|Year : 2020 | Volume
| Issue : 2 | Page : 23-29
Pregnancy and infections: A review
Department of Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
|Date of Submission||21-Aug-2020|
|Date of Acceptance||27-Aug-2020|
|Date of Web Publication||27-Nov-2020|
M P Brundha
Department of Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai - 600 077, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Before the advent of antibiotic agents, pregnancy was a recognized risk factor for severe complications of pneumococcal pneumonia, including death.The influenza pandemic of 2009 provided a more recent reminder that certain infections may disproportionately affect pregnant women. During pregnancy, several mechanical and pathophysiological changes occur (e.g., a decrease in respiratory volumes and urinary stasis due to an enlarging uterus), and immune adaptations are required to accommodate the fetus. In this article, we review and synthesize new knowledge about the severity of and susceptibility to infections in pregnant women. We focus on the infections for which there is evidence of increased severity or susceptibility during pregnancy that is not fully explained by mechanical or anatomical changes, and we discuss these infections in light of new findings on immunologic changes during pregnancy.
Keywords: Pregnancy, virus, bacteria, fungal, infections
|How to cite this article:|
Brundha M P. Pregnancy and infections: A review. Int J Clinicopathol Correl 2020;4:23-9
| Introduction|| |
Pregnancy is a normal and healthy state that a lot of women aspire to at some point in their lives. However, pregnancy can make women more susceptible to certain infections and which may also make more severe. During pregnancy, even mild infections can lead to serious illness in women. As compared with non pregnant women, pregnant women are more severely affected by infections with some organisms, including influenza virus, hepatitis E virus (HEV), herpes simplex virus (HSV), and malaria parasites but the evidence is more limited for some organisms that cause coccidioidomycosis, measles, smallpox, and varicella HYPERLINK “https://paperpile.com/c/w8Scr6/4F0U";.
The threshold for diagnostic evaluation, hospitalization as well as treatment, may be lower for pregnant women than for other patients, and this factor might bias some of the reports of increased disease severity. Some infections that occur during pregnancy primarily pose a risk to the mother HYPERLINK “https://paperpile.com/c/w8Scr6/pRfn”. Other infections can be transmitted to the baby through the placenta or during birth. For example, HYPERLINK “https://www.healthline.com/health/pregnancy/cytomegalovirus-infection”cytomegalovirus, HYPERLINK “https://www.healthline.com/health/congenital-toxoplasmosis#Overview1”toxoplasmosis, and parvovirus can be transmitted from mother to baby. When this occurs, the baby is at risk for health complications as well. No effective treatment yet found for a cytomegalovirus infection that's present at birth HYPERLINK “https://paperpile.com/c/w8Scr6/9BM3”. Antibiotics are available that may be able to treat toxoplasmosis successfully. But certain infection such as parvovirus has no cure with antibiotics and the infection can only be treated with intrauterine blood transfusions HYPERLINK “https://paperpile.com/c/w8Scr6/qx4N”.
Changes in immunity and physiology during pregnancy may make pregnant women more susceptible to infectious diseases. Next, the effects of infectious diseases on the fetus might be unknown or difficult to predict, and even diagnosis of infection in the fetus or infant might be challenging. Besides that, prophylaxis and treatment appropriate for the general population might not be appropriate for pregnant women. All those are several issues relevant to infectious disease which is life threatening during pregnancy HYPERLINK “https://paperpile.com/c/w8Scr6/uQXS”. There are some infections that develop during pregnancy leading to miscarriage, preterm labor, or birth defects, even be life-threatening for the mother. The medications used to treat infections can even cause serious side effects, especially for the baby. It is important to try to prevent infections during pregnancy to reduce risks for both mother and baby. In this article, we review and synthesize new knowledge about the severity of and susceptibility to infections in pregnant women.
| Pregnanacy and Infections|| |
Pregnancy is a normal and healthy state that a lot of women aspire to at some point in their lives. However, pregnancy can make women more susceptible to certain infections and which may also make more severe. During pregnancy, even mild infections can lead to serious illness in women. As compared with nonpregnant women, pregnant women are more severely affected by infections with some organisms, including influenza virus, hepatitis E virus, herpes simplex virus (HSV), and malaria parasites, but the evidence is more limited for some organisms that cause coccidioidomycosis, measles, smallpox, and varicella.
The threshold for diagnostic evaluation, hospitalization as well as treatment, may be lower for pregnant women than for other patients, and this factor might bias some of the reports of increased disease severity. Some infections that occur during pregnancy primarily pose a risk to the mother. Other infections can be transmitted to the baby through the placenta or during birth. For example, cytomegalovirus, toxoplasmosis, and parvovirus can be transmitted from mother to baby. When this occurs, the baby is at risk for health complications as well. No effective treatment yet found for a cytomegalovirus infection that's present at birth. Antibiotics are available that may be able to treat toxoplasmosis successfully. However, certain infections such as parvovirus have no cure with antibiotics and the infection can only be treated with intrauterine blood transfusions.
Changes in immunity and physiology during the pregnancy may make pregnant women more susceptible to infectious diseases. Next, the effects of infectious diseases on the fetus might be unknown or difficult to predict, and even diagnosis of infection in the fetus or infant might be challenging. Besides that, prophylaxis and treatment appropriate for the general population might not be appropriate for pregnant women. All those are several issues relevant to infectious disease which is life-threatening during pregnancy. There are some infections that develop during pregnancy leading to miscarriage, preterm labor, or birth defects, even be life-threatening for the mother. The medications used to treat infections can even cause serious side effects, especially for the baby. It is important to try to prevent infections during pregnancy to reduce the risks for both mother and baby. In this article, we review and synthesize new knowledge about the severity of and susceptibility to infections in pregnant women.
| Pregnancy and Severity of Infection|| |
Pregnant women are at increased risk for severe illness from influenza virus infection. Cardiopulmonary adaptive changes occurring during pregnancy, such as increased heart rate and stroke volume and reduced pulmonary residual capacity, may increase the risk of hypoxemia and contribute to the increased severity. During the pandemic of 1918, maternal mortality was 27% (50% when influenza was complicated by pneumonia), and during the pandemic of 1957, 50% of deaths among reproductive-age women occurred among those who were pregnant. During the 2009 H1N1 influenza A pandemic, pregnant women were generally at increased risk for severe disease, including disease leading to hospitalization, admission to an intensive care unit, or death, as compared with nonpregnant women and the general population. Although pregnant women represent only about 1% of the U.S. population in the United States, 5% of all deaths from pandemic influenza were among pregnant women. Higher rates of hospital admission and medical encounters for pregnant women with confirmed or suspected influenza, as compared with the general population, and a greater severity of disease during late pregnancy were also found in interpandemic periods. Women in the third trimester of pregnancy were at high risk for severe disease (e.g., disease requiring admission to an intensive care unit or resulting in death) during the 2009 H1N1 pandemic and during interpandemic periods when compared with women in an earlier stage of pregnancy.
Hepatitis B virus infection
Hepatitis B virus (HBV) infection is also more severe in pregnant women, with high mortality during the third trimester. In areas in which HBV infection is highly endemic (India, Southeast Asia, the Middle East, and Africa), it can be a major cause of maternal death and fetal loss. The pathophysiological basis of this increased mortality is not well understood. In a review of all consecutive cases of acute liver failure from 1989 to 1996 in a region of India in which HBV infection is endemic, 49 of 83 women of child-bearing age with acute liver failure were pregnant (33 in their third trimester). In 47 of these pregnant women, the liver failure was due to HBV infection. In a case series from India, 33%–43% of pregnant women with HBV infection had severe disease or infection that led to fulminant hepatic failure. A review indicated that the case fatality rate among pregnant women with HBV infection is between 15% and 25%, as compared with a range of 0.5%–4% in the population overall. Among 220 consecutive pregnant women presenting with jaundice caused by acute viral hepatitis, fulminant hepatic failure and death were more common among women with HBV infection than among those without HBV infection (relative risk of fulminant hepatic failure – 2.7 and relative risk of death – 6.0).
Herpes simplex virus infection
Pregnant women with primary HSV infection have an increased risk of dissemination and hepatitis (an otherwise rare complication in immunocompetent adults), particularly during the third trimester. After patients with immunosuppression, pregnant women are the largest group of adults with disseminated HSV infection. In one review, the mean gestational age at presentation was 31 weeks, and the case fatality rate was 39% for both mothers and neonates. Other reviews have confirmed a high burden of HSV hepatitis among pregnant women;, however, data on the incidence of primary HSV infection among pregnant women are limited. Recurrences of genital HSV infection increase in the frequency during pregnancy, although the clinical characteristics of recurrent genital HSV infection are similar in pregnant women and nonpregnant women.
The severity of or susceptibility to Plasmodium falciparum malaria is determined by the level of immunity, which depends mainly on the intensity and stability of malaria transmission. In the areas of low or unstable transmission, infected women become symptomatic, and if untreated, the infection can progress rapidly to complications, with a high case fatality rate. In three districts in India, 23% or more of maternal deaths between 2004 and 2006 were attributable to malaria, which was the most common cause of maternal death during pregnancy. Pregnant women have a risk of severe malaria that is three times as high as that among nonpregnant women; a median maternal mortality of 39% has been reported in studies in the Asia–Pacific region. Maternal death also has been reported in association with Plasmodium vivax infection. In the areas of high transmission, most women harboring parasites do not present with symptoms. It was thought that, in such areas, cases of severe or fatal malaria during pregnancy were rare. However, the number of maternal deaths from malaria in sub-Saharan Africa may have been underestimated, and malaria during pregnancy may be an important direct cause of maternal complications and death., Of pregnant women who are symptomatic, the majority are women having their first pregnancy; women who have been pregnant more than once and who live in the areas where malaria is highly endemic are less likely to present with clinical signs or symptoms of malaria, even if they have high parasite loads., The predominant theory to explain this phenomenon is that P. falciparum parasites accumulate selectively in the placenta, and particular anti-genic variants interact with syncytiotrophoblastic chondroitin sulfate A. Women have a malaria episode caused by chondroitin sulfate A–binding parasites during their first pregnancy because they lack immunity to antigenic variants presented by these strains (even though they may be immune to other antigenic variants of parasites that bind endothelial receptors from previous infections) and are thus highly susceptible to the new infection.
Several reports and case series have suggested that pregnancy is a risk factor for the development of severe and disseminated coccidioidomycosis, particularly during the third trimester and the immediate postpartum period, with an estimated rate of 7.7–11 cases/10,000 pregnancies However, the rate of disease during pregnancy was much lower than expected in a large 1988 survey of records from three delivery centers in Tucson, Arizona, covering more than 47,000 deliveries. During the 1993 epidemic in Kern County, California, only 32 cases were identified among pregnant women, a lower number than expected; disseminated disease occurred in three of these cases, with no maternal deaths which suggested that many pregnant women have asymptomatic or clinically mild disease. Taken together, these data suggest that the incidence of coccidioidomycosis is decreasing and that pregnant women may not be at increased risk for dissemination.
Early studies postulated that pregnancy, particularly in the third trimester, is a risk factor for severe varicella. These studies involved mostly case reports or small case series. A review of reports published from 1965 to 1989 on varicella pneumonia in adults showed that of 99 cases, 46 were in women; 28 of these women were pregnant (21 in the third trimester). This suggested an increased rate of varicella pneumonia during pregnancy; however, mortality among pregnant women (10%) was not higher than that among men and nonpregnant women. Paryani and Arvin reported a varicella pneumonia rate of 9%, with one death among 43 pregnant women with varicella. In a 1990 review of 34 published cases of varicella pneumonia, mortality among pregnant women was 35%, higher than that among nonpregnant adults, reported as 11.4% in another study. Other studies do not support the idea that illness due to varicella is more severe during pregnancy. In a New York City survey for the period from 1957 to 1964, only 1 of 144 women with varicella died. In a study from Britain and Germany, in which 1373 women with varicella were followed during pregnancy, no maternal deaths were reported.
| Pregnancy and Susceptibility to Infection|| |
In contrast to the rather strong evidence for increased severity of certain infections among pregnant women, the evidence regarding initial susceptibility is weaker. The evidence for increased susceptibility during pregnancy is most credible for infections with organisms such as P. falciparum and Listeria monocytogenes, both of which have tropism for the placenta; evidence is more limited for human immunodeficiency virus type 1 infection.
The harmful effects of malaria (mainly due to P. falciparum) during pregnancy – maternal anemia, low birth weight, and preterm birth – have long been recognized. Up to 25% of pregnant women have acute infection in the areas of stable endemic transmission; for example sub-Saharan Africa, which leads to placental malaria, and this frequency is higher than that among of nonpregnant women. In several studies in Africa and Asia, the prevalence of malarial parasitemia was found to be higher among pregnant females than among nonpregnant females within 15–45 years of age.,P. falciparum is the only species associated with placental sequestration, which is believed to be the cause of many of the manifestations of P. falciparum disease during pregnancy. Many studies have shown decreasing susceptibility to malaria with increasing parity, probably as a result of acquisition of immunity to parasites expressing pregnancy-specific variant surface antigens. This association is most pronounced in areas where malaria is highly endemic. Young maternal age may be an additional and independent risk factor for malaria during pregnancy. The third trimester of gestation has been associated with the highest risk of clinical malaria in some studies, but not others. However, maternal parasitemia, placental parasite burden, and episodes of clinical malaria may be the expressions of disease severity rather than of initial susceptibility in areas with a high prevalence of malaria.
Primarily, a food-borne pathogen, listeria can contaminate a variety of raw foods, such as uncooked meats and vegetables, unpasteurized milk, and soft cheeses. Infection may be asymptomatic or may be manifested as an influenza-like illness; severe infection is rare during pregnancy, and no maternal deaths due to listeriosis have been reported among pregnant women who are hospitalized.L. monocytogenes infections most commonly occur during the third trimester and seem to be rare earlier in pregnancy. However, listeria has a predilection for the placenta and fetus, and depending on the stage of pregnancy, listeriosis can lead to pregnancy loss, stillbirth, preterm birth, or serious neonatal disease. Active, population-based surveillance showed that 17% of 762 listeriosis cases reported in 10 U.S. sites between 2004 and 2009 were in pregnant women. Hispanic women seemed to be particularly at risk. It has been estimated that invasive listeriosis during pregnancy is 13 times to more than 100 times as frequent as in the general population However, in one study, surveillance data indicated that more than 50% of listeriosis cases during pregnancy were associated with a neonatal case, which suggests that neonatal disease leads to recognition of listeria infections during pregnancy in a substantial proportion of cases and may therefore bias estimates of pregnancy-conferred risk.
| Evolving Concepts of Immunologic Alterations during Pregnancy|| |
Immunologic alterations during pregnancy may help explain the altered severity and susceptibility to infectious diseases during pregnancy. As pregnancy progresses, hormone levels change dramatically and are considerably higher than at any other time. The interplay between sex hormones and the immune system is complex and multifactorial, and it affects many organ systems. In humans, estradiol can enhance several aspects of innate immunity and both cell-mediated and humoral adaptive immune responses., In general, low estradiol concentrations promote CD4 + type 1 helper T-cell (Th1) responses and cell-mediated immunity, and high estradiol concentrations augment CD4 + type 2 helper T-cell (Th2) responses and humoral immunity. Progesterone can suppress the maternal immune response and alter the balance between Th1 and Th2 responses. Increasing estrogen and progesterone concentrations with advancing pregnancy lead to a reversible thymic involution. The mechanisms of estrogen and progesterone modulation of individual components of the immune system have been extensively studiedin vitro but not in humans. There is evidence that aspects of innate immunity (phagocytic activity, α-defensin expression, and numbers of neutrophils, monocytes, and dendritic cells) are maintained or enhanced during pregnancy, particularly during the second and third trimesters. Conversely, the number of CD3 + T-lymphocytes (both CD4 + and CD8+) decrease during pregnancy as do Th1 and Th2 responses to mitogenic or antigenic lymphocyte stimulation. However, there are limited data on the longitudinal trends of such alterations during pregnancy. Levels of several cytokines are altered including levels of interferon-γ, monocyte chemoattractant protein 1, and eotaxin are decreased in most pregnant women, whereas tumor necrosis factor α, interleukin-10 and granulocyte colony-stimulating factor levels rise. In general, levels of inflammatory cytokines are reduced, whereas the levels of cytokines that induce phagocytic-cell recruitment or activity increase; these alterations do not necessarily follow a clear Th1 or Th2 phenotype. Regulatory T-cells become more numerous. Several theories have been proposed to explain the immunologic alterations that occur during pregnancy. It was initially thought that pregnancy confers general immunosuppression to ensure tolerance of the semiallogeneic fetus. However, data indicating that fetus-specific cytotoxic T-cell responses can be generated during pregnancy without loss of the fetus, as well as data from studies of pregnant mice showing normal memory T-cell development after lymphocytic choriomeningitis virus infection, contradict the idea of systemic immunosuppression during pregnancy. Adequate immunologic responses to vaccination in pregnant women have been demonstrated in several studies and for several pathogens. The fact that pregnant women do not seem, on the basis of epidemiologic evidence, to be more susceptible to infections in general also contradicts this theory. A more recent theory proposed a shift from Th1 to Th2 immunity during pregnancy. Th2 cells stimulate B-lymphocytes, increase antibody production, and suppress the cytotoxic T-lymphocyte response, decreasing the robustness of cell-mediated immunity. A shift to Th2 immunity is postulated to be responsible for altered responses to respiratory viral infections or autoantigens during pregnancy and could explain the increased severity of infections such as influenza or coccidioidomycosis, in which cell-mediated immunity is important. Elucidation of the immunologic alterations and adaptations that occur during pregnancy suggests that older concepts of pregnancy as a state of systemic immunosuppression are oversimplified. A more useful model may be the view of pregnancy as a modulated immunologic condition, not a state of immunosuppression. Decreases in adaptive immunity seen in the later stages of pregnancy are consistent with the observed increase in the severity of certain infectious diseases during later pregnancy. Decreases in the numbers and function of CD4+, CD8+, and natural killer cells could affect antiviral, antifungal, or antiparasitic responses and delay clearance of the offending microorganism. However, the increases in innate immunity observed during pregnancy may help to prevent acquisition of infection and thus explain the absence of increased susceptibility to infections. Furthermore, the placenta is an active immunologic site, capable of interacting with and responding to pathogens. The placental tropism of specific pathogens (e.g., listeria or P. falciparum) affects the susceptibility to and severity of certain infectious diseases during pregnancy, as well as pregnancy outcomes. Placental infection that elicits the production of inflammatory cytokines may activate the maternal immune system and lead to placental damage and miscarriage or preterm labor. Although a viral infection of the placenta that triggers a mild inflammatory response may not terminate the pregnancy, it can activate the maternal immune system or that of the fetus, potentially promoting an inflammatory response that may lead to long-term neurodevelopmental or other sequelae, including diseases in adulthood, in the offspring.
| Conclusion|| |
Even though pregnant women do not seem to be more susceptible than nonpregnant women to initial infection in general, immunologic alterations with advancing pregnancy may impair pathogen clearance, resulting in an increased severity of disease caused by some pathogens. Increased disease severity may also be due to other physiological changes of pregnancy. There are many unanswered questions regarding the immunologic changes that occur as pregnancy progresses and the interplay of infection, pregnancy, and the fetus and placenta. Vaccination before and during pregnancy, which has proved safe and effective for a number of infectious agents. The beneficial effects of maternal vaccination may not be limited to the mother but, by reducing fetal and placental inflammation, may also provide long-term benefits for the child. The education of pregnant women about prevention of infections and the early identification and appropriate treatment of infectious diseases during pregnancy remain important strategies for protecting maternal and infant health.
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Conflicts of interest
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