Pregnancy and Non-Sexually Transmitted Infections
- Ana Luiza Vilela Borges, Ana Luiza Vilela BorgesUniversity of Sao Paulo, School of Nursing
- Christiane Borges do Nascimento ChofakianChristiane Borges do Nascimento ChofakianUniversity of Sao Paulo, School of Arts, Sciences, and Humanities
- and Ana Paula Sayuri SatoAna Paula Sayuri SatoUniversity of Sao Paulo, School of Public Health
The focus on non-sexually transmitted infections during pregnancy is relevant, as they are one of the main causes of fetal and neonatal morbidity and mortality in many regions of the world, especially in low- and middle-income countries, respecting no national boundaries. While their possible vertical transmission may lead to adverse pregnancy outcomes, congenital rubella syndrome, measles, mumps, varicella, influenza, Zika virus, dengue, malaria, and toxoplasmosis are all preventable by measures such as vector control or improvement in sanitation, education, and socioeconomic status. Some are likewise preventable by specific vaccines already available, which can be administered in the first years of childhood. A package for intervention also includes adequate preconception care, routine antenatal screening, diagnosis, and treatment during pregnancy. Non-sexually transmitted diseases during pregnancy have different worldwide distributions and occasionally display as emerging or re-emerging diseases. Their epidemiological and clinical aspects, as well as evidence-based prevention and control measures, are relevant to settings with ongoing transmission or those about to be in vulnerable situations. Non-sexually transmitted infections are major public and global health concerns as potential causes of epidemics or pandemics, with numerous social, economic, and societal impacts..
It has long been recognized that pregnant women are uniquely vulnerable to many transmitted infections. In several situations, they are more severely affected by transmitted infections that predispose them to untoward consequences compared with the general population.
During pregnancy, numerous mechanical and pathophysiologic transformations occur (e.g., a decrease in respiratory volumes and urinary stasis due to an enlarging uterus; increased heart rate, stroke volume, and oxygen consumption; decreased lung capacity; among others), and immune adaptations are necessary to accommodate the fetus (Jamieson, Theiler, & Rasmussen, 2006).
Infections during pregnancy are one of the main causes of fetal and neonatal morbidity and mortality. Some non-sexually transmitted infections are more serious in pregnant than non-pregnant women mainly due to the potential of vertical transmission to the embryo, fetus, or neonate and increased risk of poor maternal outcomes. With adequate prevention, routine antenatal screening, diagnosis, and treatment of infectious diseases during pregnancy, it is possible to reduce maternal and neonatal morbidity and mortality, as well as to decrease the adverse effects of maternal infections to both mothers and newborns.
Vaccination is one of the most effective measures to prevent infectious diseases during pregnancy, particularly for rubella, varicella, measles, mumps, and influenza. Except for the influenza vaccine, the others must be taken before pregnancy. A challenge of the immunization programs is vaccine hesitancy, that is, refusal or delay in accepting vaccines (MacDonald & SAGE Working Group on Vaccine Hesitancy, 2015). This phenomenon certainly makes pregnant women more vulnerable to vaccine-preventable infections. In addition, reluctance by drug developers to test vaccines on pregnant women limits their options.
In this article, we address the most important non-sexually transmitted infections during pregnancy, especially those that have a higher risk of compromising maternal and newborn health worldwide, such as congenital rubella syndrome, measles, mumps, varicella, influenza, Zika virus, dengue, malaria, and toxoplasmosis. Furthermore, some challenging questions will be addressed, such as whether pregnant women are more susceptible to transmitted infections, the maternal and fetal outcomes, and the appropriate prophylaxis and treatment for pregnant women.
Transmitted Infections and the Immune System in Pregnant Women
The immune system during pregnancy is important, as it protects the mother from the environment and avoids harm to the fetus. It is considered to be a strengthened system of recognition, communication, and reparation; it can start a cascade process to preserve the well-being of the mother and the fetus. The way the mother’s immune system reacts to the environment is modified from the developing active immune system of the fetus. Thus, it is appropriate to denote pregnancy as a unique immune condition that is modulated rather than suppressed (Mor & Cardenas, 2010). This unique immune condition elucidates why pregnant women respond differently to transmitted infections compared with non-pregnant women. Therefore, pregnancy does not mean increased susceptibility to transmitted infections, but it means that the immune system is modulated, which implies a differentiated response that depends on both the microorganism and the stage of pregnancy (Mor & Cardenas, 2010).
Very briefly, the immune system can be divided into the innate/unspecific immune system and the acquired/adaptive immune system. The innate immune system comprises different cells such as macrophages and neutrophils, which together are in charge of defending against pathogens. Consequently, these cells activate other cells of the adaptive immune system, which contains lymphocytes (B- and T-lymphocytes). The adaptive immune system comprises the defense mechanisms and a memory (immunity) for the previously faced pathogens (Kourtis, Read, & Jamieson, 2014).
T regulatory (Treg) cells (CD4+ T cells and CD25+ T cells) are responsible for regulating the function of the T-helper (Th) cells, such as Th1, Th2, and Th17. T-helper cells have an important function in immunoregulation and immunostimulation (Saito, Nakashima, Shima, & Ito, 2010).
After contact with an antigen, the T-helper cells are activated. T-helper cells are responsible for the cell-mediated immune response and can be separated into Th1 cells (involved in cellular immunity), which produce interleukin (IL)-2 and interferon (IFN)-γ; and Th2 cells (involved in humoral immunity), which develop into IL-4, IL-5, and IL-13 (Figure 1; Kourtis et al., 2014; Saito et al., 2010).
As pregnancy advances, hormone levels are markedly modified. During pregnancy, the concentrations of estradiol and progesterone are significantly higher and increase over the progression of pregnancy, and the concentrations are highest in the third trimester. These hormonal modifications during pregnancy cause some of the different immunologic changes related to pregnancy (Figure 2; Klein, Jedlicka, & Pekosz, 2010).
Estradiol can improve some aspects of innate immunity and both cell-mediated and humoral immunity responses (Kourtis et al., 2014). Generally, low concentrations of estradiol stimulate Th1 cells’ response and, consequently, cellular immunity, as they are responsible for fighting viruses and other intracellular pathogens, in addition to promoting a pro-inflammatory response. On the other hand, high concentrations of estradiol increase the responses of Th2 cells and humoral immunity. Th2 cells are responsible for stimulating B cells to produce antibodies and fight extracellular organisms, in addition to causing an anti-inflammatory response necessary for the maintenance of the pregnancy (Mor & Cardenas, 2010; Straub, 2007). The maternal immune response can be suppressed by progesterone, which alters the balance between Th1 and Th2 responses. An imbalance between the two pathways can cause illness; thus, the Th1/Th2 dynamics plays an important role during the gestational period (Figure 2).
During the first and early second trimester, including implantation and placentation, there is a need for an inflammatory response to ensure proper repair of the uterine epithelium and elimination of cellular fragments. The increased pro-inflammatory cytokines produced by monocytes and macrophages, among other cells in this phase, lead to Th1 responses (Mor & Cardenas, 2010). On the other hand, the increase in the estrogen and progesterone hormones as the pregnancy progresses, such as observed in the second and third trimester, causes an anti-inflammatory state (Mor & Cardenas, 2010). This state supports a switch to Th2 responses, which are important to maintain pregnancy. The prevalence of Th2 cells over Th1 cells is beneficial to maintain pregnancy (i.e., to the developing embryo), increasing placental growth and function as well as increasing antibody responses. However, during labor the immune cells invade the myometrium to stimulate reactivation of an inflammatory process. The contraction of the uterus, expulsion of the newborn, and rejection of the placenta are caused by this pro-inflammatory milieu (Mor & Cardenas, 2010; Robinson & Klein, 2012; Woidacki, Zenclussen, & Siebenhaar, 2014; Figure 2).
It is important to highlight that this description of the immune system during pregnancy (the predominant Th2 cell immunity during pregnancy) is simplified (Chaouat, 2007). The Th1/Th2 response during pregnancy includes Th1/Th2/Th17 and Treg cells. Th17 cells, which generate the pro-inflammatory cytokine (IL-17), are relevant for the induction of inflammation, which is necessary for a successful implantation. Th17 cells are associated with defenses against bacteria, fungi, and viruses, as they stimulate protective immune responses against microorganisms (Saito et al., 2010).
In case of infection during pregnancy, the Th2 responses are altered, which can result in preterm labor or spontaneous abortion. In addition, the predisposition to viral infections during pregnancy requires Th1 responses for an efficient control of the disease (Klein et al., 2010).
Pregnant women are exposed to many infectious agents. Transmitted infections can cross the placenta reaching the fetus, and may cause damaging consequences on the pregnancy not only to the mother but also to the fetus, with possible devastating or long-term sequelae (Goldenberg, Hauth, & Andrews, 2000; Han et al., 2006; Seubert et al., 2000). In some cases, the infection can lead to embryonic and fetal death, induce miscarriage, or induce major congenital anomalies (Srinivas et al., 2006). Even in the nonexistence of vertical transmission, the fetus could be harmfully affected by the maternal response to the infection (Srinivas et al., 2006). Therefore, the fetus may be both affected by the direct transmission of the agent and indirectly by the consequences of maternal infection (Pan American Health Organization [PAHO]/World Health Organization [WHO]/Latin American Centre for Perinatology/Women and Reproductive Health [CLAP/SMR], 2008).
The potential impact of infectious diseases during pregnancy on the fetus and neonate can be antenatal (congenital), which means that it occurs in utero (leading to preterm labor, fetal injury, malformation, fetal congenital anomalies of the central nervous system and the cardiovascular system, intrauterine growth restriction, or intrauterine death); perinatal, which means it occurs around the time of delivery through contact with infected maternal blood and genital secretions (leading to sepsis or perinatal death); or postnatal (leading to infection, low birth weight, malformation, developmental abnormalities, or neonatal death; Jeffery & Lahra, 2007).
Intrauterine transmission varies according to the infectious agent, the gestational age at the time of transmission, and the mother’s immune status. Generally, primary infections during pregnancy are significantly more harmful than reinfections or reactivations of infection. Similarly, infections acquired at the beginning of the pregnancy can result in more severe consequences (PAHO/WHO, CLAP/SMR, 2008).
There are different routes by which an infection may reach the intra-amniotic cavity. Maternal infections can be transmitted to the embryo and the fetus by an ascending infection of the superior part of the vagina to the amniotic fluid throughout the uterine cervix, or through hematogenous spread (involving, spread by, or arising in the blood) as a result of maternal viremia, bacteremia, or parasitemia. If infections are transmitted by the ascending route, the pathogens can cause funisitis (inflammation of the connective tissue of the umbilical cord) and chorioamnionitis (inflammation of the placenta), and may cause premature rupture of the membranes and preterm labor. And, in cases in which infections spread hematogenously, which is more commonly observed in viral infections, the placenta is often infected, resulting in chronic deciduitis of the placenta (chronic inflammation of the placenta, predominantly involving the maternal side of the placenta) and villitis (placental injury; PAHO/WHO, CLAP/SMR, 2008).
The Placenta: An Active Immunologic Site
The placenta is an active immunologic organ with an innate immune system that can identify and respond to pathogens. More than a barrier, the placenta can be viewed as a controller of the traffic between the mother and fetus (Mold et al., 2008; Stevens et al., 2004). In fact, most congenital fetal infections (caused by viral infections) never occur due to the powerful immune-regulatory system of the placenta, which defends the fetus from systemic infection (Mor, Romero, Aldo, & Abrahams, 2005; Stevens et al., 2004). Nevertheless, the placenta is also a favorable environment for infections by microorganisms, which in non-pregnant woman would never occur (Kourtis et al., 2014).
The placental tropism of specific microorganisms affects the gravity of certain transmitted infections during pregnancy. A viral infection in the placenta provokes the production of inflammatory cytokines, which may activate the maternal and fetal immune system. Therefore, during pregnancy it is not only the maternal immune system that responds, but also the fetal/placental unit. This activation may have numerous consequences, such as exposing the mother to other microorganisms and, therefore, increase the risk of pregnant women to infection; disseminate an inflammatory response in the fetus, although there is no viral transmission; damage the placenta; cause miscarriage; or cause adverse long-term neuro-developmental or other sequelae (Kourtis et al., 2014; Mor & Cardenas, 2010).
Beyond morphologic sequelae that affect the fetal brain, the occurrence of fetal inflammatory response syndrome increases the risk of future autism, schizophrenia, neurosensorial deficits, and psychosis induced in the neonatal period (Golan, Lev, Hallak, Sorokin, & Huleihel, 2005; Mor & Cardenas, 2010; Shi et al., 2009). Furthermore, the fetal immune response may predispose the fetus to diseases not only in childhood, but also later in life (Romero, Gotsch, Pineles, & Kusanovic, 2007).
It is important to emphasize that antenatal infections may have an important effect on the responses to similar infectious agents. This type of outcome can be observed in other circumstances associated with placental infection, such as malaria. Surviving newborns with placental malaria may experience adverse neurodevelopmental sequelae and may have abnormal responses to a later parasitic infection (Desai et al., 2007; Labeaud, Malhotra, King, King, & King, 2009). The placenta restricts the passage of the malaria parasite to the fetus, thus transplacental transmission of the malaria parasite and consequently of congenital malaria occurs infrequently (Uneke, 2007). However, the inflammatory process in the placenta affects normal fetal development (Desai et al., 2007).
Nine non-sexually transmitted diseases that may occur during pregnancy, with poor outcomes for the mother, for the fetus, or for both, are presented. All of them are preventable by specific vaccines or other measures, such as vector control or improvement in sanitation, education, and socioeconomic status. Emerging and reemerging diseases, and even diseases that have previously been controlled in several regions of the world, are global health challenges in the early 21st century, due to societal and ecologic issues. Such challenges are mainly related to climatic changes, crossing national and territorial boundaries (e.g., commuting), resistance to medicines, living conditions, and access to health services. Therefore, the non-sexually transmitted diseases selected for discussion have some unique and challenging characteristics and provide important materials for progress in the area of health care.
Rubella, so-called German measles, is a self-limiting and mild viral disease that usually affects children and young adults. It is an important public health concern due to the teratogenic potential of the rubella virus, which causes Congenital Rubella Syndrome (CRS). Before immunization programs were well implemented, rubella was usually seen in late winter and spring, and epidemics occurred in 3- to 4-year intervals (Cooper & Alford, 2006).
Vaccination led to a substantial reduction in the incidence of rubella and CRS worldwide (Leeper & Lutzkanin, 2018; Neu, Duchon, & Zachariah, 2015; World Health Organization [WHO], 2011). Reported cases of rubella to the World Health Organization decreased 97% from 670,894 cases in 165 countries in 2000 to 22,361 cases in 102 countries in 2016. In the Americas, the elimination of CRS was achieved in 2015 (Grant, Reef, Patel, Knapp, & Dabbagh, 2017).
The rubella virus is an enveloped, positive single-stranded RNA virus with a single serotype that belongs to the Togaviridae family and genus Rubivirus. Humans are the only known host (Cooper & Alford, 2006).
The infectious period lasts 8 days before and after the rash. The transmission occurs by the respiratory route through contact with nasopharyngeal secretions of an infected person (aerosolized particles or direct contact). The rubella virus replicates in the nasopharyngeal mucosa and local lymph nodes and then spreads to different organs via the systemic circulation. In pregnant women, the virus infects the placenta and the developing fetus (Bouthry et al., 2014; Cooper & Alford, 2006; Neu et al., 2015; WHO, 2011).
Disease Characteristics (Effects on Maternal and Child Health)
After the infection, the clinical signs appear within 12–23 days of the incubation period, including a prodromal illness (fever <39°C, malaise, and adenopathy), followed by the maculopapular rash that lasts 1–3 days. The rash starts at the face and the neck and progresses down the body. Adult women frequently have joint symptoms such as arthritis and arthralgia of short duration. Post-infection encephalitis occurs in 1/6,000 cases (Neu et al., 2015; WHO, 2011).
The most important consequence of rubella is CRS. Infection with rubella just before conception or in 8–10 weeks of gestation can cause multiple fetal defects in more than 90% of the cases, resulting in miscarriage, fetal death, or congenital defects. The risk decreases in the second trimester (10–20%) but increases again at term (>60%; Bouthry et al., 2014; Lambert, Strebel, Orenstein, Icenogle, & Poland, 2015; Leeper & Lutzkanin, 2018; WHO, 2011). Birth defects associated with CRS include ophthalmic (e.g., cataracts, microphthalmia, glaucoma); auditory (e.g., sensorineural deafness); cardiac (e.g., peripheral pulmonary artery stenosis, patent ductus arteriosus, or ventricular septal defects); and craniofacial (e.g., microcephaly). There are also developmental disabilities (e.g., visual and hearing impairments) and an increased risk for type I diabetes mellitus, thyroiditis, and developmental delay such as autism (Lambert et al. 2015; WHO, 2011).
Prevention of CRS is achieved by providing rubella vaccination to non-pregnant women who are of childbearing age. A single dose of rubella vaccine confers more than 95% long-lasting immunity. Proof of rubella immunity should be documented at the first prenatal visit either through serologic testing or through documentation of immunization (Leeper & Lutzkanin, 2018; WHO, 2011).
Varicella (chickenpox) is a self-limiting, mild viral disease, but can be serious in early pregnancy due to the high risk of congenital varicella syndrome, and for the neonate, if the infection occurs around the time of delivery. The disease is present worldwide, and if the vaccine is not embedded in immunization programs, most people may be infected before adulthood. The disease has a strong seasonality with peaks during the winter and spring (WHO, 2014). The annual incidence in pregnancy is low (0.4/0.7/1,000) due to natural or acquired immunity (Leeper & Lutzkanin, 2018).
The varicella-zoster virus (Herpesvirus varicellae) is a double-stranded DNA virus and one of the most communicable viruses in humans, with no extra reservoir (Gershon, 2006).
The transmission occurs by direct contact with the varicella rash or by inhalation of aerosolized droplets from respiratory tract secretions, 1–2 days before the rash to 5 days after the onset of the rash. The incubation period is 15 days, varying from 13 to 17 days. In pregnancy, the virus may be transferred across the placenta and cause congenital or neonatal varicella (Gershon, 2006; WHO, 2014).
Disease Characteristics (Effects on Maternal and Child Health)
In adults, the rash is often preceded by moderate fever and systemic symptoms. The disease is characterized by a maculopapular rash of centripetal distribution, beginning on the face or scalp and spreading to the trunk (red macules), which becomes vesicles, and evolves rapidly to pustules and then crusts (Gershon, 2006).
Although varicella is considered a self-limiting disease, it may be associated with severe complications when mediated to secondary bacterial infection (WHO, 2014). Infection during pregnancy may cause pneumonia with a high case-fatality rate in 10–20% of women (Leeper & Lutzkanin, 2018).
In pregnancy, if an acute infection occurs between 5 days before and 2 days following delivery, the infant has a high risk of acquiring the varicella-zoster virus. Infection before 20 weeks of gestation could result in fetal demise, prematurity, low birth weight, intrauterine growth restriction, skin lesions, limb deformities, ocular abnormalities (e.g., cataracts, microphthalmia, chorioretinitis, Horner syndrome, anisocoria, and nystagmus), and neurologic abnormalities (e.g., cortical atrophy, mental retardation, microcephaly, seizures, dysphagia, limb paresis, and congenital varicella syndrome; Bialas, Swamy, & Permar, 2015; Enders, Miller, Cradock-Watson, Bolley, & Ridehalgh, 1994; Gershon, 2006; Lamont et al., 2011). If the infection occurs near term, the risk of the neonate developing varicella within the first 10 days of life is high. The postnatally acquired varicella (between 10 and 28 days after birth) could also occur by a nosocomial infection in the newborn nursery (Gershon, 2006).
For treatment, acyclovir is the antiviral drug indicated, even during pregnancy (Gershon, 2006).
Varicella vaccine is contraindicated during pregnancy. Women without evidence of immunity should be vaccinated at least 4 weeks before the pregnancy or in the postpartum period, to prevent infection during subsequent pregnancies. If a non-immune pregnant woman is exposed to an infected person with varicella, varicella-zoster immune globulin should be administered, as it is highly effective in protecting infants against neonatal and congenital varicella infection (WHO, 2014).
Measles is a highly contagious disease. Despite the availability of a safe and effective vaccine, measles remains a major problem worldwide, causing more than 100,000 deaths among young children annually (WHO, 2017). Measles was a childhood disease in the pre-vaccine era, so an infection during pregnancy was unusual. Its incidence decreased dramatically after the success of measles vaccine programs, but adults could become vulnerable to the disease with no natural booster anymore (Cherry, 2009a; Gershon, 2006; WHO, 2017).
The measles virus is a single-stranded, enveloped RNA paramyxovirus that is a member of the Morbillivirus genus.
Transmission occurs by respiratory route (aerosolized droplets of respiratory secretions) with contact with the nose and possibly the conjunctivae of the new host. No animal reservoir exists, and an asymptomatic carrier has not been documented. The incubation period of measles is about 10 days (range of 8–12 days). The infectious period occurs 4 days before the appearance of the rash until 3 days after the rash onset (Cherry, 2009a; Gershon, 2006).
Disease Characteristics (Effects on Maternal and Child Health)
Measles is a distinct disease characterized by malaise, fever, conjunctivitis, coughing, coryza (runny nose), and a generalized maculopapular rash that usually appears after Koplik’s spots (specific enanthem). The rash appears around the 14th day after exposure, and it spreads centrifugally from the head to the feet. Complications frequently involving the respiratory tract could occur in about one-third of the cases and are more common among young children and adults. Bacterial pneumonia is a complication that most frequently results in death, particularly caused by Streptococcus pneumonia, Staphylococcus aureus, and Streptococcus pyongenes (Cherry, 2009a).
Available data show that pregnant women with measles are at greater risk of having severe complications, being hospitalized, and dying compared to non-pregnant women (Chiba, Saito, Suzuki, Honda, & Yaegashi, 2003; Gershon, 2006).
The teratogenic potential of measles is unclear due to the rarity of infection during pregnancy. Most published studies are case series with no comparison groups (Gershon, 2006). Measles during pregnancy could result in higher risk of spontaneous abortion, premature labor, and low birth weight infants (Atmar, Englund, & Hammill, 1992; Chiba et al., 2003; Ornoy & Tenenbaum, 2006; Rasmussen & Jamieson, 2015; White, Boldt, Holditch, Poland, & Jacobson, 2012). Birth defects have rarely been reported (Gershon, 2006).
The live-attenuated measles vaccine is contraindicated in pregnant women. Passive immunization is recommended for preventing measles in exposed and susceptible pregnant women, neonates, and their contacts in the delivery room or newborn nursery (a dose of intramuscular immunoglobulin within 72 hours of exposure; Cherry, 2009a; Gershon, 2006).
Mumps is an acute contagious disease, with the swelling of one or both parotid glands noticeably occurring. It is a childhood disease, particularly occurring between ages 5 and 15, with peak incidence in the winter. The disease is uncommon among children in countries with optimal mumps vaccine coverage (Cherry, 2009b; Gershon, 2006). The incidence of mumps during pregnancy is unknown, but it was probably low even before the vaccination programs, despite the large exposure to the virus. Prospective studies found an incidence rate starting from 0.8 to 10 cases per 10,000 pregnancies (Gershon, 2006).
Transmission occurs by the respiratory route through contact with nuclei droplets from an infected person and fomites. After entering the host, the virus initially replicates in the epithelium of the upper respiratory tract. The incubation period (exposure to infection and onset of parotids) lasts 14–18 days, varying from 7 to 23 days (Cherry, 2009b).
Disease Characteristics (Effects on Maternal and Child Health)
Unilateral or bilateral parotids usually appear within 24 hours after the prodromal period (fever, malaise, myalgia, and anorexia 14–18 days after exposure), but may be delayed for a week or more. The swelling of the glands is accompanied by tenderness to palpation and obliteration of the space between the ear lobe and the angle of the mandible. Complications like aseptic meningitis resulting in death or disability can occur in 10% of the cases. Other possible complications are orchids in males, permanent deafness, meningoencephalitis, and pancreatitis (Ornoy & Tenenbaum, 2006).
Unlike varicella and measles, mumps during pregnancy is generally benign. Spontaneous abortion or intrauterine fetal death are associated with gestational mumps when exposure occurs during the first trimester. However, definitive evidence of teratogenic potential is lacking or inconclusive. An association between maternal mumps infection and endocardial fibroelastosis in the fetus was found in some studies, but refuted by others (Gershon, 2006; White et al., 2012).
Treatment for mumps infection is symptomatic. Analgesics and application of heat or cold to the parotid area may be helpful. Mastitis may be managed by the application of ice packs and breast binders (Gershon, 2006). Adequate attention should be given to hydration and alimentation (Cherry, 2009b).
A live-attenuated mumps virus vaccine is not recommended for pregnant women. Passive immunization for mumps is ineffective (Gershon, 2006).
Influenza A and B
Influenza is an acute respiratory infection that annually affects about 5–10% of adults and 20–30% of children in the world. Seasonal epidemics are more likely to occur during the winter in temperate climates and throughout the year, with irregular outbreaks in the tropics (WHO, 2012). Despite the availability of vaccines and improvement in therapy, the impact of influenza on mortality rates is still important (Maldonado, 2006).
The influenza virus is a single-stranded RNA virus and belongs to the Orthomyxoviridae family. There are three major types: A, B, and C. Influenza A and B virus are more relevant as human diseases. Influenza A virus is characterized by a pair of surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). The virus is genetically unstable, and minor mutation in the HA gene (“antigenic drift”) occurs relatively often. Major mutation (“antigenic shift”) is caused by the reassortment of genetic material from different A subtypes (Maldonado, 2006; WHO, 2012).
Influenza virus transmission mainly occurs by droplets and aerosols inhaled by susceptible hosts from the respiratory secretions of infected people, or through contact with contaminated fomites. The incubation period of influenza is 2 days, but can vary from 1 to 4 days (WHO, 2012).
Disease Characteristics (Effects on Maternal and Child Health)
Common symptoms of influenza include fever, coughing, malaise, coryza, headache, and muscle and joint pain (WHO, 2012). There are several complications of influenza such as primary influenza pneumonia, staphylococcal pneumonia, encephalitis, and Reye’s syndrome (Maldonado, 2006). Pregnant women are at risk of developing severe disease, resulting in hospitalization or death from influenza, as are older adults, children under 5 years old, and individuals with chronic disease (Maldonado, 2006; WHO, 2012). Influenza infection during pregnancy can result in stillbirth, preterm delivery, low birth weight, and neonatal death (Creanga et al., 2010; Mosby, Rasmussen, & Jamieson, 2011; Omer et al., 2011). There is a lack of data on the teratogenic role of influenza, but intrauterine exposure to the virus does not cause any disease in the fetus (Maldonado, 2006).
Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, and laninamivir) are recommended by the WHO as the first-line treatment for those who require antiviral therapy. Oseltamivir is the most widely used and data on its safety for pregnant women and young children is available (WHO, 2012).
Pregnant women should be vaccinated with the trivalent inactivated vaccine (TIV). There is evidence that TIV is safe during pregnancy and substantially reduces the risk of severe disease. It is effective in preventing influenza transmission between women and their young children (WHO, 2012).
Dengue is a mosquito-borne viral infection with public health importance due to its growing incidence and geographic spread. It is endemic in more than 100 countries, mostly in South America, Southeast Asia, and the Western Pacific, and most frequent in urban areas with tropical and subtropical temperatures. The disease is also spreading to new areas, like some countries in Europe. WHO estimates that almost half of the world’s population is now at risk of acquiring the disease (WHO, 2019).
The disease is caused by four viral serotypes (DENV-1, DENV-2, DENV-3, and DENV-4), which can succeed each other or even co-occur. Lifelong immunity against one particular serotype has been observed, but cross-immunity to the other serotypes after recovery is partial and temporary. It is important to note that subsequent infections by other serotypes increase the risk of developing severe dengue (WHO, 2019).
Dengue virus is transmitted to humans through the bite of infected female mosquitoes of Aedes aegypti and, in some areas, Aedes albopictus. Aedes aegypti also transmits chikungunya, yellow fever, and Zika virus.
Disease Characteristics (Effects on Maternal and Child Health)
Dengue can affect both children and adults. After an incubation of 4–10 days after the bite of an infected mosquito, affected individuals may have high fever (40°C/104°F) and at least two other symptoms, such as severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands, or rash. Symptoms usually last for 2–7 days (WHO, 2019).
Little is known about specific adverse effects of dengue infection during pregnancy. There is some evidence that dengue during pregnancy has been associated with poor fetal and maternal outcomes. Poor outcomes include complications such as postpartum hemorrhage and increased rates of caesarean section (Adam, Jumaa, Elbashir, & Karsany, 2010; Machain-Williams et al., 2018; Nagoya, 2018), increased risk of maternal death (Feitoza, Koifman, Koifman, & Saraceni,, 2017; Machain-Williams et al., 2018), and congenital malformations (Paixão et al., 2018). Researchers recommend that health professionals dedicated to antenatal care should test women for dengue and if they are positive, should perform a careful evaluation to be able to distinguish between severe dengue and common obstetric conditions, which may allow them to intervene in a timely way and avoid maternal death (Feitoza et al., 2017; Malhotra, Chanana, & Kumar, 2006; Nagoya, 2018; Paixão et al., 2018).
Dengue prevention and control rely on avoiding mosquito bites through vector control measures such as preventing mosquitoes from laying eggs by eliminating habitats; keeping outdoor containers and other water storage barrels clean and covered; and using personal protection such as repellents and window screens (CDC, 2019; WHO, 2019). A live attenuated viral vaccine to prevent dengue infection is licensed. The WHO Global Advisory Committee on Vaccine Safety concluded that the product is effective and safe in individuals who have had dengue infection in the past, but brings risks of severe dengue in those who experience their first natural dengue infection after vaccination; thus, there is still a need to develop a safe and effective vaccine that prevents dengue (WHO, 2018a).
According to WHO, approximately 219 million cases of malaria occurred worldwide in 2017, with an estimated 435,000 deaths. Sub-Saharan Africa is the most burdened region, but malaria is also observed in the Eastern Mediterranean, Southeast Asia, West Pacific, and Latin America. Except for Southeast Asia, where the incidence rate among the population at risk fell from 2010 to 2017, all other endemic regions have seen either little slowing or even an increase in the incidence rate in the same period (WHO, 2018b).
Children under 5 years of age and pregnant women are the most vulnerable groups affected by malaria. Pregnant women are vulnerable to become infected, to have a recurrence, to develop severe complications, and to die from malaria (WHO, 2018b, 2018c).
Malaria is a disease caused by parasites of the Plasmodium family (P. falciparum, P. vivax, P. malariae, P. knowlesi, and P. ovale) that are transmitted to humans by female Anopheles mosquitoes.
P. falciparum is the most prevalent malaria parasite in Africa, Southeast Asia, the Eastern Mediterranean, and the Western Pacific, whereas P. vivax is the most prevalent in Latin America. Both species coexist in South America, Southeast Asia, and the Western Pacific (Bauserman et al., 2019; WHO, 2018b).
Malaria is transmitted to humans through the bites of female Anopheles mosquitoes that are infected with Plasmodium species.
Disease Characteristics (Effects on Maternal and Child Health)
The symptoms of malaria are similar to other febrile diseases, including fever, sometimes accompanied by chills, sweats, headache, or other unspecific symptoms (WHO, 2015a, 2015b). Among pregnant women, the clinical signs and symptoms vary from no signs at all to severe anemia and death (Bauserman et al., 2019).
Although most malarial infections during pregnancy remain asymptomatic in high-transmission areas (Eisele et al., 2012), changes in placental development and function lead to disrupted nutritional exchange between mother and fetus, especially under P. falciparum. Therefore, the effects of the parasites on reproductive outcomes may include abortion, stillbirth, preterm birth, low birth weight, and perinatal mortality (Bauserman et al., 2019; Katz et al., 2013; McGready et al., 2012; Moore, Fowkes et al., 2017).
The disease symptoms and consequences for pregnant women, the fetus, and the newborn vary according to a given geographic area (whether it is a low- or high-transmission area), the infecting Plasmodium species, the intensity of parasite transmission, and the individual’s level of acquired immunity (Rogerson, Hviid, Duffy, Leke, & Taylor, 2007; WHO, 2015a, 2018c). The adverse effects of P. falciparum infection in pregnancy in high-transmission areas, for example, are most pronounced for primiparous women, but with P. vivax, the effect appears to increase with successive pregnancies (Bauserman et al., 2019; WHO, 2018c). In low-transmission settings, however, all pregnant women, regardless of how many times they have been pregnant, are highly vulnerable to malaria due to relatively little acquired immunity (WHO, 2018b, 2018c). Even in high-transmission settings, some women are more vulnerable to malaria during pregnancy than others: an increased risk of malaria in pregnancy was associated with women who lived in the poorest households, in traditional houses, and who had low educational status (Okiring et al., 2019).
Malaria prevention is necessary throughout pregnancy, as the strongest associations between malaria in pregnancy and negative outcomes such as preterm birth and low birth weight were observed among women with malaria detected in the third trimester, despite treatment (Moore, Simpson et al., 2017).
Malaria can be treated. All individuals who are suspected to have malaria should have the diagnosis confirmed by parasite detection methods such as microscopy or a rapid diagnostic test. Access to prompt diagnosis and treatment is the most effective way to prevent an uncomplicated case of malaria from progressing into severe disease and death.
Combination therapy treatment in pregnancy is recommended according to the disease status (uncomplicated versus severe), to the Plasmodium species, and to the pregnancy trimester (WHO, 2015b). After diagnostic confirmation, every individual with uncomplicated malaria should be promptly treated with the indicated therapy, but it is to be considered that some P. falciparum resistance to artemisinin has already been reported (Bauserman et al., 2019). Severe malaria requires urgent medical care.
An important challenge to malaria control is that many infected pregnant women with malaria parasites remain asymptomatic or undiagnosed and are therefore invisible to health care services. These individuals contribute to the cycle of malaria transmission; thus, preventive measures should be taken alongside rapid diagnosis and treatment (WHO, 2015a, 2018b).
For pregnant women in moderate-to-high malaria transmission areas in sub-Saharan Africa, malaria prevention is provided through intermittent preventive treatment in pregnancy (IPTp; WHO, 2018b, 2018c). The use of long-lasting insecticidal nets (LLINs) is also indicated for preventing malaria in pregnant women (WHO, 2018b).
IPTp is a full therapeutic course of antimalarial medicine given to pregnant women at routine antenatal care visits, regardless of whether the woman is infected with malaria. IPTp reduces maternal malaria episodes, maternal and fetal anemia, placental parasitemia, low birth weight, and neonatal mortality. Updated WHO policy recommends IPTp using a minimum of three doses of sulfadoxine-pyrimethamine (SP; WHO, 2018c). Thus, after the first trimester, every pregnant woman should receive the recommended doses of SP at every antenatal care visit, beginning the first dose at 13–16 weeks of pregnancy (second trimester). The next dose should be given at least 1 month apart from each other, until delivery. SP currently targets only P. falciparum; therefore, other types of IPTs need to be developed for other types of malaria (WHO, 2018c).
Unfortunately, poor implementation of IPTp policy has been observed (Yaya, Uthman, Amouzou, & Bishwajit, 2018). A study showed that, among 33 African countries that reported on IPTp coverage levels in 2017, only 22% of eligible pregnant women received the recommended three or more doses of SP (WHO, 2018b). Investments in increasing the number of antenatal care visits and on improving the quality of antenatal care are important to provide effective coverage with IPTp, to provide enough doses to protect women and fetuses from the parasites (Buh, Kota, Bishwajit, & Yaya, 2019; Okiring et al., 2019). Alongside efforts to maintain high coverage with IPTp, LLINs, and prompt and effective diagnosis and treatment, housing improvements and education initiatives could be explored as supplementary approaches to reduce malaria in pregnancy (Okiring et al., 2019).
Also, widespread parasite resistance to SP among P. falciparum parasites (Eijik et al., 2019) and mosquito resistance to the pyrethroids used in LLINs have led to concern over the future efficacy of such interventions (Okiring et al., 2019; WHO, 2018b).
Concerning malaria prevention, several vaccine products are currently in various stages of development to prevent P. falciparum and P. vivax infections. The benefits of a new vaccine will be in addition to the measures already mentioned, such as the use of insecticide-treated nets, prompt diagnosis, and effective antimalarial treatment, and, clearly, IPTp (Bauserman et al., 2019; WHO, 2018b).
To date (2020), 86 countries and territories worldwide have reported evidence of Zika virus infection, in the Americas, Africa, Asia, and the Pacific (WHO, 2018d). The number of cases of Zika virus reached its peak in 2016, and the consequences on maternal and infant health from the disease served as an example of the need to consider reproductive rights as an unalienable part of health policies and programs (Burke & Moreau, 2016).
Zika virus is a mosquito-borne flavivirus.
Zika virus is primarily transmitted by infected Aedes mosquitoes, mainly Aedes aegypti, which bites during the day. A. aegypti is the same mosquito that transmits dengue, chikungunya, and yellow fever. Zika virus is also transmitted from human to human through vertical transmission, sexual contact, blood transfusion, and organ transplantation (Perry, Khalil, Aarons, Russell, & O’Brien, 2017; WHO, 2018d).
Disease Characteristics (Effects on Maternal and Child Health)
Most people with Zika virus infection do not develop any symptoms. If symptoms present, they are usually mild and include fever, rash, conjunctivitis, arthralgia, and headache and last from 2 to 7 days. Some neurologic complications are associated with Zika virus infection, such as Guillain-Barré syndrome, neuropathy, and myelitis (WHO, 2018d).
Zika virus does not seem to affect pregnant women differently from the general population (Perry et al., 2017), but maternal-fetal transmission is associated with severe adverse outcomes (Pomar et al., 2018), such as fetal loss, stillbirth, fetal growth restriction, preterm birth, miscarriage, and a spectrum of fetal central nervous system abnormalities (Brasil et al., 2016; Shapiro-Mendoza et al., 2017; WHO, 2018d). These congenital malformations are known as congenital Zika syndrome (WHO, 2018d).
There is no treatment available for Zika virus infection or the associated diseases (WHO, 2018d). The WHO recommends that individuals with symptoms and signs such as fever, rash, or arthralgia should rest, stay hydrated, and treat pain and fever with common medications. If symptoms worsen, medical care should be sought.
Prevention of Zika virus includes the elimination of mosquito breeding sites, the use of larvicides, and other evidence-based strategies to decrease the mosquito population, and the avoidance of mosquito bites, through the use of insect repellents and other barriers, such as window screens and bed nets (WHO, 2018d).
The severe consequences of Zika virus on maternal and perinatal health call for a broader range of public health interventions, including more equitable access to sexual and reproductive health care services, especially in areas where Zika virus is endemic. In addition to prenatal care, this includes access to family planning services, safe abortion, and post-abortion care (Borges, Moreau, Burke, Santos, & Chofakian, 2018; Burke & Moreau, 2016). Avoiding sexual contact or using condoms during sexual intercourse with a person suspected of or at risk of having Zika virus infection is also a preventive measure (Perry et al., 2017).
To date, there is no vaccine available; thus, continued surveillance of Zika virus infection and its adverse effects on maternal, fetal, and infant health is still needed (Britt, 2018).
Toxoplasmosis is a disease found throughout the world, but the highest seroprevalence levels are found in Latin America, parts of Eastern and Central Europe, in the Middle East, and some parts of Asia and Africa. A review showed that seroprevalence ranges from 8.2% in Switzerland to 77.5% in Brazil, with evidence that it has decreased in recent decades in high-income countries (Pappas, Roussos, & Falagas, 2009). The worldwide presence of Toxoplasma in humans may be explained by the fact that the exposure to the parasite is common in places where cats live, which are the primary hosts for the parasites.
Even though a small proportion of women are susceptible to infection when they reach reproductive age, as most of them have been exposed to the parasite, infection with Toxoplasma during or just before pregnancy can be particularly serious and can result in miscarriage, stillbirth, or congenital disorders among those who have had no exposure to the parasite (seronegatives; Robert-Gangneux & Dardé, 2012). It has been estimated that the incidence rate of congenital toxoplasmosis is approximately 1.5 cases per 1,000 live births (Torgerson & Mastroiacovo, 2013).
Toxoplasmosis is caused by Toxoplasma gondii, a protozoan parasite that infects most species of warm-blooded animals, including humans. The parasite has a complex life cycle: the sexual cycle occurs solely in the gastrointestinal tract of felines (domestic and wild cats), whereas the asexual cycle occurs in nucleated cells of infected humans and other animals (Robert-Gangneux & Dardé, 2012; Torgerson & Mastroiacovo, 2013).
Cats are the primary hosts of the parasite. Once infected, a cat usually sheds oocysts for 1–2 weeks. The oocysts then sporulate in the environment and become infective. Intermediate hosts in nature, such as birds and rodents, become infected after consuming soil, water, or plants contaminated with oocysts. Cats may become infected with tissue cysts (both within intermediate hosts and humans, the oocysts form tissue cysts) after eating these intermediate hosts or by ingestion of sporulated oocysts (Robert-Gangneux & Dardé, 2012).
In humans, infection is usually acquired by consumption and manipulation of raw or undercooked meat of animals with tissue cysts; by consuming food or water contaminated with cat feces; by manipulating contaminated soil and sand samples, such as cleaning the litter box or eating unwashed fruits or vegetables; through blood transfusion or organ transplantation; and, finally, by vertical transmission from mother to fetus, when women acquire primary disease during pregnancy. It is assumed that approximately half of the cases of toxoplasmosis are foodborne (Robert-Gangneux & Dardé, 2012).
Disease Characteristics (Effects on Maternal and Child Health)
Among those who are infected, symptoms are rare, as the individual’s immune system prevents the parasite from causing illness. However, among pregnant women and immunosuppressed individuals, Toxoplasma may have serious health consequences. Recent infection with Toxoplasma or infection just before pregnancy among non-immune pregnant women may lead to miscarriage, stillbirth, or congenital toxoplasmosis. Infants infected during pregnancy often show no symptoms at birth but may develop them later in life with potential neurologic and neurocognitive deficits, blindness, seizures, hearing loss, and chorioretinitis, among other significant disabilities. Rates of transmission and severity of congenital disease vary according to the pregnancy trimester when the woman is first affected as well as her immunologic status: the risk of congenital infection is higher if infection occurs at the later stages of pregnancy, but the severity of pregnancy outcomes such as abortion, stillbirth, and premature birth are higher if the first infection occurs during the first trimester (Borges, Silva, Brito, Teixeira, & Roberts, 2019).
Confirmed diagnosis made via detection of antibodies to Toxoplasma gondii does not necessarily require treatment, unless the individual is immunosuppressed. In that case, the individual should take specific medications to treat the disease, including accurate follow-up. Among pregnant women, an early diagnosis and prenatal and postnatal treatment with specific medications can decrease the chance that the infant will become infected and the severity of disease outcomes (Borges et al., 2019; Pfaff & Tillett, 2016).
Hygienic measures are vital to avoiding infection (Robert-Gangneux & Dardé, 2012). Precautions to avoid infection include eating well-cooked meat, peeling or washing fruits and vegetables thoroughly before eating, ensuring that the cat litter box is changed daily (it takes many days for the oocytes to become infective), and washing hands with soap and water after cleaning out a cat’s litter box, gardening, and handling sand or raw meat (Pfaff & Tillett, 2016).
In many countries around the world, testing for the presence of Toxoplasma antibodies in early pregnancy is part of the antenatal care guidelines (Pfaff & Tillett, 2016). In cases of pregnant women with negative serology, some countries adopt a recommendation to test regularly until childbirth (Peyron et al., 2017).
At present, no vaccine exists to prevent human disease caused by Toxoplasma gondii.
All non-sexually transmitted diseases approached in this article are preventable in many ways. The key to their prevention, and consequently to a healthy pregnancy and childbirth, is multidimensional: it includes actions required varying across the life course (vaccination, education, and sanitation), actions targeted when actively planning a pregnancy, and actions during antenatal care.
An adequate number of visits and high quality antenatal care should be sufficient to screen, diagnose, and treat these diseases early in the pregnancy, reducing the adverse effects of maternal infections to both mothers and newborns. Even though there has been progress in the offer of antenatal care worldwide, coverage is still far from universal, with persistent disparities within regions and between income groups (Moller, Petzold, Chou, & Say, 2017). Accordingly, there is a lot to be achieved, and in order to extend not just antenatal care, but also intergestational and preconception care to every woman, everywhere.
Even though the most frequent non-sexually transmitted diseases that can negatively affect maternal and child health have been discussed, there is a need to pay attention to other rare or emerging diseases. COVID-19 is an example, as there was little evidence on its effects on reproductive outcomes when the pandemic occurred globally, with considerable impact in terms of national and local economies and pressure on primary and tertiary health services. Thus, the knowledge on how to manage and prevent the disease had to be learned simultaneously to its spread, the same way that happened with Zika virus during its outbreak. The lessons learned from these epidemics is that strong, organized, and universal health systems, as well as lasting investments in social equality and development, are fundamental for healthier reproductive lives.
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