This chapter should be cited as follows:
Giardina I, Di Lauro E, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416363

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 6

Pregnancy complaints and complications: clinical presentations

Volume Editor: Professor Gian Carlo Di Renzo, University of Perugia, Italy

Chapter

Bacterial and Protozoan Infections in Pregnancy

First published: December 2021

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INTRODUCTION

Infections during pregnancy are still a relevant cause of maternal, fetal and neonatal morbidity and mortality.

Mother to baby infection may occur prenatally (vertical transmission, congenital infection) by the transplacental route, at and around the time of delivery (perinatal infection) by blood or vaginal secretions, or subsequently (postnatal infection) as demonstrated by breastfeeding transmission.

The transmission and the potential damage to the fetus or newborn occur variably depending on a number of factors, such as the infectious agent involved, gestational age at the time of infection, primary versus re-activation or re-infection, and maternal immune status. In general, primary infections during pregnancy are more damaging than the others. In many circumstances, the maternal infection is asymptomatic or paucisymptomatic and the diagnosis is difficult.

A key element is that a large percentage of these infections are preventable.

There are several main prevention strategies, variably available and feasible, to consider so as to reduce perinatal infections and their potential negative outcome:

  • Education programs (often the only available preventive strategy against many microorganisms. Maternal pre-conceptional counseling and/or education during the first obstetric visit play a key role)
  • Systematic screening programs (detection of seroprevalences, seroconversions, serological follow-up)
  • Immunization.

This chapter reviews updated information on the most common bacterial and protozoan infections that the mother may transmit to her baby during pregnancy, at birth, or during breastfeeding. The discussion is focused on the current available preventive measures, diagnosis and treatments. Viral infections in pregnancy are presented separately in a dedicated chapter.

TOXOPLASMOSIS

Epidemiology and pathogenesis

Toxoplasmosis is an important zoonosis caused by an obligate intracellular parasitic protozoan, Toxoplasma gondii. The disease is distributed worldwide and can affect all warm-blooded vertebrates, including humans. The incidence of congenital toxoplasmosis ranges from 1 in 1000 to 1 in 10,000 births. The more mature the placenta, the easier the passage. The risk of maternal–fetal transmission of toxoplasma is low in early pregnancy (5–15% in the 1st trimester) and increases as gestational age progresses (20–40% in the 2nd trimester and 50–60% in the 3rd trimester).1,2,3

Contagion occurs by ingestion or handling of raw meat containing tissue cysts, or by ingestion of food (for example fruit and vegetables) contaminated by oocysts contained in the feces excreted by infected cats.2

Most adults with positive serological tests are unaware that they have had the disease, as in about 80% of cases the acute infection has an asymptomatic course. Even when symptoms occur, they are nonspecific or appear as a common viral syndrome (often confused with mononucleosis). Often a single enlarged cervical lymph node is the most common clinical presentation among women, and negative test results for mononucleosis should lead to suspicion of toxoplasma or cytomegalovirus infection. Only one Toxoplasma species exists, but it possesses great genetic diversity. It thrives all over the world and has different levels of virulence. This genetic diversity shows that the clinical and epidemiological profile of the disease is not uniform and that the impact of congenital toxoplasmosis (CT) on public health must be evaluated country by country.4

Obstetrics outcomes

During the phase of parasitemia, T. gondii can pass through the placenta; thus, it is crucial to treat as early as possible. The risk of severe CT is inversely proportional to gestational age.

Early maternal infection (first and second trimester) has a low probability of fetal infection, but if it occurs, it can cause severe congenital pathologies up to spontaneous abortion or fetal death. Conversely, late maternal infection (third trimester) is more likely to cause fetal infection (up to 60%), but fetal harm is less likely and, if it occurs, less severe. Overall, manifestations of CT are polymorphic, ranging from fetal death, to severe neurological and ocular damage, to absence of any clinical signs. Management of this latter situation is difficult if healthcare providers have no information about maternal infection and the newborn is clinically healthy; there would be no reason to screen the infant for CT.

Prevention of toxoplasmosis is mainly based on education: pregnant women must be informed of the risk and possible modes of transmission in order to try to avoid infection.

Diagnosis

The diagnosis of previous or current toxoplasma infection can be established with a direct test such as PCR (polymerase chain reaction) or by indirect means such as serological tests (more common). Usually the toxotest is recommended in early pregnancy (or in the preconceptional phase).

The woman may be immune to infection, susceptible or at risk of passing it on to the fetus, depending on which immunoglobulins are recovered in the serum.

The anti-toxoplasma IgM, in fact, are formed in the first phase of the acute infection (usually within 2 weeks of contagion), therefore they signal that the disease is recent and in progress; they reach their peak between the 4th and 8th week, before becoming indeterminable at 3–4 months. IgG, on the other hand, appear more slowly and remain in circulation to signal that the body has come into contact with the parasite in the past.

It is therefore necessary to know how to interpret the immunoglobulin levels in order to make a correct diagnosis:

  • IgG absent, IgM absent: indicate that the woman has no anti-toxoplasma antibodies, so she has never contracted the infection, either in the past or recently. The patient should therefore scrupulously observe the hygiene rules aimed at preventing infection and  the toxotest should be repeated every 30–40 days until delivery.
  • IgG absent, IgM present: indicate that the woman had never contracted toxoplasmosis in the past, but at the time of the examination the acute infection is in its initial phase.
  • IgG present, IgM present: indicates an infection still in progress or recent (which occurred up to 3–4 months earlier).
  • IgG present, IgM absent: this means that the woman has already contracted toxoplasmosis in the past but does not have a recent infection in progress. Therefore, she does not need to repeat the test as there are no maternal or fetal risks.

In cases of doubt or in which it is not possible to establish the time at which the infection was acquired, it is possible to make a certain diagnosis by quantifying the avidity of IgG:

  • Low avidity IgG means infection in progress or occurred within the previous 3 months;
  • High avidity IgG means previous or latent infection, occurred in the period prior to the last 3 months.

Prenatal diagnosis should be offered with an amniocentesis to perform a PCR assay for toxoplasmosis DNA in the amniotic fluid.5 This procedure should not be performed before 18 weeks of gestation or less than 4 weeks after the estimated date of maternal infection, in order to reduce the risk of false negatives due to delayed transplacental passage of the parasite.6 The sensitivity and the specificity of current PCR testing are 92% and 100%, respectively.7 The risk of procedure-related fetal loss (or preterm delivery in more advanced gestation) is estimated in recent studies to be less than 0.1%.8 An amniocentesis is useful, since appropriate care can be provided during pregnancy and for the neonate in case of a positive result, and the parents can be reassured in the case of a negative result. There is no indication for medical termination of pregnancy on the basis of positive amniocentesis alone.

Prenatal follow-up with ultrasound should be performed monthly, since abnormalities may appear several weeks or months after infection. In case of a positive amniocentesis, the follow-up may be intensified to every 2 weeks. This evaluation should be performed by a sonographer specialized in prenatal diagnosis and CT (opinion of the working group). Fetal brain MRI is not recommended routinely; however, it may be performed in cases where the interpretation of ultrasound imaging is difficult.9

Prevention and treatments

If an ongoing infection is diagnosed, attempts can be made to block the transplacental passage of the parasite to the fetus with antibiotic treatment based on spiramycin or a combination of pyrimethamine and sulphadiazine, depending on several factors.

Moreover, the newborn who has congenital toxoplasmosis, even if apparently healthy, will still have to be monitored for at least the first years of life.

In many European countries, women diagnosed during pregnancy with acute toxoplasma infection are started on spiramycin, a macrolide antimicrobial that is concentrated in the placenta. Spiramycin is safe to use in pregnancy. This antibiotic is traditionally given for the first 21 weeks of gestation or until term in fetuses who do not manifest signs of congenital infection. The recommended dosage of spiramycin is 3 g/day or 1.5 g twice a day.10 Although spiramycin appears to reduce the risk of transmission by almost 60%, it is not effective in treating an infected fetus or infant. Thus, if fetal infection is confirmed after 18 weeks of gestation, or if congenital toxoplasma infection is documented after birth, more potent antibiotic regimens than spiramycin are indicated. Pyrimethamine and sulfadiazine therapy has been associated with resolution of signs of active congenital toxoplasmosis, usually within the first week after initiation of therapy. The dosage of this regimen includes pyrimethamine 50 mg/day and sulfadiazine 1 g orally three times a day. Folinic acid is given at a dosage of 10–20 mg/day to provide folic acid. Pyrimethamine, a folic acid antagonist, is traditionally not used in the first trimester because of its teratogenic effects.9

The prevention of primary maternal infection by modifying habits that may increase contact with infectious agents is the key intervention.11 In particular, maternal pre-conceptional counseling and/or education during the first obstetric visit (many pregnancies are not planned) play a key role in informing and giving guidelines to follow.

MALARIA

Epidemiology and pathogenesis

During the past decade, considerable efforts have been made to reduce the global burden of malaria. These efforts have led to significant reductions in malaria-related morbidity and mortality. Although in some continents, several countries have eradicated malaria as endemic infectious disease in the past 50 years, malaria still remains endemic to other countries with varying trends and outcomes over time, especially in sub-Saharan Africa. In 2018, 19 sub-Saharan African countries and India bore 85% of the world’s malaria burden, with 94% of malaria-related death occurring in sub-Saharan Africa.12

Pregnancy and obstetrics outcomes

All malaria infections are harmful to both the pregnant mother and the developing fetus. One in ten maternal deaths in malaria endemic countries are estimated to result from Plasmodium falciparum infection. Pregnant women are highly susceptible to P. falciparum malaria. Pregnancy-associated malaria (PAM) represents a major public health problem, leading to poor outcomes for both mother and infant, including maternal mortality, maternal anemia, miscarriage, stillbirth, low birth weight, and preterm birth.13 In endemic regions, primigravidae are at greatest risk of PAM, and the frequency and density of both placental and peripheral P. falciparum infection decreases with successive pregnancies. During pregnancy, the burden of adverse obstetric and neonatal outcomes occurs as a result of placental malaria, when the parasite-infected red blood cells sequester in the intervillous spaces of the placenta. Increased levels of pro-inflammatory cytokines, oxidative stress, and apoptosis due to P. falciparum infection lead to pathological changes in the placenta and, thus, poor pregnancy outcomes. Recently, it has also been shown that histopathological changes related to placental malaria enhance the risk of pre-eclampsia in pregnant women, especially in primigravidas.14

These pathologic alterations in the placenta may limit exchange of nutrients between mother and fetus, increasing risk for fetal growth restriction and low birth weight babies. Moreover, during early pregnancy they lead to alterations in the vascular structure of the placenta, such as decrease of transport villi volume and increase of diffusion distance and diffusion vessel surface, which influence birth weight and gestational length. Even so, plasmodium infection mid-pregnancy has been linked increased risk of preterm birth, possibly due to the changes in angiogenic, metabolic, and inflammatory states.

Risk factors for malaria in pregnancy include:

  • Parity, infection is more common in younger women and in primigravidas or secundigravidas compared with women who have been pregnant more than twice, with primigravidas having nearly three times the risk of placental malaria as multigravidas due to immunity specific features.
  • Maternal HIV infection that increases susceptibility to and severity of placental malaria by impairing antibody development to variant surface antigens expressed by malaria-infected erythrocytes, dysregulating cytokine production, and reducing protective interferon-gamma (IFN-γ) responses. A systematic review found that malaria incidence is decreased in the setting of antiretroviral treatments, particularly protease inhibitors.15 These data have not largely been conclusively confirmed and further studies are needed.
  • Low socioeconomic status, antenatal stress and mental health disorders due to poor-quality housing, making it easier for mosquitos to enter, inability to afford protective insecticide-treated bed nets, and lack of access to antimalarials and malaria preventative tools.

Congenital malaria, while rare, has been associated with already cited placental malaria. One study demonstrated significant increased odds of this outcome in neonates born to women with placental malaria.16 Yet, a systematic review of 14 studies found that there was insufficient evidence to confirm or exclude the causal association between malaria in pregnancy and malaria in infancy. Additionally, there is no clear evidence of vertical transmission17 and the outcome of congenital malaria is rare, making it a challenge to study.

Diagnosis

Placental malaria is difficult to diagnose during pregnancy. Peripheral blood smear, the classic diagnostic tool during clinical practice, is usually negative because parasitized red blood cells sequester in the placenta. Even though PCR is a more reliable technique for placental malaria diagnosis, it is inconvenient to use in primary care facilities and largely unavailable in low-resource settings. Loop-mediated isothermal amplification (LAMP) is an alternative nucleic acid amplification technique that can be used outside a reference laboratory for molecular detection of placental malaria by analysing placental blood that is quick, easy, and as accurate as nested PCR. Nonetheless, the gold standard for placental malaria diagnosis is via placental histology, although it cannot be applied during ongoing pregnancies. The pathological classification system has been first described by Bulmer et al. in 1993, then further modified by Rogerson et al.18 and named as Rogerson Criteria. They categorized the placentas into four groups: (1) active infection; (2) active-chronic infection; (3) past-chronic infection; (4) not infected (Table 1).

1

Rogerson criteria for histopathologic diagnosis of placental malaria.18

Active infection

Presence of parasitized red blood cells (RBCs) in the intervillous space with malaria pigment in RBCs and monocytes in the intervillous space; no pigment in fibrin

Active-chronic infection

Pigment accumulation in fibrin, fibrin-containing cells, syncytiotrophoblasts, stroma accompanies the previous findings

Past-chronic infection

Malaria pigment confined to fibrin or cells within fibrin in the absence of parasites

Non-infected

Absence of parasite in placental RBCs without malaria pigment

Prevention and treatment

Current treatment and prevention strategies reduce, but do not eliminate, malaria's damaging effects on pregnancy outcomes. Although evidence supports the safety and treatment efficacy of artemisinin-based combination therapies in the first trimester, these therapies have not been recommended by World Health Organization (WHO) for the treatment of malaria at this stage of pregnancy. Intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine is contraindicated in the first trimester and provides imperfect chemoprevention because of inadequate dosing, poor (few and late) antenatal clinic attendance, increasing antimalarial drug resistance, and decreasing naturally acquired maternal immunity due to the decreased incidence of malaria. Alternative strategies to prevent malaria in pregnancy are needed.

To curb the burden of malaria globally with specific attention in endemic areas, it is important to accurately analyse epidemiological data with the aim of informing policy makers, and hence produce tailored public health interventions (Table 2).

2

Key issues on malaria in pregnancy.

Epidemiology

  • Geographical distribution: the global burden of malaria infection is primarily in low- and middle-income countries (sub-Saharan Africa and India carried about 85% of all cases)
  • As the overall number of endemic regions decreases, studies are finding that malarial immunity in previously endemic regions is dropping, leading to more adverse pregnancy outcomes in women who become infected

Pathogenesis

  • Malaria infection occurs due to the protozoan parasite which has five species that infect humans: P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi
  • P. falciparum and P. vivax are the most prevalent
  • Humans acquire the Plasmodium parasite via the bite of an infected Anopheles mosquito
  • Placenta malaria:
    • is thought to occur via Plasmodium avoidance of spleen clearance through expression of the VAR2CSA protein that binds to the chondroitin sulfate A (CSA) in the placental intervillous space
    • is characterized by the accumulation of these infected RBCs in the intervillous space and subsequent infiltration of maternal monocytes/macrophages
    • prominent inflammatory infiltration by monocytes/macrophages causing massive chronic intervillositis is related to severe placental malaria and adverse obstetrics outcome

Risk factors

  • Live or travel in endemic areas
  • Parity: primigravidas versus multigravidas (immunity features and changes)
  • Maternal HIV infection (higher susceptibility to severe malaria in pregnancy, but antiretrovirals may implemented immune response and reduce risk to Plasmodium infection. Further studies are needed
  • Low socioeconomic status, antenatal stress, mental health disorders (all factors linked to poverty, low access to healthcare services and therapies)

Obstetrical outcome

  • Miscarriage
  • Low-birth weight
  • Preterm birth
  • Small for gestational age
  • Stillbirth
  • Maternal anemia
  • Pre-eclampsia (recent hypthothesis)

Diagnosis and management

  • Antimalarial drugs show important limitations to use in pregnancy due to still not being recommended by associations or due to possible teratogenic risk (artemisinin-based combination therapies, intermittent preventive treatment with sulfadoxine-pyrimethamine)
  • Further studies are needed

TUBERCULOSIS

Epidemiology and pathogenesis

Globally each year, 3.2 million women become sick with tuberculosis (TB).19 In low- and middle-income countries (LMIC), HIV/AIDS, maternal conditions, and TB account for nearly 50% of deaths among women in their reproductive years.19 Approximately 216,500 pregnant women were estimated to have TB in 2011, and it is not known how many pregnant women had drug-resistant TB (DR-TB).20

Maternal presentation and obstetric outcome

TB in pregnancy poses a substantial risk of morbidity to both the pregnant woman and the fetus if not diagnosed and treated in a timely manner. Assessing the risk of having Mycobacterium tuberculosis infection is essential to determining when further evaluation should occur. The clinical presentation of tuberculosis may be similar to some manifestations of pregnancy, making tuberculosis diagnosis in this population difficult. The presence of tuberculosis during pregnancy may result in a three-fold increase in adverse birth outcomes such as preterm birth, low weight at birth and fetal growth restriction. Obstetrician-gynecologists are in a unique position to identify individuals with infection and facilitate further evaluation and follow up as needed. A TB evaluation consists of a TB risk assessment, medical history, physical examination, and a symptom screen; a TB test should be performed if indicated by the TB evaluation. If a pregnant woman has signs or symptoms of TB or if the test result for TB infection is positive, active TB disease must be ruled out before delivery, with a chest radiograph and other diagnostics as indicated.

Prevention and management

If active TB disease is diagnosed, it should be treated; providers must decide when treatment of latent TB infection is most beneficial. Most women will not require latent TB infection treatment while pregnant, but all require close follow up and monitoring.

There is limited research to guide TB treatment specifically in pregnant women and few studies have described the presentation of TB in pregnant women. Treatment should be coordinated with the TB control program within the respective jurisdiction and initiated based on the woman's risk factors including social history, comorbidities (particularly human immunodeficiency virus [HIV] infection), and concomitant medications and should be established in a multidisciplinary setting, involving a specialist in infectious disease, gynecologist and neonatologist.21

Currently, first-line treatment for drug-susceptible TB is recommended during pregnancy.19 First-line TB regimens – with isoniazid, rifampicin, pyrazinamide, and ethambutol – have been shown to be safe for pregnant women throughout all trimesters.22,23

Second-line drugs are also used during pregnancy, with more limited safety evidence.24 For example, aminoglycosides (such as kanamycin, amikacin, and streptomycin) should be avoided, especially within the first 20 weeks of pregnancy, due to the risk for ototoxicity and fetal malformation. Ethionamide and prothionamide can increase the risk of nausea and vomiting during pregnancy, thus these drugs are often avoided until after delivery.24 However, most other second-line drugs are considered U.S. Food and Drug Administration class B (animal studies demonstrate no risk, no human studies) or C (animal studies demonstrate risk, no human studies), meaning they can be used in pregnancy without known adverse effects.24

A high index of suspicion of tuberculosis is necessary and factors such as a history of tuberculosis contact should prompt clinicians to consider tuberculosis in their differential diagnosis, especially in a setting of outbreaks and high HIV-tuberculosis burden.

In conclusion, high-quality evidence on these topics is needed, as are detailed guidelines to inform efforts by TB control programs and clinicians working with pregnant women and their infants.

SYPHILIS

Epidemiology and pathogenesis

In the past few years, syphilis has become a re-emerging disease in some countries in the world. We are facing “the modern epidemic of an ancient disease” as regards syphilis.

Maternal infection is the same as for any non-pregnant woman and may be acquired at any stage of pregnancy. It is caused by the bacterium Treponema pallidum, which is transmitted sexually during vaginal, anal, or oral sex. Syphilis is easy to treat with antibiotics in the early stages of the disease.

It is caused by the spirochete T. pallidum, which enters the body through the mucous membranes or the skin, reaches the peripheral lymph nodes within a few hours, and rapidly spreads throughout the body. Syphilis occurs in three stages: primary, secondary and tertiary. There are long periods of latency between the various phases. Infected individuals are contagious during the first two stages (Table 3).

The infection is usually transmitted by sexual contact (including genital, orogenital, and anogenital contact), but can also be non-sexually transmitted through skin contact or transplacental passage, causing congenital syphilis.2

3

Classification of syphilis.

Stage

Description

Symptomatology

Acquired

Primary

Contagious

Syphiloma (one or more painless indurated ulcer or chancre at the infection site), local lymphadenopathy

Secondary

Contagious

Occurs weeks or months after the primary stage

Skin rashes (which can be confused with others caused by other disorders), sores on the mucous membranes, hair loss, fever, many other symptoms

Latent

Asymptomatic; generally not contagious

Can persist indefinitely or be followed by the late stage

  • Early latent syphilis (infection <1 year duration), sometimes with recurrence of infectious lesions
  • Late latent syphilis (infection lasting ≥1 year), rarely with recurrence; positive serological tests

Late or tertiary

Not contagious

  • Clinically classified as benign tertiary syphilis, cardiovascular syphilis, or neurosyphilis (e.g., asymptomatic, meningovascular or parenchymatous neurosyphilis, dorsal tabes)

Congenital*

Early

Symptomatic

Occurs up to the age of 2

Overt disease

Late

Symptomatic

Occurs late in life

Hutchinson's teeth, eye and bone anomalies

*It can also exist in a permanently latent stage (asymptomatic).

Diagnosis

Diagnostic tests for syphilis include serological tests which consist of:10

  • Screening test (a reaginic, or non-treponemal) (Venereal Disease Research Laboratory (VDRL) or Rapid Plasma Reagin (RPR)): they are sensitive, simple and inexpensive tests used for screening; however, they are not completely specific for syphilis. The result can be defined qualitatively (e.g., reactive, weakly reactive, borderline, non-reactive) and quantitatively as titer (e.g., positive at a dilution of 1:16).
  • Confirmation tests (treponemics) (e.g. T. pallidum hemagglutination assay (TPHA)): Treponemal tests detect antitreponemal antibodies and are very specific for syphilis. If treponemal infection is not confirmed after a positive reagin test, the test result is biologically considered a false positive.
  • Darkfield microscopy: directs the light in an oblique direction towards a slide of exudate taken from the primary syphiloma or the draining lymph node, and directly visualizes the spirochetes. Although not always available, darkfield microscopy is the most sensitive and specific test for diagnosing early primary syphilis.

T. pallidum cannot be grown in vitro. Traditionally, reaginic tests should be performed initially, and positive results are confirmed by a treponemal test. Neither reaginic nor treponemal tests become positive until 3–6 weeks after the initial infection.

Congenital syphilis

The overall risk of transplacental infection of the fetus is about 60–80%, and the probability is increased during the second half of pregnancy. Primary or secondary syphilis in the untreated mother is usually transmitted, but latent or tertiary syphilis is only transmitted in about 20% of cases. Untreated syphilis in pregnancy is also associated with a significant risk of fetal death and neonatal death. In infected infants, manifestations of syphilis are classified as early congenital (i.e., onset with the age of 2 years) and late congenital (i.e., after 2 years).25

Early congenital syphilis usually occurs during the first 3 months of life. Manifestations include the characteristic vesiculo-bullous rash or copper-colored macular rash on the palms and soles and papular lesions around the nose and mouth and in the diaper area, as well as petechial lesions. Lymphadenopathy and hepatosplenomegaly are often present. Some infants may develop meningitis, choroiditis, hydrocephalus or seizures in addition to slowing their growth rate, and others may have intellectual disabilities.

Diagnosis of early congenital syphilis is usually suspected on the basis of maternal serological tests, which are routinely performed in pregnancy and often repeated in the third trimester and at delivery. Infants of mothers with serological evidence of syphilis should undergo a thorough examination of any skin or mucosal lesions and a quantitative non-treponemal serological test; umbilical cord blood is not used for serological investigations as the results are less sensitive and specific. The placenta or umbilical cord should be analysed using darkfield microscopy or fluorescent antibody staining, if available.

Late congenital syphilis typically does not manifest until after 2 years of life and causes gummy ulcers (affecting the nose, septum, hard palate) and periosteal lesions that result in saber tibias and swelling of the frontal and parietal bones. Neurosyphilis is usually asymptomatic (juvenile paresis and tabes may sometimes develop). Optic nerve atrophy can also occur, sometimes leading to blindness. Interstitial keratitis, the most frequent eye injury, frequently recurs, often causing corneal scarring. Sensory hearing loss, which is usually progressive, can develop at any age. Characteristic, though infrequent, sequelae are Hutchinson's incisors, blackberry-shaped molars, perioral fissures (fissures) and malformations of the jaw that give the so-called "bulldog" facies.

Diagnosis of late congenital syphilis is based on history, characteristic physical signs, and positive serological tests. The Hutchinson triad of interstitial keratitis, Hutchinson incisors, and 8th cranial nerve deafness is diagnostic.

The diagnosis of syphilis should be considered in cases of deafness that cannot otherwise be explained, progressive intellectual deterioration, or keratitis.

Screening, prevention and treatment

All women should be screened serologically by treponemal or non-treponemal antibody testing and, if syphilis is confirmed, they must receive adequate treatment. For communities and populations where the prevalence of syphilis is high, serological testing should be repeated during the third trimester, at 28–32 weeks’ gestation, and at delivery. Finally, no infant should leave the hospital without the maternal serological status having been determined at least once during pregnancy.

Presumptive diagnosis is possible using non-treponemal and treponemal tests. The use of only one type of test is insufficient for diagnosis due to false positive non-treponemal tests results. This can occur with a variety of medical conditions unrelated to syphilis. False positive treponemal test results can occur with other spirochetal diseases.

Based on many years of clinical experience, penicillin G that is administered parenterally is the preferred drug for treatment. Treatment during pregnancy should be the penicillin regimen appropriate for the stage of syphilis diagnosed. Parenteral penicillin G is the only therapy with documented efficacy during pregnancy.10

Prevention of T. pallidum infection should be the goal of each public health system by sensibilization and education, pre-conceptional and antenatal screening, maintaining an high grade of attention in higher-risk groups of population. Syphilis is a re-emerging infection not only in poor countries, but also in developed areas. It is on the rise in the United States and Europe for example. Without adequate health carer awareness and preventive strategies, early recognition of infection and treatment can be neglected resulting in significant perinatal morbidity and mortality.26

LISTERIOSIS

Epidemiology and pathogenesis

Listeriosis is a rare and severe foodborne infection caused by Listeria monocytogenes (Gram-positive facultative intracellular bacillus). It manifests as septicemia, neurolisteriosis, and harmful maternal–fetal infection. In pregnancy, it may cause maternal fever, premature delivery, fetal loss, neonatal systemic and central nervous system infections. Maternal listeriosis is mostly reported during the second and third trimester of pregnancy, as sporadic cases or in the context of outbreaks. After ingestion, L. monocytogenes can actively cross the intestinal barrier, disseminate via the bloodstream, and eventually cross the placental barrier, leading to placental and fetal infection. The incidence of maternal–neonatal (MN) listeriosis, defined by the presence of Listeria spp. in any sample of maternal, fetal or neonatal origin (infant 1-month old or younger), is now estimated around 4–10/100,000 pregnant women/year in Europe and North America.27,28 MN listeriosis cases are more frequent in countries where surveillance is not thoroughly implemented.29,30,31 Infections account for 11–20% of hospitalizations for invasive listeriosis in France and Spain.30,32 Among pregnant women, higher incidences have been reported in ethnic minorities, probably reflecting specific dietary habits, such as for American Hispanic women in the US,33 women of African origin in France,32 and in women from ethnic minorities in the United Kingdom.34,35 They may not be as aware as others of the preventive measures and may not have ready access to medical care in case of fever or obstetrical signs. L. monocytogenes is ubiquitous in nature and can contaminate a large array of unprocessed and processed food of animal and vegetal origin. Most outbreaks have involved unpasteurized dairy products, but also meat-derived products and ready-to-eat food. Other food vehicles have also been reported, such as caramel apples or soybean sprouts. MN listeriosis is associated with a median incubation time of 19–27.5 days according to available studies (range: 7–67 days), longer than for neurolisteriosis (9 days; range: 1–14 days) and bacteremia (2 days; range: 1–12 days).36 This may reflect the time needed for maternal bacteremia, placental, and fetal infection to develop

Maternal presentation

There are two main patterns of maternal presentation, namely nonspecific obstetric signs (uterine contractions, labor or abnormal fetal heart rate) and fetal loss,32 reported in 75% and 21%, respectively, in the prospective MONALISA cohort from France.

Obstetric outcome

Upon maternal listeriosis, only 5% of pregnant women experience uneventful subsequent pregnancy and delivery.32 Data from the MONALISA cohort evidenced major complications in 82% of pregnant mothers, including fetal losses, premature deliveries before 32 weeks of gestation (19% of the maternal cohort and 42% of all prematurely born children), and birth of infants with early or late onset listeriosis in the remaining cases.32 Importantly, despite recommendations for ampicillin-based preventive therapy for maternal fever in France, the rate of fetal losses related to listeriosis has not decreased over recent years.

Prevention and management

Prevention of MN listeriosis is based on adequate education in order to be aware of nutrition aspects. Ready-to-eat meats and dairy products made with unpasteurized milk should be avoided, and care should be taken to prevent cross contamination of foods by ensuring that preparation and cooking utensils and food preparation surfaces are clean. CDC recommendations give useful advice for prevention of listeriosis for general population and higher risks groups, such as pregnant women and immunodepressed patients (Table 4).

Treatment of listeriosis in pregnancy requires collaboration with an infectious diseases specialist, and should also involve neonatologists-pediatricians. Irrespective of the gestational age at which infection occurs in pregnancy, treatment is directed toward improving neonatal outcome. Early recognition and intervention are associated with improved outcome, and some physicians have advocated the use of antibiotics for the suspicion of Listeria infection for high-risk cases after samples for culture have been obtained. During pregnancy, the recommendation for therapy should include ampicillin or gentamicin.37 The duration for both regimens is 14 days, though the length of course may be longer in different clinical syndromes or if the pregnant woman is immunosuppressed.39 Although Listeria infections in pregnancy are rare, they should be considered as a cause of fever of unknown origin during pregnancy.

4

Key advices for MN listeriosis (From CDC recommendations for the Prevention of Listeriosis – www.cdc.gov/ncidod/dbmd/diseaseinfo/listeriosis_t.htm).38

For the general public:

  • Thoroughly cook raw food from animal sources, such as beef, pork, or poultry
  • Wash raw vegetables thoroughly before eating
  • Keep uncooked meats separate from vegetables and from cooked foods and ready-to-eat foods
  • Avoid unpasteurized (raw) milk or foods made from unpasteurized milk
  • Wash hands, knives, and cutting boards after the handling of uncooked foods
  • Consume perishable and ready-to-eat foods as soon as possible

For persons at high-risk, such as pregnant women and persons with weakened immune systems, in addition to the recommendations listed above:

  • Do not eat hot dogs, luncheon meats, or deli meats, unless they are reheated until steaming hot
  • Avoid getting fluid from hot dog packages on other foods, utensils, and food preparation surfaces, and wash hands after handling hot dogs, luncheon meats, and deli meats
  • Do not eat soft cheeses, such as feta, brie, and camembert; blue-veined cheeses; or Mexican-style cheeses, such as queso blanco, queso fresco, and Panela, unless they have labels that clearly state they are made from pasteurized milk
  • Do not eat refrigerated pâtés or meat spreads. Canned or shelf-stable pâtés and meat spreads may be eaten.
  • Do not eat refrigerated smoked seafood, unless it is contained in a cooked dish, such as a casserole. Refrigerated smoked seafood, such as salmon, trout, whitefish, cod, tuna or mackerel, is most often labeled as “nova-style,” “lox,” “kippered,” “smoked,” or “jerky.” The fish is found in the refrigerator section or sold at deli counters of grocery stores and delicatessens. Canned or shelf-stable smoked seafood may be eaten.

GROUP B STREPTOCOCCUS (GBS)

Epidemiology and pathogenesis

Group B streptococcus (GBS, or Streptococcus agalactiae) still remains a leading global cause of severe neonatal disease, affecting 0.5–3 newborns for every 1000 live births.40,41,42,43 Amongst infants with GBS invasive disease, two different clinical syndromes are identified according to age at onset:

  • Early-onset disease (EOD) mainly presenting with sepsis during the first week of life (0–6 days);
  • Late-onset disease (LOD) affecting infants aged >1 week to 3 months old (7–90 days), with bacteriemia and/or meningitis.10,40,44,45,46

Screening

Since the end of the 1990s, various strategies for prevention of the EOD have been implemented and have subsequently evolved. The widespread use of GBS antenatal screening and intrapartum antibiotic prophylaxis (IAP) of all GBS pregnant carriers, led to a reduction of more than 80% in early-onset neonatal disease being observed.10,41

However, recommendations are still a matter of debate, due to the challenges and controversies on how best to identify carriers and to use intrapartum antibiotic prophylaxis. Countries in Europe and around the world recommend either antenatal GBS screening and/or risk-based strategies. Other countries do not have national or any other kind of guidelines to follow.

The key points of the currently recommended strategy is a universal GBS screening, antepartum (35–37 weeks GBS culture screening), or intrapartum screening (with a rapid real-time PCR testing or other nucleic acid amplification tests (NAAT) showing high analytical performance). Where and when available, the intrapartum non-culture rapid tests are a good option for detecting pregnant GBS carriers. Picchiassi et al. recently evaluated the potential improvement of introducing an intrapartum test for the detection of GBS during labor and estimated its cost-effectiveness versus antepartum GBS screening culture.47,48

Treatments

Intrapartum GBS antibiotic prophylaxis is indicated in the situations summarized in Table 5. Agents and dosing for intrapartum prophylaxis should be administrated according to the recommendations adopted from revised CDC 2010 guidelines.43 A duration of IAP ≥4 hours of beta-lactam antibiotics (the first choice) has been shown to be highly effective in preventing vertical transmission of GBS to newborns and thus EOD consequences.49,50,51 Even though not ideal, a duration of IAP ≥2 hours can provide acceptable coverage.52

In case of less than acceptable coverage (<2 hours of IAP), the neonatologist should be informed. Moreover, the administration of IAP is unnecessary for elective cesarean delivery performed before labor onset with intact membranes. Another useful strategy to reduce maternal GBS colonization and potential vertical transmission could be the vaginal chlorhexidine application. Its use was associated with a significant reduction in both maternal and early neonatal infection in several studies, even though other studies didn’t show this correlation.

These different results may be influenced by methods of chlorhexidine use (0.2–0.4% vaginal chlorhexidine wash, antepartum or intrapartum); for this reason, further studies are needed.

5

Intrapartum GBS antibiotic prophylaxis (IAP).

Indications

  • Previous infant with GBS invasive disease
  • GBS bacteriuria documented during any trimester of the current pregnancy
  • Positive late antenatal GBS vaginal-rectal screening culture (35–37 weeks)
  • Positive intrapartum GBS vaginal screening with rapid test real-time PCR
  • Unknown GBS status at the onset of labor
  • Amniotic membranes rupture ≥18 hours
  • Intrapartum maternal temperature ≥38°C
  • Preterm labor (<37 weeks)

Antibiotics
(main regimens)

  • Ampicillin/amoxicillin (2 g IV initial dose, then 1 g IV every 4 hours until delivery)
  • Cefazolin (2 g IV initial dose, then 1 g every 8 hours until delivery – For patients allergic to penicillin, if no history of anaphylaxis or angioedema or respiratory distress or urticaria after receiving penicillin or a cephalosporin)
  • Clindamycin (900 mg IV every 8 hours until delivery)
  • Vancomycin (1 g IV every 12 hours until delivery)
  • Clindamycin and vancomycin for patients with history of penicillin anaphylaxis, angioedema, respiratory distress or urticaria

Vaginal chlorhexidine

  • Studies support vaginal chlorhexidine use to reduce maternal GBS colonization and early neonatal infection

CONCLUSIONS

This paper aims to give a practical overview on the most relevant non-viral infections that may occur in pregnancy and may variably damage the couple mother-baby.

All healthcare professionals and the entire population should have a high grade of awareness towards prevention and risks related with infections contracted during a vulnerable periods such as pre-conception, pregnancy and even postpartum.

PRACTICE RECOMMENDATIONS

Within separate infection sections above.


CONFLICTS OF INTEREST

Author(s) statement awaited.

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STUDY ASSESSMENT

Question 1

The risk of maternal–fetal transmission of toxoplasmosis is:

(a)up to 60% in the first trimester
(b)low in early pregnancy (about 5–15% in the first trimester)
(c)decreases as gestational age progresses
(d)a and c


Question 2

Pregnancy associated malaria:

(a)shows a homogeneous geographical distribution worldwide
(b)parity seems to be related with susceptibility to the malaria infection
(c)Rogerson criteria give a histopathological diagnosis of so called “placental malaria”
(d)b and c


Question 3

Tuberculosis (TB) in pregnancy:

(a)adverse obstetrics outcomes include preterm birth, low weight at birth and fetal growth restriction
(b)Risk for TB is estimated to be lower associated with HIV-burden
(c)Typical first-line TB regimen (with isoniazid, rifampicin, pyrazinamide, and ethambutol) have been shown to be dangerous for pregnant women throughout all trimesters
(d)b and c


Question 4

About congenital syphilis:

(a)the differentiation between early and late congenital syphilis was abandoned
(b)maternal serological tests usually guide the early diagnosis, and the short- and long-term newborn follow-up
(c)in late congenital syphilis signs and symptoms do not usually manifest until after 8 years of life
(d)all the previous are false


Question 5

Listeriosis during pregnancy:

(a)is a frequent and severe foodborne infection caused by a Gram-negative facultative intracellular bacillus
(b)fetal losses and preterm births are the major obstetrics outcomes reported
(c)L. monocytogenes is ubiquitous in nature and can contaminate a large array of unprocessed and processed food of animal and vegetal origin
(d)b and c


Question 6

Intrapartum antibiotic prophylaxis (IAP) for group B streptococcus:

(a)is not necessary in a pregnancy with physiological course
(b)is indicated in case of previous delivery of a baby with GBS sepsis
(c)endovenous vancomycin is the first-line antibiotic
(d)is not indicated in case of vaginal/rectal swab screening not available, but intact amniotic membrane