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R, D.C.;  Shailaja, A.;  Mary, A.S.;  Kandiyil, S.P.;  Savithri, A.;  Lathakumari, V.S.;  Veettil, J.T.;  Vandanamthadathil, J.J.;  Madhavan, M. Pregnancy and Vaccination during COVID-19 Pandemic. Encyclopedia. Available online: https://encyclopedia.pub/entry/25382 (accessed on 03 July 2024).
R DC,  Shailaja A,  Mary AS,  Kandiyil SP,  Savithri A,  Lathakumari VS, et al. Pregnancy and Vaccination during COVID-19 Pandemic. Encyclopedia. Available at: https://encyclopedia.pub/entry/25382. Accessed July 03, 2024.
R, Dhanya C, Aswathy Shailaja, Aarcha Shanmugha Mary, Sumodan Padikkala Kandiyil, Ambili Savithri, Vishnu Sasidharan Lathakumari, Jayakrishnan Therthala Veettil, Jiji Joseph Vandanamthadathil, Maya Madhavan. "Pregnancy and Vaccination during COVID-19 Pandemic" Encyclopedia, https://encyclopedia.pub/entry/25382 (accessed July 03, 2024).
R, D.C.,  Shailaja, A.,  Mary, A.S.,  Kandiyil, S.P.,  Savithri, A.,  Lathakumari, V.S.,  Veettil, J.T.,  Vandanamthadathil, J.J., & Madhavan, M. (2022, July 21). Pregnancy and Vaccination during COVID-19 Pandemic. In Encyclopedia. https://encyclopedia.pub/entry/25382
R, Dhanya C, et al. "Pregnancy and Vaccination during COVID-19 Pandemic." Encyclopedia. Web. 21 July, 2022.
Pregnancy and Vaccination during COVID-19 Pandemic
Edit

Pregnancy, alone, being associated with a state of immune alterations, exposes the maternal immune system to many challenges. Pregnant women, being a highly vulnerable group, need to be administered vaccines as early as possible; however, there is a lot of vaccine hesitancy among the population regarding immunization of pregnant women, who are avoided in the initial phases of most clinical trials. A look at available studies on the mechanisms of immune response in pregnant women and further, the reports of vaccine efficacy and outcomes among pregnant women against COVID-19 and EVD would definitely yield many insights that could be useful in the surveillance and planning of vaccination strategies for pregnant women against impending pathogenic RNA viruses.

Covid-19 Ebola Pregnancy Immune response Vaccination

1. Impact of COVID-19 and EVD on Pregnancy

Alterations in hormone levels and the immune system in pregnancy may predispose pregnant women to viral infections. There have been many reports that indicate that viral infection during pregnancy is correlated with undesirable obstetric consequences [1][2][3]. In any viral outbreak, pregnant women constitute a high-risk group because of various reasons such as increased susceptibility and infrequent antenatal hospital visits due to fear of contracting the disease. Since they pose a risk for nosocomial infection to healthcare workers through exposure to body fluids, proper obstetric care might not be available to pregnant women. Various concerns regarding occurrence of viral infections in pregnancy are discussed below, focusing on COVID-19 and EVD.
Pregnancy is not believed to put women at higher risk of getting infected by EBOV [4][5] or COVID-19 [6]. However, in the case of COVID-19, there are studies that report a higher infection rate among pregnant women in comparison with non-pregnant women [7][8]. The high levels of estrogen and progesterone are thought to induce the upper respiratory tract to swell, which in turn could make pregnant women more susceptible to SARS-CoV-2 infection [9].

2. Maternal and Neonatal Outcomes Associated with COVID-19 and EVD

Several investigators have assessed the clinical complications and risk posed by SARS-CoV-2 and EBOV infections in pregnancy, with results of heterogeneous nature. Numerous aspects regarding maternal and neonatal outcomes in the context of COVID-19 and EVD need to be discussed so as to allow effective management of obstetric healthcare during viral outbreaks. Case studies and cohort studies relating to pregnancy and neonatal outcomes in COVID-19 and EVD have been summarized in Table 1a,b, respectively.
Table 1. (a) Case studies and cohort studies relating to pregnancy and neonatal outcomes in COVID-19. (b) Case studies and cohort studies relating to pregnancy and neonatal outcomes in EVD ETU-Ebola Treatment Unit.
(a)
Year of Study Country Study Approach Case Type Sample Size Pre-Existing Medical Conditions Need for Hospitalization Maternal Mortality Obstetric Complication Perinatal Outcome Reference
2020 22 countries Retrospective cohort study Pregnant women with confirmed SARS-CoV-2 infection 388 Not available ICU admission (11.1%) Mechanical Ventilation (9.3%) 0.80% Miscarriage (19.4%) Termination of pregnancy (1.1%) Termination of pregnancy (1.1%) Pre-term birth (26.3%) Still birth (2.3%) Neonatal death (2%) SARS-CoV-2 positive (0.4%) [10]
2020 United Kingdom Prospective observational cohort study pregnant women with confirmed SARS-CoV-2 infection 427 Asthma (7%) Hypertension (3%), Diabetes (3%) Critical care (10%) 1% Pregnancy loss (1%) Stillbirth (1%) Neonatal death (1%) Loss of Pregnancy (1%) SARS-CoV-2 positive (2%) [11]
2020 Singapore Prospective Cohort Study Pregnant women with diagnosis of COVID-19 16 Asthma (12.5%) HCV carriers (6.25%) ICU admission (6.25%) NIL Spontaneous miscarriage (22.2%) Neonatal death (6.25%) [12]
2020 China Retrospective Cohort study Pregnant women who gave a single live birth between January 13 and March 18, 2020 65 Not available Higher need for Caesarean section (80%) NIL Gestational diabetes (3%) Gestational hypertension (11%) Pre-eclampsia (1%) Pre-term birth (14%) Diarrhea (1.7%) Fever (5.17%) [13]
2020 Iran Prospective Cohort Study Pregnant women with diagnosis of COVID-19 56 Diabetes (16.1%) Hypertension (10.7%) Hypothyroidy (19.6%) ICU admission (10.7%) Mechanical Ventilation (6.15%) Higher need for Caesarean section (67.3%) NIL Pre-eclampsia Pre-term birth (34.5%) Perinatal death (3.6%) [14]
2020 France Retrospective Cohort study Pregnant women with diagnosis of COVID-19 having a code for hospitalization for COVID-19 874 Diabetes (1.3%) Hypertension (1.9%) ICU admission (5.9%) Higher need for Caesarean section (33%) 0.20% Pre-eclampsia (4.8%) Gestational hypertension (2.3%) Postpartum hemorrhage (10%) Pre-term birth (11.3%) [15]
2020 Democratic Republic of the Congo Case Study Pregnant woman with confirmed SARS-CoV-2 infection 1 NIL Caesarean section NIL Thrombotic vasculopathy in the placenta, Inflammatory appearance in the pelvic organs SARS-CoV-2-infected Neonate, Perinatal death [16]
2020 China Retrospective Case Control study Pregnant woman with confirmed SARS-CoV-2 infection, pregnant women with suspected infection and Control groups 11 Gestational diabetes (18.75%) Gestational hypertension (18.75%) Hypothyroidism (12.5%) Caesarean section (87.5%) NIL Pre-eclampsia (6.25%) Pre-term birth (18.8%), Low birth weight (17.6%) [17]
2020 China Case Study Pregnant woman who was exposed to SARS-CoV-2 1 NIL Hospitalization Caesarean section NIL NIL SARS-CoV-2-infected Neonate [18]
2020 USA Case Series Pregnant women with suspected COVID-19 infection 92 NIL Hospitalization (1.1%) NIL low morbidity One fetal demise, but not sure whether it is due to COVID-19 [19]
2020 Sweden Case Series Critically ill pregnant or newly delivered women positive for COVID-19 5 Gestational diabetes (2 out of 5) Gestational Hypothyroidism (1 out of 5) Situs Inversus (1 out of 5) Hospitalization for an average of 20 days (4 out of 5) Intubation (4 out of 5) NIL Severe respiratory distress syndromeCardiac arrest (1 out of 5) NIL [20]
2020 USA Retrospective cohort study Possible exposure or infection and positive COVID-19 test 1609 Chronic pulmonary disease (12.6%) Cardiac arrhythmia (10.4%) Hypertension (6.5%) Hypothyroidism (5%) Diabetes (3%) Hospitalization (60.5%) 0.20% Not available NIL [21]
2020 USA Retrospective cohort study Pregnant and post-partum patients with SARS-CoV-2 infection 2352 Chronic pulmonary disease (12%) Hypertension (6.9%) Thyroid disease (3.9%) Diabetes (3.8%) ICU admission (3.7%) 0.20% Post-partum hemorrhage (2.6%) Other infections (2.3%) Hypertensive disorders of pregnancy (10.1%) Fetal/neonatal death (2.5%) Miscarriage (1.2%) Stillbirth (0.5%) Preterm birth (17.7%) [22]
2020 USA Observational Cohort study Women who delivered and had SARS-CoV-2 infection during pregnancy 252 Gestational diabetes (3%) Chronic hypertension (5%) Hospitalization (6%) NIL Pre-eclampsia (11%) Chorioamnionitis (10%) Excessive blood loss (7%) Neonatal SARS-CoV-2 infection (3%) [23]
2020 Iran Retrospective case Control study Pregnant women with COVID-19 positive test and a positive chest X-ray result 110 Hypertension (5.45%) Diabetes (9.09%) Asthma (5.45%) ICU admission (6.9%) Requirement for invasive ventilation (1.7%) NIL Abortion (21.42%) Post-partum hemorrhage (5%) Pre-term birth (25%) Still birth (5%) Fetal distress (10%) Low birth weight (10%) NICU admission (10%) [24]
2021 18 countries Cohort study Pregnant women with diagnosis of COVID-19 706 Hypertension (3.7%), Diabetes (4.7%), Chronic respiratory disease (3.5%), Endocrine dysfunction (10.6%) ICU admission (8.4%) 1.60% Hypertension Pre-eclampsia Anemia Infections Pre-term birth (22.5%) Low birth weight (20.5%) SARS-CoV-2 positive (57.1%) [25]
(b)
Year of Study Country Study Approach Case Type Sample Size Maternal Age Gestational Age of Infection Comorbidity Clinical Presentation Need for Hospitalization/ICU Admission Maternal Mortality Obstetric Morbidity Perinatal Outcome Reference
1995 Kikwit Cohort Study Ebola positive Pregnant women 15 24–38 (mean age 32) First trimester (27%), second trimester (40%) and third trimester (33%) Not available Fever (100%), asthenia (100%), abdominal pain (100%), conjunctivitis (100%), anorexia (100%), diarrhea (100%), arthralgia (100%), dysphagia (100%), headache (100%) Admitted to General Hospital 95.5% death Genital bleeding (100%) Abortion (67%), curettage performed due to incomplete abortion (20%), still birth (6.7%) [26]
2000 North Uganda Case study Ebola positive Pregnant women 1 31 28 weeks Placenta had a moderate amount of malarial parasite pigment Conjunctival injection, diffuse abdominal tenderness, and slight pulmonary rales Admitted to ETU Maternal survival Placenta had mild subchorionitis Still birth [27]
2012 Congo Case study Ebola positive Pregnant women 1 29 7 months Not available Fever, vomiting, dysphagia and diarrhea, drowsiness and wheezing, Dyspnea, coma stage 1b, light exophthalmos, cold limbs and sub icterus Admitted to ETU Maternal death Dystocia Death of neonate [28]
2014 Liberia Case Study Ebola positive Pregnant women 1 31 Third trimester Not available vomiting, diarrhea, bleeding, and semi consciousness Admitted to ETU Maternal death Not available Intrauterine fetal death [29]
2014 Guinea Case Study Ebola positive Pregnant woman 1 40 4th month Not available abdominal pain, diarrhea and fever Admitted to ETU Maternal survival Vaginal bleeding Still birth [30]
2014 Southern Guinea Case study Ebola positive Pregnant women 2 20’s 7 months Malaria (50%) Asthenia, fever, and vomiting, Anasarca (50%) Admitted to ETU Maternal survival (100%) Absence of uterine contraction, cervical dilation (50%) and fetal heartbeat, hypertonic uterus (50%), post-partum hemorrhage (50%), suspected chorioamnionitis (50%) Still birth (100%) [31]
2014 Sierra Leone Case study Ebola positive Pregnant women 1 34 36 Not available Headache, cough, and arthralgia Admitted to ETU Maternal survival Hydropic Placenta Still birth [32]
2014 Sierra Leone Cohort Study Ebola positive Pregnant women 55 Mean age 25 Not available Not available Fever (86.8%), fatigue or weakness (81.1%), nausea or vomiting (64.2%), headache (66%), muscle or joint pain (58.5%), vaginal bleeding (32.1%), unexplained bleeding (20.8%), and sore throat (13.2%) Admitted to ETU Not available Vaginal bleeding (32%) Not available [33]
2014 Sierra Leone Cohort Study Ebola positive Pregnant women 67 Mean age 23 28–37 weeks Not available Fever (86.8%), abdominal pain (75.5%), fatigue (81.1%), nausea (64.2%) Admitted to ETU Maternal death (79%) Vaginal bleeding (32%), obstetric hemorrhage (29.8%) and eclampsia (1.5%) Spontaneous abortion (20.9%), Fetal death (5 out of 6), Still birth (8) [34]
2014 Sierra Leone Case study qPCR negative, IgG positive 1 19 36 weeks Sickle cell anemia Symptom free Admitted to ETU Maternal survival Not available Intrauterine fetal death, heavily macerated baby [35]
2014–15 Liberia and Sierra Leone Retrospective Cohort study Ebola positive Pregnant women 13 20-32 Not available Not available Abdominal pain (85%) and nausea/vomiting (69%), Bleeding (30%), Hiccups (8%) and non-hemorrhagic rash (8%) Admitted to ETU 46% death Not available Preterm delivery (15%), Perinatal death (15%), Abortion (15%), Termination of pregnancy (7.6%), [36]
2014–2015 Sierra Leone Case series Ebola positive Pregnant women (83.3%), Ebola survivor (16.6%) 6 18-38 Third trimester Not available Muscle pain (16.6%), headache (16.6%), diarrhea (16.6%), vomiting (16.6%) Admitted to ETU Maternal death (66.6%) Postpartum hemorrhage (50%), hypovolemic shock (16.6%) Neonate death (83.3%), still birth (16.6%) [37]
2015 Sierra Leone Case Study Ebola positive Pregnant woman 1 22 5 months Not available Anorexia, muscle pain, and joint pain Admitted to ETU Maternal survival Leaking fluid Intrauterine fetal death [30]
2015 Sierra Leone Case Study IgG, IgM positive 1 20   Not available Severe back pain, loss of appetite, and intense fatigue Delivery attended by village traditional birth attendant Maternal survival Leakage of bloody fluid from vagina Still birth [38]
2016 Guinea Case Study Ebola positive Pregnant women 1 25 28th week Not available Hyperthermia, asthenia, and conjunctival infection Admitted to ETU Maternal death post delivery Severe vaginal bleeding with signs of coagulopathy Survived after treatment [39]

3. Effects of COVID-19 and EVD on Placenta and Vertical Transmission

The importance of the placenta in mediating inflammatory and immune responses has been profusely studied in pregnant women infected with SARS-CoV-2. A study of the placenta conducted in COVID-19 patients revealed that the placenta of infected women are characterized by conditions such as maternal thrombosis [40]. SARS-CoV-2 placentitis has been reported to be a complication of maternal COVID-19 infection and is likely to result in fetal compromise [41][42][43]. It has been reported that activation of robust placental immune response during maternal SARS-CoV-2 infection may contribute to poor pregnancy outcomes associated with COVID-19 and infection at the maternal-fetal interface is not even required for this [44]. Interestingly, fetal sex has been proposed to play a significant role in the maternal-placental-fetal immune crosstalk in the setting of maternal SARS-CoV-2 infection. Sexually dimorphic placental immune responses have been observed between male and female fetuses with associated reduced antibody transfer to male fetuses [45]. Still birth, macerated fetus, pre-term birth and miscarriages imply a role of placenta in adverse pregnancy outcomes in EBOV-infected women (Table 1). However, the researchers  could not come across any supporting studies in existing scientific literature and hence more investigations in this direction are needed.
Vertical transmission of a pathogen can occur via placenta, vagina or breast milk [27]. Viruses in amniotic fluid and placenta are infectious and contribute to intrauterine transmission when they cross the placental barrier and infect the fetus [35][46]. This has been supported by the detection of SARS-CoV-2 virus in the placenta of COVID-19 positive women [47]. Additionally, among EBOV positive pregnant women, placenta has been reported to be a reservoir of the virus which could result in transplacental transmission to the fetus [27]. The mechanisms of macropinocytosis and clathrin-mediated endocytosis used by placenta for acquiring nutrients is exploited by EBOV to gain entry into the cells [48].
The placenta has specialized epithelial cells known as trophoblast cells that immunologically protect the neonate by controlling the spread of contagions [49]. Immunohistochemical analysis has evidenced the presence of Ebola viral antigens in syncytiotrophoblast, cytotrophoblast and placental maternal mononuclear cells [27]. SARS-CoV-2 is speculated to enter trophoblasts with the help of entry factors such as ACE2 and Transmembrane protease serine 2 (TMPRSS2) expressed on the villous placental trophoblasts [50]. Transplacental transmission of SARS-CoV-2 has been documented in neonates born to mothers infected in the last trimester [51]. Case studies carried out in EBOV-infected pregnant women whose fetus died in utero also suggest infection of the fetus through the placenta [31][35].
Vertical transmission potential of SARS-CoV-2 has been discussed in the earlier days of the pandemic itself, when a neonate born to a COVID-19 positive mother had elevated IgM antibody levels [52]. Fenizia et al. reported around 10% vertical transmission in SARS-CoV-2-infected mothers [53]. Incidentally, maternal SARS-CoV-2 infection in the third trimester has been reported to cause compromised placental antibody transfer, possibly due to compensatory mechanisms that boost immunity in the neonates [54]. However, some authors think that the risk of vertical transmission of SARS-CoV-2 to neonates is very low [55][56]. To our limited knowledge, there are no studies illustrating transplacental antibody transfer with regard to EBOV infection.
There are several concerns regarding breastfeeding in the context of viral diseases, where the risk for the infant contracting the disease through breast milk remains a research question. In the case of SARS-CoV-2, reports indicate that viral RNA is rarely found in breast milk [57] and even when present, it does not represent a risk factor for transmission to the infant [58]. However, investigators have detected EBOV in breast milk [59][60][61], and the viral RNA was found to persist in breast milk of EBOV positive mothers up to 500 days post-treatment [62]. A systematic study demonstrated that 80% of children who ingested EBOV positive breast milk died of the disease [59]. This indicates the risk of mother to child transmission of EBOV through breast milk, though the inadequate number of samples studied is insufficient to emphasize it. Moreover, WHO guidelines recommend discontinuing breastfeeding when a woman is suspected of EBOV infection [5].
The presence of EBOV in female genital tracts in animal models [63] and vaginal fluid in infected humans [64] suggests the possibility of transvaginal transmission of the virus from mother to neonates. The presence of SARS-CoV-2 virus has also been detected in the lower genital tract of women with COVID-19 infection [65]. On the other hand, certain investigators have reported that SARS-CoV-2 virus is rarely detected in vaginal secretions [66][67].
The impact of mode of delivery on pregnancy outcomes and intrapartum transmission of the virus has been debated at large. A systematic review conducted by Cai et al. concluded that there is no significant difference in the rate of neonatal infection, neonatal deaths and maternal deaths between women who had undergone vaginal and cesarean delivery [68]. However, certain other studies have demonstrated association of vaginal delivery with a low risk of intrapartum transmission of SARS-CoV-2 [69][70]. In another cohort study, women who underwent cesarean section were reported to face adverse maternal and neonatal outcomes, while women with mild symptoms who delivered vaginally had excellent outcomes [71]. Hence, it can be inferred that cesarean delivery is no better than vaginal delivery in preventing adverse outcomes and the decision for the mode of delivery may be based on individual cases and the severity of the disease.

4. Alterations in Immune Response in Pregnant Women with SARS-CoV-2 and EBOV Infections

Pregnancy is a unique immunological condition that attracts intense discussion on the need to evaluate the risk posed by the exposure of pathogens to the materno-fetal unit [72]. During pregnancy, the mother has to adapt to the semi-allogenic fetus and at the same time sustain defense against pathogen attack. A proinflammatory atmosphere prevails during the first trimester while an anti-inflammatory environment builds up during the second and third trimesters to assist fetal growth [73]. Pregnant women exposed to viral infections experience several significant alterations in immune response which are summarized in Figure 1.
Pathogens 11 00800 g006 550
Figure 1. Alterations in immune response in pregnant women during viral infections.
COVID-19 infection in pregnancy is accompanied by higher levels of neutrophils and C-reactive protein that indicate an enhanced innate immune response, suppressed cytokine storm and increased activity of CD8+ T-cells and NK cells [74]. Neutrophil activation has also been reported in neonates born to women infected with SARS-CoV-2 [75]. IL-8, a pro-inflammatory cytokine that plays a key role in neutrophil recruitment, has been found to be increased in SARS-CoV-2-infected mothers and their neonates [76]. Pregnant women with moderate or severe COVID-19 were also observed more likely to have leukopenia [77]. Alterations in innate and adaptive immune response are present at the maternal-fetal interface as evidenced by studies carried out in decidua basalis tissues collected at the time of delivery from women with COVID-19 infection, and these changes are found to be correlated with the gestational stage of maternal infection [78].
The innumerable pregnancy complications and fetal outcomes reported in women infected with EBOV, accompanied by very high maternal and fetal mortality rates, as discussed in Table 1, indicate a possibility of an adverse immune response in pregnant women with EVD. Nevertheless, we could hardly find any literature investigating the immune response in EBOV-infected pregnant women. More research is required to answer queries regarding cellular sources and targets of inflammatory molecules in placenta so as to develop approaches to circumvent the obstetric intricacies in EVD.

This entry is adapted from 10.3390/pathogens11070800

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Dhanya C R
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Aarcha Shanmugha Mary
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Sumodan Padikkala Kandiyil
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Ambili Savithri
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Vishnu Sasidharan Lathakumari
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Jayakrishnan Therthala Veettil
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Jiji Joseph Vandanamthadathil
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Maya Madhavan
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Update Date: 27 Jul 2022
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