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Toxoplasmosis in pregnancy

Maimoona Ahmed, Akanksha Sood, Janesh Gupta

PII: S0301-2115(20)30632-1
DOI: https://doi.org/10.1016/j.ejogrb.2020.10.003
Reference: EURO 11643

To appear in: European Journal of Obstetrics & Gynecology and Reproductive

Biology

Received Date: 13 August 2020

Revised Date: 30 September 2020
Accepted Date: 5 October 2020

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TOXOPLASMOSIS IN PREGNANCY

AUTHORS:

1. Dr. Maimoona Ahmed MS OBGY, Fellow of National Board (High Risk Pregnancy
and Perinatology), Specialist, Women’s Health Department, Aldara Hospital and
Medical Centre, Riyadh, Kingdom of Saudi Arabia

2. Dr. Akanksha Sood MS OBGY, DNB, MRCOG, FACOG, Senior Clinical Fellow in
Reproductive Medicine, St. Mary’s Hospital, Manchester University Hospitals
NHS Foundation Trust, Manchester, U.K.

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3. Professor Janesh Gupta MSc, MD, FRCOG, Professor of Obstetrics and
Gynaecology, Editor-in-Chief of EJOG

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Centre for Women's and Newborn Health, Institute of Metabolism and Systems
Research (IMSR), University of Birmingham, Birmingham Women's and Children's
NHS Foundation Trust, Birmingham, U.K.
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Abstract

Toxoplasmosis is one of the common chronic infections caused by the parasite Toxoplasma gondii.
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Even though its infection in healthy non-pregnant women is self-limited and largely asymptomatic,
the main concern is the risk to the fetus by vertical transmission in pregnancy. Congenital
toxoplasmosis can result in permanent neurological damage and even serious morbidity such as
blindness. Screening programs are implemented in various countries depending on the prevalence
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and virulence of the parasite in the respective regions. Upon diagnosis of infection, appropriate
antibiotic therapy should be initiated as it has been proven to reduce the risk of fetal transmission.
Primary prevention remains the key intervention to avoid the infection and hence patient education
is an important aspect of the management.
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Keywords: Toxoplasmosis, Mother-to-child transmission, congenital toxoplasmosis

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Introduction:
Toxoplasmosis is an infection caused by an intracellular parasite, Toxoplasma gondii (T gondii).
Affecting one-third of the world’s population, it is one of the most prevalent chronic infections (1).
The incidence and prevalence differ among the geographical areas. Among women of reproductive
age group in industrialized countries with temperate climate, the seroprevalence range from 10-50
percent (2).Some areas of the tropics, especially in communities with exposure to contaminated soil,
undercooked meat, or unfiltered water have a higher prevalence of up to 80% (3).
Toxoplasmosis is generally a self-limited and asymptomatic illness in people who are
immunocompetent. However, it can get reactivated and cause severe and fatal symptoms if the
patient becomes immunosuppressed. The reason this infection needs to be taken seriously is that if
the infection is acquired by the mother in pregnancy, the parasite can result in significant adverse
outcomes to the fetus. Congenital toxoplasmosis can cause debilitating neurological or ocular
diseaseeven resulting in blindness (4).

In the United States, an estimated 500 to 5,000 cases of congenital toxoplasmosis occur annually
(1).In England and Wales, the incidence of congenital Toxoplasmosis was3.4/100 000 live births in
2002-04 (5).The rates range from less than 1 per 10,000 live births in Austria, Sweden, and Norway;
2–3 per 10,000 live births in Poland and Brazil; to 1 per 1000 in France(6).In addition to the serious
sequelae in affected infants, there is also the emotional and financial burden faced by the parents
and society.

This review article provides a comprehensive understanding of the disease along with a practical,

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evidence-based approach to its management in pregnancy.

Epidemiology:

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The life cycle of T gondii involves definitive and intermediate hosts. Cats and other felines are the
definitive hosts in which the parasite reproduces sexually and forms oocytes. These are passed in
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faeces and contaminate the soil and water and thus fruits and vegetables. Animals like cows, pigs,
lambs, and even humans are the intermediate hosts that incidentally ingest these oocytes. In these
new hosts, the parasite multiplies in the digestive tract and invades the lining to cause parasitemia,
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which can last for up to 10 days. The parasites in this phase can affect any organ. In an
immunocompetent host, the parasites morph into the dominant cyst form that persists in tissues
likethe brain and striated muscle for long periods, even lifelong (7).
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It is in the phase of parasitemia that the parasites can cross the placenta and affect the fetus. The
placental transfer gets easier with increasing maturity of the placenta. The risk of fetal infection
therefore increases with the gestational age(8).
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Table 1: Sources of Toxoplasma infection for pregnant women (9)

1. Contact with soil contaminated with T gondii from cat faeces:

- Touching mouth with hands after gardening
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- Cleaning a cat’s litter box

- Touching anything that has been in contact with cat faeces
- Eating unwashed fruit or vegetables contaminated with infected soil
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2. Contact with contaminated meat:

- Eating undercooked meat from infected animals, especially pork, lamb, or venison
- Touching mouth after handling raw contaminated meat
- Using kitchen utensils or chopping boards that have been in contact with raw
contaminated meat
3. Other:
- Drinking unpasteurized raw milk
- Drinking contaminated water
- Receiving an infected organ transplant or blood transfusion (rare)
There is no evidence to prove that T gondii is transmitted via breastfeeding or by direct human-to-
human contact(4).

Implications of Toxoplasmosis in pregnancy

Miscarriage

In acute Toxoplasma infection, the overall incidence of miscarriage is 0.5 percent which is
comparable to that in uninfected pregnant women (10).

Preterm Birth

In a study done by Freeman et al, infected pregnancies were associated with reduced length of
gestation. Around 25% of infected babies were born preterm compared to 9% of uninfected babies
but none of the preterm births were less than 34 weeks. They concluded that further studies are

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needed to determine whether the shorter length of gestation is related to obstetric intervention or
is a consequence of fetal infection(6).

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Low birth weight

Sever et al. reported an association between low birthweight and high titres of toxoplasma specific
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IgG (11).In contrast, Freeman et al in their population-based study did not find any association
between low birth weight and congenital infection. They argued that in the previous study, other
confounding factors contributing to maternal infection were not considered (6).
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Perinatal mortality

There are reported cases of perinatal death or severe disseminated infection in 1–2% of cases (12).
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Maternal to Child Transmission (MTCT)

The main risk is the vertical transmission of infection to the fetus. In the absence of treatment, the
overall risk of MTCT from acute T gondii infection in pregnancy ranges from 20 to 50 % (13).
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Congenital Toxoplasmosis can occur in three ways (14, 15, 16):

(a) transmission of T gondii infection to the fetus from a previously seronegative, immunocompetent
mother who acquired acute primary infection during pregnancy or shortly before conception (even
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within 3 months before conception)

(b) reactivation of a Toxoplasma infection in previously T gondii negative immune women who has
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been immunocompromised during gestation e.g. women with HIV infection or who are on
immunosuppressive medications.

(c) reinfection with a new higher virulence strain e.g. after eating undercooked meat from areas with
more virulent atypical strains or after international travel.

The risk of MTCT is lower when maternal infection is acquired in the earlier gestational period but
the outcome can be severe or life-threatening to the fetus. Conversely, while maternal infection
acquired later in pregnancy has a higher risk of transmission to the fetus, the clinical outcome is less
severe, or the child may even be born asymptomatic. Infection acquired in the 2-3 months before
conception can very rarely present a risk of damage to the fetus (17). A delay of 6 months has been
suggested in planning pregnancy after acute Toxoplasma infection (Grade III-B recommendation,
SOGC)even though the parasitemia is short-lived (13).

Table 2: Risk of vertical transmission and frequency of fetal morphological abnormalities with
increasing gestational age (18).

Vertical Transmission Fetal morphological abnormalities

6-20 weeks 21% 11%
21-30 weeks 63% 4%
≥ 30 weeks 89% 0%

Increased risk of MTCT isassociated with (a) acute T gondii infection in pregnancy,
(b)immunocompromise, (c) lack of antepartum treatment, (d) more virulent strain of T gondii, and

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(e) high parasiticload (19).

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Clinical presentation
Maternal Toxoplasmosis
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Majority cases (> 80%) of T gondii infections are asymptomatic. Symptomatic patients usually
present with mild and non-specific symptoms such as fever, chills, sweats, headaches, myalgia,
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pharyngitis, lymphadenopathy, hepatosplenomegaly, and/or a diffuse non-pruritic maculopapular
rash. The febrile episode lasts for around 2-3 days. Of these symptoms, lymphadenopathy is the
most common and can persist for several weeks. It is typically bilateral, symmetrical, non-tender,and
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cervical. Rarely generalized lymphadenopathy can occur. In severe cases, especially those that are
due to reactivation of infection, chorioretinitis can be a presentation with floaters or even loss of
vision(20).

The T gondii genotype determines the type of presentation. The less virulent types (type 2 and 3) are
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more prevalent in Europe and North America. The more virulent types (types 4,5,8,9, and 10) are
prevalent in South and Central America and are associated with higher rates and increased severity
of maternal infection along with more severe fetal infection (21, 22).
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Fetal toxoplasmosis

The most common ultrasound finding in fetal toxoplasmosis is intracranial calcifications and
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ventricular dilatation. A European cohort study found the incidence to be 6 % (23). Ventricular
dilatation is generally bilateral and rapidly progressive. The various ultrasound findings are listed
intable 3.

Table 3: Ultrasound findings in congenital toxoplasmosis (24):

Intracranial hyper echogenic foci (calcifications/densities)

Ventricular dilation/hydrocephalus
Microcephaly
Echogenic bowel
Hepatosplenomegaly
Intrahepatic calcifications/densities
Growth restriction
Ascites
Pericardial and/or pleural effusions
Hydrops fetalis
Fetal demise
Placental densities and/or increased thickness

These ultrasound findings are non-specific and can be seen in other congenital infections or genetic
diseases. Hence, these findings on ultrasound must be followed up with laboratory investigations to
confirm the diagnosis of toxoplasmosis.

In an infected fetus, the prognosis depends on the severity of cerebral damage. Not all the fetal

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findings are linked with serious sequelae especially if there is early treatment (25).Ultrasound
findings that have been associated with poor prognosis are severe ventricular dilatation, brain

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necrosis, gyration disorders, and microcephaly (23).

A European prospective cohort study analysed the fetuses with abnormal ultrasound findings. They
found in these cases the risk of serious neurological sequelae such as cerebral palsy, blindness,
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epilepsy, or death was estimated to be around 43%. The higher scores were seen in women who
were infected early in pregnancy or those that did not receive any treatment (23).
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Neonatal toxoplasmosis

Approximately 80% of live born with congenital toxoplasmosis are asymptomatic at birth (26). Of the
symptomatic newborns, 2/3rdhave moderate disease with intracranial calcifications and peripheral
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retinochoroiditis. Around 1/3rd have a severe form of the disease that is a disseminated form with
hydrocephalus or macular retinochoroiditis. The three most common presentations are
retinochoroiditis, intracranial calcifications, and hydrocephalus(10).
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In a French study, it was shown that the risk of having a symptomatic infant decreased with
increasing gestational age at maternal seroconversion. Accordingly, they calculated that the
maximum risk of delivering a symptomatic infant was 8%–14% which occurred at approximately 24-
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30 weeks of gestation(12).

Diagnosis of toxoplasmosis
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The main aim is to determine recently acquired infection in the pregnant woman and congenital
infection in the fetus and newborn.

Diagnosis of maternal infection

Secondary prevention programs with maternal serological screening have been instituted in
countries with high disease prevalence. French High Authority for Health guidelines mandate
screening for toxoplasma immunoglobulins IgG and IgM, during preconception care and as early as
possible in the first trimester of pregnancy (10).However, countries with low prevalence rates such
as the United States and Canada do not recommend universal screening. Instead, current practice
suggests maternal serological screening when abnormal fetal ultrasound findings indicate possible
infection (grade II-3Erecommendation, SOGC) (13, 27).

There are important questions to be considered when evaluating whether a pregnancy is at risk from
Toxoplasma infection or not (28).

Is there evidence of maternal Toxoplasma infection? Use IgG assay

Is the infection recent? Use IgM assay

When did the infection occur in relation to conception? Use IgG avidity assay

High IgG avidity is a hallmark of chronic infection (>4 months old) and a high avidity in the early
gestation essentially rules out fetal risk. In the later gestation > 16 weeks, a high avidity result can
help to ascertain the timing of infection to determine the extent of severity. On the other hand, low
avidity is not diagnostic of recent infection as low IgG avidity can persist for years in some women.

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Using rising IgG titres for diagnosis has not been adequately evaluated and is subject to errors
(29).Figure1 shows the algorithm for suspected maternal infection.

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Figure 1: Maternal investigations in suspected infection (28).
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If both IgG and IgM are positive, a second serum sample should be sent to the reference laboratory
for confirmation (30).

Diagnosis of fetal infection

Every maternal toxoplasma infection will not result in fetal infection. The diagnosis of fetal infection
is based upon the detection of the parasite and/or specific antibody responses in the fetus.
Ultrasound alone cannot confirm the diagnosis.Direct detection of the parasite from fetal blood or
amniotic fluid using Polymerase Chain Reaction (PCR) provides the undisputed evidence of fetal
infection (28).

The polymerase chain reaction [PCR] amplification of toxoplasmosis DNA from amniotic fluid is the
most reliable and safe method of prenatal diagnosis. It has replaced the direct sampling of fetal
blood (31).

Amniocentesis for identification of T gondii in the amniotic fluid by polymerase chain reaction should

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be offered (a) if maternal primary infection is diagnosed, (b) if serologic testing cannotconfirm or
exclude acute infection, or (c) in the presenceof abnormal ultrasound findings such as intracranial
calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine

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growth restriction(Grade II-2B recommendation, SOGC). The timing of the invasive test should not be
< 18 weeks of pregnancy and not less than 4 weeks after suspected acute maternal infection to
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avoid false-negative results (Grade II-2D recommendation, SOGC)(13).Amniocentesis for PCR is not
recommended in pregnancies with maternal human immunodeficiency virus [HIV] infection due to
procedural risks of fetal HIV transmission (31).
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PCR withamniotic fluid had a positive predictive value of 100%, a specificity of 100%, anegative
predictive value of 88%, and a sensitivity of 64%. Congenital infection cannot be ruled out
completely even with a negative PCR atany gestation. Obstetricians should consider continued
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follow-upvia serial ultrasounds, prophylaxis with spiramycin therapy, and neonatal testing(32).

Histopathology

The placentae of infected mothers or fetal tissues can be examined for T gondii cysts using Wright-
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Giemsa staining. Immunoperoxidase staining using T gondii specific antibodies can also be used(33).
However, routine placental histology or parasitology is not recommended for postnatal diagnosis as
the sensitivity and specificity are not significant enough to make a confirmed diagnosis of congenital
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infection (34).

Diagnosis in newborns
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Newborn infants with suspected congenital toxoplasmosis shouldbe evaluated by

specialistsincluding experienced neonatologists, retinal specialists, neurologists, and paediatric
infectious disease specialists. Serology tests for IgM, IgG and IgA should be done as soon as possible
after birth along with PCR of blood, urine, and CSF (35).

Prevention
Primary prevention
Primary prevention of congenital toxoplasmosis hinges on effective avoidance of infection during
pregnancy. Table 4 lists the recommendations by the Centre of Disease Control (CDC) to prevent
such infection.

Table 4: Measures for Primary prevention of T gondii in seronegative pregnant women (36):

Transmission Recommendations/Considerations
Meat and • Meat should be cooked up to at least 63°C (145°F) for whole cut meat (excluding
other edibles poultry), up to at least 71°C (160°F) for ground meat (excluding poultry), and up to
at least 74°C (165°F) for all poultry (whole cuts and ground) (a food thermometer
should beused)
• Meat should be frozen at –20°C (–4°F) for at least 48 hours
• Freezing and thawing at specific temperatures for specific time can kill T gondii
tissue cysts
• Infected meat that has been smoked, cured in brine, or dried may still be

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infectious
• Contact with mucous membranes should be avoided when handling raw meat

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• Gloves should be worn when handling raw meat and hands should be
thoroughly washed after handling raw meat
• Kitchen surfaces and utensils should be thoroughly washed after contact with
raw meat -p
• Drinking unpasteurized goat milk should be avoided
• Eating raw oysters, clams, or mussels should be avoided
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• Skinning or butchering animals without gloves should be avoided
Untreated • Drinking untreated water, including that from wells, or water with potential
water contamination by faeces from domestic or wild cats should be avoided
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Cat faeces • Contact with material/soil potentially contaminated with cat faeces, especially
and soil handling of cat litters or gardening, should be avoided.However, if it is not
possible to avoid, disposable gloves should be worn when gardening and during
any contact with soil or sandand hands should be washed with soap and warm
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water afterward.
• Cats should be kept indoors. Stray cats should not be handled or adopted while
the woman is pregnant.
• Cat litter box should be changed daily, because T gondii does not become
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infectious until 1 to 5 days after it is shed in a cat’s faeces.

• Cats should be fed canned or dried commercial food, not raw or undercooked
meat.
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Secondary prevention (Screening)

This involves screening of pregnant women for Toxoplasma infection. The balance of risks and
benefits of prenatal screening needs to be individualised by countries depending on the disease
prevalence and prevalence of more virulent strains of T. gondii. United States, Canada, United
Kingdom, and some parts of Europe recommend against routine universal screening for
toxoplasmosis in pregnancy because of the low disease prevalence and incidence of maternal
infection making screening costly (13, 37, 38). In other countries such as France,screening is
performed at regular intervals throughout pregnancy as part of routine prenatal care(20).

Management of toxoplasmosis
Fetal infection may lead to some women choosingthe option of termination of the pregnancy. In
France, termination is discouraged unless there is definitive evidence of fetal infection based on PCR
performed in a reference laboratory along with evidence of severe cerebral abnormalities on fetal
ultrasound (39).Most infected infants have a good prognosis and, on average, have the same
developmental milestones at three to four years of age compared with uninfected children(40).

Among the cohorts of women identified by routine screening and getting timely treatment upon
diagnosis, the mother-to-child transmission (MTCT) rate was <5% after an acute primary maternal
infection (19).

Toxoplasmosis in pregnancy should be managed by a Multi-disciplinary team including maternal-

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fetal medicine, infectious disease, and neonatology specialists to review available data and help the
patient make an informed decision (Grade III-B recommendation, SOGC) (13).

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Figure 2: Approach to management of Toxoplasmosis in pregnancy (Grade I-B recommendation,
SOGC) (30)
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Obstetric management

Other than the diagnostic and treatment issues discussed before, the rest of prenatal care is routine.
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Upon diagnosis of fetal infection by PCR, fetal ultrasound follow-up is recommended at least
monthly.Congenital toxoplasmosis does not affect the decisions of timing or mode of delivery (34).

Breastfeeding
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There has been no documentation oftransmission of T gondii in humans through breastmilk.

Mothers with Toxoplasmosis can continue to breastfeed their infants but should be cautious if their
nipples are cracked and bleeding (36).
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Management in immunocompromised

In immunosuppressed patients, especially with the Acquired Immunodeficiency Syndrome (AIDS),

reactivation infection can occur especially when the CD4 lymphocyte count falls below 100
cells/μL(41). All immunosuppressed patients should be screened for Toxoplasma gondii
antibodies(Grade I-A recommendation, SOGC).Counselling on preventing toxoplasmosis should be
given to seronegative and prophylaxis to seropositive patients. Even with HIV infection, vertical
transmission of Toxoplasma gondii from a chronically infected mother does not occur often unless
there is severe immunocompromise (42).In the European Collaborative Study, a prospective study of
1058 children born to women with HIV, 71 children were born to mothers with latent Toxoplasma
infection and none had serologic evidence of congenital infection (43).

Conclusion
Toxoplasmosis infection, although largely harmless in non-pregnant women, can cause serious harm
to the fetus during pregnancy. Primary preventive measures are the hallmark to avoid infection in
seronegative women. Prenatal testing should be performed for those who acquire the infection in
pregnancy. After establishing the diagnosis, the patient should be counselled regarding congenital
toxoplasmosis and the need for invasive tests, such as amniocentesis, and antibiotic therapy. Timely
intervention hasbeen shown to reduce the risk of mother to child transmission and save the family
emotional and financial pains.

Table 5: Quality of evidence assessment (44)

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Quality of evidence assessment Classification of recommendations
I: Evidence obtained from at least one properly A. There is good evidence to recommend the

randomized controlled trial
II-1: Evidence from well-designed controlled
trials without randomization
II-2: Evidence from well-designed cohort
(prospective or retrospective) or case–control
studies, preferably from more than one centre
or research group
II-3: Evidence obtained from comparisons
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clinical preventive action
B. There is fair evidence to recommend the
clinical preventive action
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C. The existing evidence is conflicting and does
not allow to make a recommendation for or
against use of the clinical preventive action.
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However, other factors may influence decision-
making
D. There is fair evidence to recommend against

between times or places with or without the the clinical preventive action
intervention. Dramatic results in uncontrolled E. There is good evidence to recommend
experiments (such as the results of treatment against the clinical preventive action
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with penicillin in the 1940s) could also be

included in this category
III: Opinions of respected authorities, based on L. There is insufficient evidence (in quantity or
clinical experience, descriptive studies, or quality) to make a recommendation; however,
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reports of expert committees other factors may influence decision-making

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Declaration of interests

The authors declare that they have no known competing financialinterestsor personal relationships
that could have appeared to influence the work reported in this paper.
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