the patients included in the study were as follow: two infants with intracranial calcification, four infants with retinal ulcers, one infant with intracranial calcification and retinal ulcers, and one infant with hepatosplenomegaly and lymphadenopathy. Overall, in this investigation, the reported prevalence of toxoplasmosis was 17%.[22] Paraguassú-Chaves et al., in 2008 in the USA, reported the highest prevalence (91%) of toxoplasmosis in a study performed with the aim of clinical presentation and follow-up of patients with congenital toxoplasmosis. Due to the fact that Amazon is a region with a hot and humid climate, the production of parasite eggs is higher, and therefore, the prevalence of toxoplasmosis infection in this region is higher in comparison to the other regions.[51]

In the study of Paraguassú-Chaves et al., in 2019, the number of live births was 114,793, a total of 126 children out of 102,963 screened children with congenital toxoplasmosis were treated and followed up.[47]

Another study in 2011 by Gomez Marin found that 51.7% of infants were confirmed by toxoplasmosis by Western blotting and retesting, of which 0.39% by IgM-specific parasites were considered infected.[39]

Asia

The lowest prevalence of newborn toxoplasmosis in Asia was in Iran. According to the study of Mehbod et al., with the aim of investigating the seroepidemiology of toxoplasmosis in newborns, the prevalence of toxoplasmosis was reported to be 5.6% in Iran.[30] A 2013 study by Noorbakhsh et al. found that 50% of IgM-positive infants had eye problems and 50% had neurological problems, of which 1.5% were positive for toxoplasmosis. Timely treatment of this parasite is considered a medical measure.[42]

Europe

In a study conducted by Schmidt et al., with a screening program for congenital toxoplasmosis in Denmark, 14.9% of eye lesions were detected by screening, which according to the findings, despite early treatment, may also be healthy. The lesion is more common in people with immunodeficiency.[31] In another study performed by Pinon et al., with the aim of the early diagnosis of toxoplasmosis in newborns, the result revealed that during the 1^st month of life (newborn period), the prevalence of toxoplasmosis is 70%–81%.[24]

Africa

The study, which was conducted to determine the risk of transmitting toxoplasmosis from mother to infant, found that of the 106 samples, the prevalence of toxoplasmosis was 57.5% in infants born from mothers with toxoplasmosis. According to this study, the presence of tissue cysts carries the risk of congenital transmission due to reactivation. So that with the release of bradyzoite in the bloodstream, it is transformed into tachyzoite and transferred.[27]

CONCLUSION

The results of our study showed that the toxoplasmosis infection has high prevalence worldwide; this high prevalence of toxoplasmosis in the world, if not diagnosed in time, can affect the growth and development of the child in the future, which can disrupt the various functions of the child, such as intelligence, physical, and psychological. However, the prevalence rate of this disease based on geographical area, socioeconomic condition, and lifestyle varies. Furthermore, different diagnostic methods such as enzyme-linked immunosorbent assay and polymerase chain reaction tests and laboratory diagnosis of IgG and IgM can measure the incidence of this parasitic infection in different people, particularly newborns, and by early detection of the disease and appropriate treatment, complications of toxoplasmosis infection can be prevented.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.