An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection

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JOGOH-132; No. of Pages 8 J Gynecol Obstet Hum Reprod xxx (2017) xxx–xxx

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Review

An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection S. Fallahi a, A. Rostami b,*, M. Nourollahpour Shiadeh c,**, H. Behniafar d, S. Paktinat e a

Department of Parasitology and Mycology, School of Medicine, Lorestan University of Medical Sciences, 68138-33946 Khorramabad, Iran Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, 47176-47745 Babol, Iran c Department of Midwifery and Reproductive Health, Nursing and Midwifery School, Mazandaran University of Medical Sciences, Sari, Iran d Department of Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran e Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, 48175-866 Tehran, Iran b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 27 September 2017 Received in revised form 1st December 2017 Accepted 4 December 2017 Available online xxx

Background. – Toxoplasma gondii infection is one of the most prevalent infectious disease with worldwide distribution. Congenital toxoplasmosis is annually responsible for 1.20 million disabilityadjusted life years around the world, but often it is overlooked many countries. Methods. – We performed an updated review to summarize the current researches on fetal, neonatal and maternal consequences of T. gondii infection and also adverse effects of toxoplasmosis on women reproductive organs. Results. – T. gondii infection could be cause of several abnormalities from hydrocephalus, microcephaly, deafness, abortion and still birth in fetal to psychomotor retardation, intellectual disability, hearing loss, slower postnatal motor development during the first year of life; and chorioretinitis, cryptogenic epilepsy and autism spectrum disorders in newborns. Moreover, this infection is related with neuropsychiatric disorders such as anxiety, schizophrenia spectrum disorders, depression, decreased weight, autoimmune thyroid diseases, self-directed violence, violent suicide attempts in mothers. This literature review emphasized that toxoplasmosis could be an important neglected factor endometritis, ovarian dysfunction, impaired folliculogenesis, ovarian and uterine atrophy, decrease in reproductive organs weight and reproductive performance in women. We reviewed role of the immunological profile such as pro-infiammatory cytokines and hormonal changes as main potential mechanisms related to this infection and development of maternal-fetal and reproductive disorders. Conclusion. – T. gondii is associated with several brain related disorders in both mothers and newborns, and also it is cause of several abnormalities in reproductive organs. Early diagnosis and treatment of the infection could be effective to significantly improve the clinical outcome.

C 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Toxoplasma gondii infection Reproductive health Abortion Infertility

Introduction Infectious diseases in pregnancy include TORCH complex (toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, Rubella, Cytomegalovirus, Herpes infections, hepatitis infections and human immunodefciency virus) and other such as listeriosis, malaria and ZIKA virus are responsible several adverse maternal and fetal outcomes [1,2].

* Corresponding author. Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, IR Iran. ** Corresponding author. E-mail addresses: [email protected] (A. Rostami), [email protected] (M. Nourollahpour Shiadeh).

Toxoplasma gondii is an obligate intracellular protozoan that causes a worldwide distributed zoonotic disease known as toxoplasmosis [3]. T. gondii infects most genera of warm-blooded animals including humans. It is generally assumed that approximately one third of people around the world be chronically infected with T. gondii [4]. The prevalence of toxoplasmosis is different between countries from lowest seroprevalence (1%) found in some countries in the Far East to the highest (90%) in some parts of European and South American countries [4]. The main pathways for T. gondii infection among humans are eating of raw or undercooked meat containing T. gondii tissue cysts, ingesting sporulated oocysts from soil, water, unwashed vegetables or contaminated hands, and acquiring congenital infection through the placenta [5–7].

https://doi.org/10.1016/j.jogoh.2017.12.003 C 2017 Elsevier Masson SAS. All rights reserved. 2468-7847/

Please cite this article in press as: Fallahi S, et al. An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/j.jogoh.2017.12.003

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Table 1 Prevalence of Toxoplasma infection among pregnant women in different countries in last six years. Country

Year

Method

Sample size

Overall prevalence (acute infection) %

Ref.

Japan Ethiopia Taiwan Egypt Iran Turkey Brazil Thailand Poland Democratic Republic of Congo Norway Mexico Italy Saudi Arabia

2011 2011 2012 2012 2012 2013 2014 2014 2014 2014 2015 2016 2016 2016

Latex agglutination ELISA ELISA, IgG avidity ELISA ELISA IgG avidity ELISA, IgG avidity ELISA, IgG avidity ELISA ELFA ELISA ELISA, IgG avidity ELISA ELISA

4466 201 1783 323 555 4651 487 760 8281 781 1922 338 36,876 326

10.3% (0.25) 83.6% (1.4) 9.3% (0.0) 67.5% (2.8) 41% (1.4) 39.9% (88) 68.3% (5) 25% (0.0) 40.6% (ND) 80.3% (4.4) 9.3% (ND) 6.5% (0.2) ND (0.192) 21.2% (1.2)

[21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]

ND: not determined; ELISA: enzyme-linked immunosorbent assay; ELFA: enzyme-linked fluorescent immunoassay.

Although infection of healthy individuals is mild and frequently self-limited, the neurotropic complications of toxoplasmosis such as encephalitis, brain abscess and sometimes death are manifested when it is reactivated in immunocompromised patients [6]. Congenital T. gondii infection can lead to abortion or several abnormalities such ocular and neurological impairment [8]. In addition to above-mentioned manifestation, several recent studies performed in human and animal model have demonstrated that latent or acute toxoplasmosis is associated with reproductive organs disorders, infertility, sperm abnormalities, behavioral changes and neurological disorders in pregnant women and other people [9–18]. Although many epidemiological and casual evidences suggest that toxoplasmosis is an important disease in reproductive medicine, but it is often overlooked in obstetrics and gynecology or reproductive health clinics and is considered as a neglected tropical disease. In this paper we briefly reviewed maternal, fetal and neonatal consequences of T. gondii infection and also reviewed routine strategies for diagnosis and treatment of infection. Congenital toxoplasmosis Congenital infection occurs often when pregnant women become infected during gestation, and preconception infection confers little or no risk to the fetus [19]. Furthermore, vertical transmission could be occurred throughout reactivation of infection in immunocompromised pregnant women with previous latent toxoplasmosis [20,21]. The rate of transplacental transmission and the severity of fetal damage depend on gestational age and applying, or not, of prenatal anti-parasitic treatment [8]. Transmission rate of tachyzoites, one of the infective forms of T. gondii that can be colonized in placental tissues, during the first and second trimesters of pregnancy is less than 10% to 30% respectively, and increases to nearly 90% during the last weeks of third trimesters [8,22]. The placenta plays an important role in trans-placental transmission, as it is a natural barrier to protection of the fetus against infectious agents and also a target tissue for parasite multiplication [8,23]. In fact, the placental barrier is more efficient to inhibit the tachyzoites transmission at the beginning of gestation, but becomes more permeable at the end of pregnancy [24]. It is estimated that global incidence and burden of disabilityadjusted life years (DALYs) related with congenital toxoplasmosis be 190 100 cases (95% credible interval, CI: 179 300–206 300) and 1.20 million DALYs (95% CI: 0.76–1.90), annually [25]. High burdens were seen in South America and in some Middle Eastern and low-income countries low burdens were seen in some European countries. The prevalence of toxoplasmosis among

pregnant women in different countries [26–39] is presented in Table 1. The consequences of Toxoplasma infection during pregnancy for fetal and neonatal Transplacental transmission Toxoplasma tachyzoites during embryogenesis can result to very bad consequences for fetal development and often leading to widely abnormalities from hydrocephalus, microcephaly, deafness, and psychomotor retardation to abortion and still-birth [8,40–44]. It is observed in a study by ultrasound scan that development of fetuses at week 16 of pregnancy in women with latent toxoplasmosis is lower than healthy controls [45]. Ocular manifestations are also more severe when infection is acquired in first trimesters; these complications include increased intraocular pressure, microphthalmia, strabismus, optic neuritis, cataract, and retinal necrosis that can result to blindness [8,40,46–49]. It seemed that immunological profile against T. gondii plays a significant role to induce of these manifestations. Whereas interleukin-10 (IL-10) and other cytokines related with T helper2 (Th-2) are main immune response in the placental microenvironment [50], Th1-associated immune profiles are responsible for host resistance to T. gondii infection, which secrete interferon-g (IFN-g), pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) [51,52]. Shiono et al. have demonstrated that IFN-g synthesized following T. gondii infection can led to abortion in pregnant wild type mice [53]. Hackmon et al. reported also that IFN- g is involved in preeclampsia in pregnant women [54]. Moreover, inflammation and parasite multiplication can result to destruction of the white substance and block the aqueduct of Sylvius in the fetal brain tissue, resulting brain abnormalities such as hydrocephaly, microcephaly and psychomotor retardation [8]. Fetal infection at the second trimester resulting to milder complications include, splenomegaly, hepatomegaly, cerebral calcifications, pneumonitis, anemia, epilepsy, thrombocytopeniainduced petechiae, rash, and retinochoroiditis [48,55–57]. When maternal infection occurs during the third trimester the most of neonates (more than 80%) are asymptomatic, however retinochoroiditis and neurologic deficits in childhood or early adulthood might be developed, if these newborns not treated appropriately in early age [40–59,60,61]. Moreover, some retrospective or prospective cohort studies have reported that the risk of schizophrenia and related psychoses and also intellectual disability, hearing loss, slower postnatal motor development during the first year of life, chorioretinitis during the ages of 20–30, cryptogenic epilepsy, autism spectrum disorders, Down syndrome, Alzheimer’s

Please cite this article in press as: Fallahi S, et al. An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/j.jogoh.2017.12.003

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Fig. 1. A schematic illustration of Toxoplama gondii life cycle and its hypothesized relationship with mental disorders in pregnant women.

disease are increased in infants of mothers with latent toxoplasmosis [62–70]. The consequences of Toxoplasma infection during pregnancy for mothers Acute infection in immunecomponent pregnant women is asymptomatic, although 10% of women have some symptoms include lymphadenopathy, flu-like illness, fever, fatigue, headache, polymyositis, dermatomyositis, and chorioretinitis [57,71]. According to study by European Multicentre Study on Congenital Toxoplasmosis (EMSCOT), infection during pregnancy was associated with an increased risk of preterm labor when seroconversion occurred before 20 weeks (OR: 4.71; 95% CI: 2.03, 10.9) [72]. Moreover, some researcher hypothesized that T. gondii induced pro-inflammatory cytokines such as IFN-g and TNF-a could be involved in development of preeclampsia in pregnant women [73]. Todros et al. in a cohort study indicated that pregnant women treated with spiramycin have shown lower pregnancyinduced hypertension (OR, 0.092; 95% CI, 0.021–0.399) compared to women who did not take any antibiotic during pregnancy [74]. Although in a recently conducted study in Mexico, it was reported that chronic toxoplasmosis is not associated with hypertensive disorders in pregnant women [75]. In recent years a growing rate of studies conducted in humans and rodents have corroborated the idea that latent toxoplasmosis is associated with development of neurological and mental disorders [18,51,76–80]. Considering to the pregnant women, some studies have illustrated that T. gondii infection is associated with anxiety, schizophrenia spectrum disorders, depression, decreased weight, autoimmune thyroid diseases, self-directed violence, violent suicide attempts [15,17,81–84]. The majority of

these adverese effects were increased among pregnant women with higher levels of T. gondii IgG antibody. Moreover, Ling et al. demonestrated that latent T. gondii infection is significantly linked with rate of suicide rates among women after postmenopausal age [85]. The neuropsychiatric disorders resulted from T. gondii infection could be a consequence of damage induced by host immune responses to parasite and localization of tissue cysts in the CNS [51,76]. The role of IFN-g and TNF-a to induce of depressive symptoms is significant. These cytokines stimulate production of indoleamine 2,3-dioxygenase (IDO) and tehn tryptophan (Trp) depletion along the kynurenine pathway, which results in reduced 5-hydroxytryptamine (5-HT, serotonin) production in the brain [51,86,87]. In line with this statemrnt, Kohl et al. have shown that newly delivered women with postpartum blues symptoms have lower tryptophan concentrations than those without post-partum blues [88]. Another possible mechanism could be potential effects of T. gondii infection on endocrine pathways such as up-regulation of thyroid peroxidase autoantibodies (TPO) in pregnant women [89]. This hypothesis is supported by this finding that women who are TPO positive during the postpartum period are more susceptible to bipolar disorders [90]. Moreover, some intriguing findings revealed that two genes encoding tyrosine and phenylalanine hydroxylases in T. gondii that produce L-DOPA (the precursor to dopamine), may directly affect the behavioral changes in infected hosts [51,91,92]. Despite the large number of epidemiological studies supporting the correlation between latent toxoplasmosis and the psychiatric disorders, at the present, it is difficult to definitively establish the direct causal effect of toxoplasmosis in the pathogenesis of mental disorders without cause-effect studies, and it is expected that simple presence of T. gondii parasite is not the causal factor per se, as immune responses, hormonal changes,

Please cite this article in press as: Fallahi S, et al. An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/j.jogoh.2017.12.003

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severity of infection and strain type of parasite could be effective. A schematic illustration of T. gondii life cycle and its hypothesized relationship with mental disorders in pregnant women is shown in Figure 1. Toxoplasma infection and reproductive disorders Some seroepidemiological studies investigated the relationship between T. gondii infection and infertility. Their results described more prevalence of T. gondii in infertile individuals compared to healthy controls [71–73]. Li et al. [93] showed that, infection with T. gondii in infertile women is significantly higher than control group in China (15.9% versus 5.6% respectively, P < 0.05). ElTantawy et al. [94] recorded similar result in infertile female compared with pregnant controls in Egypt (61.85% versus 44% respectively, P = 0.002). Zhou et al. [95] recorded a relation between infertility and toxoplasmosis in couples. In their study prevalence of T. gondii infection in infertile couples (34.83%) was significantly higher than fertile couples (12.11%). In addition, they founded that anti-sperm antibody is significantly higher in T. gondii infected than non-infected couples. Malik et al. in a study involving infertile females and females with bad obstetric history have found that Toxoplasma is more common in females with two or more abortions and also in patients with secondary infertility. Moreover, they found that about 40.3% patients with bad obstetric history and 20% patients with infertility had healthy live issues after treatment with spiramycin [96]. Role of Toxoplasma infection in male infertility The role of T. gondii infection on human infertility is not investigated, but several experimental studies have shown that T. gondii infection plays a deleterious role in reproduction function of male and female mice. In male mice, acute toxoplasmosis can affect testes, vas deferens epididymis, prostate and thalamus and causes adverse damages [97–99]. Additionally, it is shown that acute toxoplasmosis is associated with apoptosis and DNA damage of testicular cells, apoptosis of sperm cells especially the diploid cells, increase of oxygen free radicals and superoxide dismutase in testes, change in body weight of male reproductive organs [9,100– 103]. Interference with sperm function is another possible mechanism involved in infertility due to T. gondii infection. Several experimental studies demonstrated that toxoplasmosis is associated with decreases motility, concentration and viability of sperms in infected males [9,12,99]. Moreover, some indirect mechanisms such as over production of pro-inflammatory cytokines (IL-12, IFN-

g and TNF-a), nitric oxide (NO) and reactive oxygen species (ROS) during T. gondii infection are involved in sperm abnormalities and etiopathogenesis of other reproductive impairments in infected males (animal or human) [99]. A significant association between inflammation of the male reproductive system and infertility is well demonstrated [104,105]. In addition to above-mentioned adverse effects, T. gondii infection can be cause hormonal alternation in infected patients. Flegr et al. reported that latent toxoplasmosis is associated with higher concentration of testosterone in Toxoplasma-infected men [106]. Although subsequent experimental study by this group revealed decreased testosterone levels in both female and male mice with latent toxoplasmosis [107]. Moreover, several studies reported that acute toxoplasmosis is associated with temporary hypogonadotropic gonadal insufficiency and decreased levels of FSH, LH and testosterone in men [99,108,109]. Role of Toxoplasma infection in female infertility Chronic toxoplasmosis can be cause of endometritis, ovarian dysfunction, impaired folliculogenesis, ovarian and uterine atrophy, decrease in reproductive organs’ weight and reproductive performance, adrenal hypertrophy, vasculitis, cessation of estrus cycling, and reproductive failure in experimental female mice [110,111]. A possible mechanism is that the pro-inflammatory cytokines against T. gondii such as IFN-g reach hypothalamus and then stimulate the release of corticotropin-releasing factor (CRF) that can lead to activation of HPA axis (characterized by adrenal hypertrophy), and subsequently suppress the HPG axis by inhibiting the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. These events can lead to the pituitary gonadotropin [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] insufficiency and ovarian atrophy [112].

Diagnosis Maternal and fetal diagnosis Similar immune-competent adults, pregnant women are often asymptomatic or have only mild symptoms, causing difficulty in diagnosis. So, the role of laboratory exams in the definitive diagnosis of maternal infection is important. Early diagnosis and using appropriate anti-parasite drugs can result in a decrease in the transmission rate of infection to the fetus and severity of infected cases.

Table 2 Diagnostic strategies to detection of congenital toxoplasmosis. Period of diagnosis

Sample

Diagnostic methods

Standards for positivity

Maternal and neonatal diagnosis

Amniotic fluid and placenta

PCR, RT PCR, LAMP/mouse inoculation

Cord blood and mother serum

PCR, RT PCR, LAMP/serology (IgG, IgM)

Cord blood and mother serum

IgG avidity/Western blot

Infant serum

PCR, RT PCR, LAMP/serology (IgG, IgM, IgA)

Infant and mother serum

IgG avidity/Western blot

Positive DNA detection or its evidences/at least one positive mouse with positive serology and brain cyst detection Positive DNA detection or its evidences/detection of both IgG and IgM and also repeated examine to confirm of acute infection High avidity results rule out infection in recent 3–4 months; low avidity antibodies may be recent infection/detect of antigen or specific IgG or IgM pattern in the newborn Positive DNA detection or its evidences/detection of both IgG and IgM and IgA, lack of decrease in IgG titres over 6 months Low avidity antibodies may be recent infection/ detect of antigen or specific IgG or IgM pattern in the newborn

Newborn diagnosis

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Isolation of the parasite thorough fibroblast cell culture and mice inoculation (using amniotic fluid and fetal blood) are definitive diagnostic tools for congenital toxoplasmosis, but both methods are very time consuming, 4 days and 3–6weeks respectively [113]. Nowadays, serological tests are first-line strategy to identify the maternal infection and ultrasound imaging, amniocentesis and polymerase chain reaction (PCR) on different biological samples after confirmed serological diagnosis are very sensitive and useful (Table 2) [114]. Serological tests are based on presence or absence of antibodies (IgG and IgM) and circulating antigens in a serum samples. The major limitation of serological methods is their failure to clarify the recent or past infection, although an antibody kinetics and assessing the avidity of the IgG may be helpful [115–117]. Moreover, in recent years some full automated serological based techniques have emerged that have several advantages including highly sensitivity and specificity, reproducibility, and fast and precise measurement of IgG and IgM antibody levels [115,117–120]. PCR on amniotic fluid is most accurate method for the diagnosis of congenital infection with high sensitivity, and is feasible from week 15 of gestational age [113,121,122]. It is reported that AF-PCR has high specificity (about 100%), although its sensitivity is varying according to date of infection. It is reported that sensitivities of AFPCR in first, second and trimester were 33–75%, 80–97% and 68– 88%, respectively [123–125]. In last years, several DNA target and primers were used to diagnostic purposes, although two 529 gene target and B1 target were mostly used and more sensitive and specific than other [113]. LAMP as a new molecular method can be used, too. This method needs less equipment and is more available than PCR, but contamination rate is of LAMP more than PCR [126–128]. To decline the risk of the maternal to fetal transmission, it is suggested that monthly ultrasonography of fetus be applied throughout the gestation [129]. Brain calcification and hydrocephaly of fetus are detectable by ultrasound scanning. Also, the pathological status of the placenta is helpful for fetal diagnosis of congenital toxoplasmosis. Focal villitis, and inflammation of the

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chorial plate and extra-placatary membranes are frequent in congenital toxoplasmosis [130]. Newborn diagnosis Because of false-negative results of fetal diagnosis, all children of mothers with acute toxoplasmosis must be tested for the possible infection. Serological and clinical examinations are the most common exams for the detection of congenital toxoplasmosis in newborns. Obtaining the clinical history, physical examination and pediatric neurologic and opthamologic examination is mandatory for newborns who are suspected to have congenital toxoplasmosis [129]. Detect of maternal anti-Toxoplasma IgG by 12 months of age is gold standard, and also combination IgA and IgM antibodies results are suitable for serological diagnosis of toxoplasmosis in newborns [129]. The Enzyme-linked immunosorbent assay (ELISA) method for IgA and immunosorbent agglutination assay (ISAGA) for IgM are preferred methods to detect of anti-Toxoplasma antibodies in infants [116,129]. For discrimination between infection of newborn and maternal contamination, IgA positive exams should be repeated about 10 days after birth. Also, western blotting can separate maternal antibodies from fetal and/or infant antibodies [131–133]. Direct isolation of the parasite or amplification of the parasitespecific DNA using PCR in different biological samples such as, cerebrospinal fluid (CSF), peripheral blood, and urine can be useful to early diagnosis of congenital toxoplasmosis, especially in regions with poor antenatal screening and treatment programs [134]. PCR assay in combination with serological tests can result to definitive diagnosis of congenital toxoplasmosis in infants. Treatment Several individual studies reported that early treatment of the infected mother could prevent or lessen congenital toxoplasmosis or subsequent adverse sequelae [135–138]. Although SYROCOT (Systematic Review on Congenital Toxoplasmosis) study group

Table 3 Treatment strategies for congenital toxoplasmosis. Drug

Dosage

Duration

Spiramycin

1 g orally every eight hours without food A three-week course of pyrimethamine (50 mg once per day orally or 25 mg twice per day) and sulfadiazine (3 g/day orally divided into two to three doses), alternating with a three- week course of spiramycin (1 g orally three times per day) or pyrimethamine (25 mg once per day orally) and sulfadiazine (4 g/day orally divided into two to four doses) administered continuously until term 10 to 25 mg/day orally

Until delivery or until fetal infection is documented Until delivery

Acute Toxoplasma infection in pregnant women Confirmed fetal toxoplasmosis

Pyrimethamine plus Sulfadiazine

Congenital toxoplasmosis in infant

Plus Leucovorin (folinic acid) Pyrimethamine

Folinic acid (leucovorin)

Pyrimethamine 2 mg/kg (maximum 50 mg/dose) once daily for two days; then 1 mg/kg (maximum 25 mg/dose) once daily for six months; then 1 mg/kg (maximum 25 mg/dose) every other day (i.e., Monday, Wednesday, and Friday) Sulfadiazine 100 mg/kg per day divided in two doses every day 10 mg three times per week

Corticosteroids (prednisone)

0.5 mg twice per day

Plus Sulfadiazine

During and for one week after pyrimethamine treatment One year

One year During and for one week after pyrimethamine treatment Until resolution of signs

Data were obtained from https://www.uptodate.com/contents/toxoplasmosis-and-pregnancy?source=see_link§ionName=RATIONALE%20FOR%20 PRENATAL%20TREATMENT&anchor=H13#H13 and https://www.uptodate.com/contents/congenital-toxoplasmosis-treatment- outcome-and-prevention.

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have found a weak evidence for an association between early treatment and reduced risk of congenital toxoplasmosis [139]. Limitations to interpret the effectiveness of prenatal treatment are small sample size of available studies and also lack of large, randomized, controlled clinical trials that can be useful to provide the evidence of the potential benefit of prenatal treatment. Various dosing regimens have been proposed to treatment of congenital toxoplasmosis (Table 3). Spiramycin cannot pass the placental barrier; therefore, it’s using has less toxic effects compared to pyrimethamine-sulphonamide (PS) combination, which can lead to adverse complications such as bone marrow suppression and dermatologic and gastrointestinal disorders [140]. Moreover, population based studies have not found evidence to support that a PS combination was more effective than spiramycin [136,139,141]. In a comprehensive meta-analysis study, Li et al. [142] reported that rates of vertical transmission in pregnant women who were treated with spiramycin-only (13%; 95% CI, 7%–22%), was identical with whose were treated with PS combined with spiramycin (13%; 95% CI, 7%–25%). Therefore, it could be concluded that spiramycin (as a less toxic and nonteratogenic drug) can be prescribed alone during the pregnancy to reduce the vertical transmission. Although it should be considered that spiramycin is not effectual for treatment of documented congenital toxoplasmosis, therefore in highly suspected pregnant women (diagnosed fetal abnormalities by ultrasound) or documented infection using PCR in amniotic fluid or seroconversion after 18 weeks of gestation, the combination of PS and folinic acid should be administered to the pregnant women for early treatment of the fetus [129]. Valentini et al. [143,144] in two recent studies evaluated effectiveness of spiramycin/cotrimoxazole (Sp/C) to reduce the vertical transmission rate and their results were promising. Conclusion Our article emphasized that T. gondii infection is associated with several brain related disorders in both mothers and newborns. In addition, this infection is cause of several abnormalities in reproductive organs. Early diagnosis and treatment of the infection could be effective to significantly improve the clinical outcome. Ethical approval Due to the retrospective nature of this review, Ethics Committee approval is not relevant. Funding There are no funding sources for this paper. Disclosure of interest The authors declare that they have no competing interest. Acknowledgement The authors would like to thank Dr. Javad Haroni, for his assistance during the preparation of this manuscript. References [1] Nardozza LMM, Caetano ACR, Zamarian ACP, et al. Fetal growth restriction: current knowledge. Arch Gynecol Obstetr 2017;295:1–17. [2] Nourollahpour Shiadeh M, Rostami A, Danesh M, et al. Zika virus as new emerging global health threat for pregnancy and child birth. J Maternal Fetal Neonatal Med 2017;30:562.

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