INFECTIONS IN PREGNANCY

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2021-1-HU01-KA220-HED-000027613 - COHRICE
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Syllabus

INFECTIONS IN PREGNANCY

(Basic level )

Learning objectives

  • Pregnancy causes physiological and immunological adaptations that allow the mother and fetus to communicate with precision in order to promote a healthy pregnancy.
  • These adaptations may make pregnant women more susceptible to infections, resulting in a variety of pregnancy complications; those pathogens may also be vertically transmitted to the fetus, resulting in adverse pregnancy outcomes.
  • Even though the placenta has developed a robust microbial defense to restrict vertical microbial transmission, certain microbial pathogens have evolved mechanisms to avoid the placental barrier and cause congenital diseases.
  • We discuss how microbial pathogens overcome the placental barrier to cause congenital diseases.
  • Prevention and treatment option are discussed

Introduction

Pregnancy is a critical “formative period” that has a significant impact on an individual’s health trajectory from fetal life to adulthood (Lash, 2015). Pregnancy is governed by a series of interconnected physiological and cellular mechanisms that promote maternal homeostasis and maintain optimal maternal-fetal interface while boosting fetal growth (Ander et al., 2019). These mechanisms enable the woman’s body to undergo, physiological and immunologic adaptations to host fetal antigens. From the mother’s immune system perspective, the fetus is an allograft that contains foreign antigens from the father (Robinson and Klein, 2012). The complexity of interaction between multiple host factors, including maternal infection or aberrant activation of the immune response during pregnancy, could lead to severe pregnancy complications and have a negative impact on pregnancy health or the developing fetus (Kumar et al., 2021a). Emerging evidence indicates that these pregnancy complications may pose significant challenges to fetal growth and development during pregnancy, as well as susceptibility to a variety of diseases later in life (Rahman et al., 2012; Nimeri et al., 2013).

MATERNAL INFECTIONS DURING PREGNANCY

Complications from various bacterial, viral, parasitic or fungal maternal infections can occur at any stage of pregnancy. Several studies suggest that pregnant women are more vulnerable to certain infections as a result of compensatory physiological and immunologic adaptations. The “TORCH” pathogens including Toxoplasma gondii, Other agents (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes simplex virus, are known to cause various pregnancy complications such as congenital infections, abortion, and intrauterine fetal growth restrictions (Megli and Coyne, 2021).

In addition to these most common infections linked to congenital defects, ZIKA infection, one of the newest TORCH pathogens, has recently sparked public concern, resulting in severe pregnancy complications ranging from fetal growth restriction to miscarriages in 2015-2017 (Coyne and Lazear, 2016). Most TORCH pathogens cause mild to moderate morbidity, but infections during pregnancy can have serious fetal consequences.

Acute maternal infection during pregnancy: may cause maternal morbidity and/or mortality or a wide range of obstetric complications, including low birth weight, stillbirth, miscarriage, and preterm labor.


  • Vertical transmission during pregnancy: which can result in congenital infection, intrauterine death, or permanent disability.

  • Perinatal transmission during delivery: which can lead to severe neonatal diseases.

Bacterial Infections

Acute bacterial infections during pregnancy can increase pregnancy complications and even have a negative pregnancy outcome. Bacterial infections, such as listeriosis, bacterial vaginosis, and sexually transmitted infections (STIs), can be caused by a single bacterial pathogen or by a microbial dysbiosis and can result in inflammasome signaling at the maternal-fetal interface and/or severe congenital anomalies in the developing fetus.

Listeriosis

Listeriosis is a foodborne bacterial infection caused by Listeria monocytogenes (Wang et al., 2021). Although this infection is uncommon in healthy people, pregnant women are particularly vulnerable to L. monocytogenes infection, possibly due to their altered immune status (Wang et al., 2021). Once transmitted through contaminated food, L. monocytogenes can cross the intestinal barrier to reach the placenta causing pregnancy complications such as preterm birth, stillbirth, congenital diseases, and sepsis (Mateus et al., 2013).

Bacterial Vaginosis

Bacterial vaginosis (BV) is characterized by the loss of healthy vaginal microbiome composition and an increase in the abundance of pathogenic microbes (Isik et al., 2016). BV is the most common gynecological infection among women during reproductive age and pregnancy (Isik et al., 2016; Kumar et al., 2021a), resulting in serious pregnancy complications such as miscarriage and preterm birth (Leitich et al., 2003).

Vaginal infections caused by group B Streptococcus (GBS), Escherichia coli, Bacteroides species, C. trachomatis, and N. gonorrhoeae can ascend to the genital tract and intraamniotic fluid causing chorioamnionitis (Galinsky et al., 2013; Jain et al., 2022). There is no clear evidence of how dysbiotic flora crosses the maternal barriers to reach the fetus, but GBS and E. coli are the most common pathogens found in the placenta and late-onset sepsis in neonates (Wilkie et al., 2019; Glaser et al., 2021).

Sexually Transmitted Infections

Changing the vaginal microenvironment during pregnancy may increase vaginal susceptibility to opportunistic STIs, which are frequently asymptomatic, but can cause severe pregnancy complications if left untreated. Ascending transmission of Chlamydia trachomatis and Neisseria gonorrhoeae can lead to pelvic inflammatory disease and endocarditis, as well as serious pregnancy complications like ectopic pregnancy, preterm birth, and low birth weight (Adachi et al., 2016; Heumann et al., 2017).

Syphilis is another common STI (caused by Treponema pallidum). Although the pathophysiology of T. pallidum ascending transmission is unknown, it may be dependent on both the gestational age of the fetus and the maternal stage of infection (Kimball et al., 2020; Primus et al., 2020). Vertical transmission of this bacterium can cause excessive inflammation at the maternal-fetal interface resulting in mild to severe pregnancy complications such as low birth weight, preterm birth, congenital anomalies, and sometimes fetal loss (Primus et al., 2020; Megli and Coyne, 2021).

Viral Infections

The majority of viruses are harmless, some pathogenic viruses can cross the maternal-fetal interface and influence placental functions, potentially causing fetal disease

Cytomegalovirus

Cytomegalovirus (CMV) is a DNA virus that belongs to the Herpesviridae family. CMV is the most common viral infection transmitted vertically in utero, causing a wide range of congenital disorders such as hearing and vision loss, intracranial calcifications, microcephaly, organ dysfunction, and intellectual disability (Liu et al., 2021). CMV is typically transmitted from person to person via infected bodily fluids such as blood, saliva, urine, and breast milk (Cannon et al., 2011). Once infected, the virus can live in bone marrow hematopoietic cells for the rest of one’s life (Collins-McMillen et al., 2018). However, it is a primary infection during pregnancy, rather than a reactivation of a persistent infection, that causes adverse pregnancy outcomes (Boppana et al., 2001; Maidji et al., 2006). Although the exact pathophysiology of CMV is unknown, the severity of the infection and fetal consequences are dependent on gestational age at the time of maternal infection: preterm birth or low birth weight, or hearing loss at birth or later in life.(Scott et al., 2012).

Herpes Simplex Virus

Herpes simplex virus (HSV) infections are often asymptomatic or cause mild symptoms in adults. Although the mechanism of its transplacental transmission is unknown, vertical transmission via direct contact with viral lesions in the genital tract during delivery is a more common route of neonatal infection (James et al., 2014). As a result, maternal HSV infection near the time of delivery increases the risk of vertical transmission, which can result in herpes simplex encephalitis, chorioretinitis, and intracranial calcification in neonates, with a 50-80% mortality rate in untreated cases (Pinninti and Kimberlin, 2013).

Rubella Virus

Rubella virus is a contagious virus in the Togaviridae family. Rubella virus is primarily transmitted via respiratory droplets, and in healthy adults, the infection causes mild illness with a low-grade fever; however, pregnant women who acquire rubella infection are 85 percent more likely to have a miscarriage or stillbirth, and the virus can induce necrosis in the syncytiotrophoblasts allowing it to cross the placental barrier (Lambert et al., 2015; Arora et al., 2017). The neonatal infection can cause severe birth defects with devastating, lifelong consequences such as ocular disorder, auditory problems, cardiovascular defects, speech disorder, and autism (Lambert et al., 2015).

Human Immunodeficiency Virus


Despite the availability of effective anti-HIV therapies, approximately 38 million people are still infected with HIV; among these 53% are women (Data, 2020). HIV can be transmitted through the placenta, perinatally (from direct contact to maternal vaginal fluids or blood during delivery), or postnatally (from breast milk or other sources) (Milligan and Overbaugh, 2014). As a result, congenital HIV transmission remains the leading cause of neonatal infections and the associated neonatal mortality or life-long devastation. Although it is unknown how HIV crosses the placental barrier, neonates born to HIV-infected women are always at a significantly high risk of vertical transmission (25 percent in the absence of antiretroviral therapy) (Bernstein and Wegman, 2018), which predispose them to serious health consequences, including developing acquired immunodeficiency syndrome (AIDS) and cardiovascular diseases (Maartens et al., 2014). Additionally, HIV infection is often associated with opportunistic infections, further increasing the risk of adverse pregnancy outcomes or vertical transmission (Johnson and Chakraborty, 2016).

Zika Virus

Zika virus (ZIKV) is an emerging arbovirus that is endemic in Africa, America, Asia, and Europe (Khaiboullina et al., 2018). ZIKV is primarily transmitted by the bite of an infected mosquito (Khaiboullina et al., 2018). Though ZIKV infection in adults causes mild symptoms with low-grade fever, headache, rash (Javanian et al., 2018), infection during pregnancy can cross the placenta and increase the risk of adverse pregnancy outcomes and postnatal developmental sequelae, such as miscarriage or stillbirth, or surviving infants show lifelong neurological defects such as enlarged ventricles, collapsing brains, and microcephaly. Accumulating evidence shows a link between ZIKV infection and congenital microcephaly (Tang et al., 2016; Gladwyn-Ng et al., 2018).

COVID-19

The most recent COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infected over 308 million subjects, and killed 5.5 million people worldwide, highlighting the importance of focusing on women’s health. SARS-CoV2 is primarily spread through close contact with an infected person, as well as through aerosols and respiratory droplets (Saadaoui et al., 2021) and can severely impact a variety of physiological and immunological processes, including pregnancy health and outcomes (Kumar and Al Khodor, 2020; Saadaoui et al., 2021). Although the virion genome has been observed in placental and vaginal samples (Dong et al., 2020), but the majority of recent reports show no evidence of vertical transmission (Saadaoui et al., 2021), suggesting that SARS- CoV2 cannot cross the placental barriers even in severely infected women. Despite the magnitude of the pandemic, pregnant women do not appear to vertically transfer the SARS- CoV2 to the fetus, but the inflammatory storm during SARS- CoV2 infection might indirectly induce pregnancy complications including maternal mortality, preeclampsia, and preterm birth (Villar et al., 2021)- and even fetal developmental obstacles.

Hepatitis

Universal screening for Hepatitis B is recommended for all pregnant women, regardless of previous testing or vaccination. (Troung A, Walker S, 2019)

Antenatal management

HBsAg-positive women, particularly those with a high viral load, should be counselled about the potential risk of transmission with invasive procedures. NIPT may be an option for some women. In those requiring invasive procedures, amniocentesis is probably safer than CVS, and transplacental amniocentesis is best avoided, if possible. All HBsAg-positive women should be tested for HBeAg anti-HBe, and HBV DNA level, to identify pregnancies at increased risk of post-exposure prophylaxis failure. Women should also have an assessment of liver function. Women with a high viral load in the third trimester (>200,000IU/ml, equivalent to 6 log copies/ml) should be offered antiviral therapy during late pregnancy to reduce viral load prior to delivery, and the risk of mother-to child transmission of Hepatitis B. In women who are candidates for antiviral therapy, tenofovir is recommended as a suitable first-line agent.(Troung A, Walker S, 2019)

Intrapartum Care

Invasive procedures such as fetal scalp electrodes and fetal scalp blood sampling in labour should be avoided. Hepatitis B infection should not alter mode of delivery and caesarean section should be reserved for usual obstetric indications. (Troung A, Walker S, 2019)

Post partum Care

All infants are offered routine HBV vaccination at birth, 6 weeks, 3 months and 5 months as per the Immunisation schedule. Infants born to HBsAg-positive mothers should also receive passive immunisation with HBIG at birth (preferably within 12 hours).

Breastfeeding 


Provided appropriate immunoprophylaxis has been given at birth, breastfeeding by HBsAg-positive women has not been shown to increase rates of perinatal transmission. Breastfeeding is not contraindicated in women with HBV receiving tenofovir.
Postpartum and long term follow up 

HBsAg-positive women receiving antiviral therapy in pregnancy should be monitored closely for several months post-partum for hepatitis flares. Lifelong follow up should be offered to HBsAg-positive women for monitoring of complications such as liver disease and hepatocellular carcinoma. (Troung A, Walker S, 2019)

Parasites

Toxoplasmosis

Toxoplasmosis is caused by Toxoplasma gondii resulting in more than 200,000 cases of congenital toxoplasmosis worldwide each year (Bigna et al., 2020). T. gondii can be vertically transmitted during pregnancy to cause toxoplasmosis and can lead to a high risk of congenital diseases (Bigna et al., 2020). Although, vertical transmission of toxoplasmosis can occur only in 30-40% of patients, but T. gondii infection during pregnancy could lead to an aberrant immune response in blood to control the infection (Sasai and Yamamoto, 2019).

Malaria

Malaria parasites, mainly Plasmodium falciparum and Plasmodium vivax, are other pathogens associated with an elevated risk of pregnancy complications, including fetal growth restriction and preterm birth (Briand et al., 2016; Romero et al., 2021). Malaria parasite-infected erythrocytes during pregnancy can adhere to placental receptors and trigger placental inflammation and subsequent damage, causing harm to both mother and her infant (Chua et al., 2021

Fungal Infections

The vast majority of fungi are harmless, and serious fungal infections are uncommon during pregnancy; however, they may occur with higher frequency in pregnant women, which potentially can increase maternal complications, including prematurity or, in some cases, even fetal loss (Rasti et al., 2014).

Candidiasis

Candidiasis is the most common cause of infection worldwide and is caused by Candida, an opportunistic yeast (Manolakaki et al., 2010). Vaginal candidiasis is the most common gynecological infection during reproductive age and pregnancy. According to emerging studies, up to 40% of women have vaginal colonization with Candida spp. during pregnancy (DiGiulio, 2012), which can easily transmit to the maternal-fetal barrier and progress to intra-amniotic infection which may lead to severe pregnancy complications including low birth weight or fetal candidiasis (Siriratsivawong et al., 2014; Drummond and Lionakis, 2018).

PREGNANCY COMPLICATIONS ASSOCIATED WITH MATERNAL INFECTIONS

Although complications caused by maternal infections or extrinsic abnormalities can occur at any stage of pregnancy, the first trimester is critical for placental development and the formation of a selective barrier between maternal and fetal tissue (Burton et al., 2016). The placental barrier, which is made up of multiple layers of maternal and fetal tissues, serves as a strong barrier against human pathogens reaching the fetus (Burton et al., 2016). Syncytiotrophoblasts (SYNs) are multinucleated cells that form a strong barrier between maternal and fetal blood within the placenta (Ander et al., 2019). Although the mechanism(s) by which pathogens breach the strong barriers remains unknown, intrauterine infection and associated inflammation are significant contributors to pregnancy complications. Surprisingly, approximately 25% of preterm births are microbially induced, either through intrauterine infection or maternal extrauterine infection (Agrawal and Hirsch, 2012).

MATERNAL SEPSIS

Sepsis may be defined as infection plus systemic manifestations of infection. Severe sepsis may be defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Septic shock is defined as the persistence of hypoperfusion despite adequate fluid replacement therapy. Symptoms of sepsis may be less distinctive than in the non-pregnant population and are not necessarily present in all cases; therefore, a high index of suspicion is necessary. (Pasupati D et al., 2012)

Disease progression may be rapid. Genital tract sepsis may present with constant severe abdominal pain and tenderness unrelieved by usual analgesia, and this should prompt urgent medical attention.

Clinical signs suggestive of sepsis include one or more of the following: pyrexia, hypothermia, tachycardia, tachypnoea, hypoxia, hypotension, oliguria, impaired consciousness and failure to respond to treatment. These signs, including pyrexia, may not always be present and are not necessarily related to the severity of sepsis. Regular observations of all vital signs (including temperature, pulse rate, blood pressure and respiratory rate) should be recorded on a Modified Early Obstetric Warning Score (MEOWS) chart. (Pasupati D et al., 2012)

Diagnostic and management of sepsis in pregnancy

Blood cultures are the key investigation and should be obtained prior to antibiotic administration; however, antibiotic treatment should be started without waiting for microbiology results.
Serum lactate should be measured within six hours of the suspicion of severe sepsis in order to guide management. Serum lactate ≥4 mmol/l is indicative of tissue hypoperfusion.
Any relevant imaging studies should be performed promptly in an attempt to confirm the source of infection.
Administration of intravenous broad spectrum antibiotics is recommended within one hour of suspicion of severe sepsis, with or without septic shock.
If genital tract sepsis is suspected, prompt early treatment with a combination of high-dose broad- spectrum intravenous antibiotics may be lifesaving. (Pasupati D et al., 2012)

In a critically ill pregnant woman, birth of the baby may be considered if it would be beneficial to the mother or the baby or to both. A decision on the timing and mode of birth should be made by a senior obstetrician following discussion with the woman if her condition allows.
If preterm delivery is anticipated, cautious consideration should be given to the use of antenatal corticosteroids for fetal lung maturity in the woman with sepsis.
During the intrapartum period, continuous electronic fetal monitoring is recommended. Changes in cardiotocography (CTG), such as changes in baseline variability or new onset decelerations, must prompt reassessment of maternal mean arterial pressure, hypoxia and acidaemia.
Epidural/spinal anaesthesia should be avoided in women with sepsis and a general anaesthetic will usually be required for caesarean section.
When a mother has been found to have invasive group A streptococcal infection in the peripartum period, the neonatologist should be informed and prophylactic antibiotics administered to the baby. (Pasupati D et al., 2012)

Future directions

Although technological advances over the past decade have made significant advances on multiple fronts, including a better understanding of molecular mechanisms, more precise diagnostics, and significantly improved therapeutic outcomes, the increasing incidences of pregnancy-related complications continue to pose daunting challenges in understanding their underlying pathogenesis, host-pathogen interaction at the maternal-fetal interface. As the incidence of maternal infections and associated pregnancy complications rises, a better understanding of the developmental events that result in host-pathogen interaction at the maternal-fetal interface and aberrant immune response is critical for the development of rational intervention strategies. With the help of advanced molecular techniques, the TORCH pathogens and their ability to cross the maternal-fetal barrier to cause congenital fetus disease, which was first proposed decades ago, have now been expanded to include emerging maternal infections and the effects of microbial dysbiosis.
Despite the progress made, there are still many unanswered and widely debated questions. For example, how the placental barrier remains uncompromised to multiple microbial pathogens that cause maternal systemic illness and bacteremia, uch as methicillin-resistant Staphylococcus aureus, E. coli, SARS- CoV2 virus, while other pathogens have mastered a variety of evasion mechanisms leading to serious maternal and fetal complications? The intriguing question now is, what levels of proinflammatory cytokines are required systematically or locally at the maternal-fetal interface to modulate placental integrity and allow vertical transmission of pathogens?


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