Preventing the transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and stopping the COVID-19 pandemic constitute public health emergencies ofinternationaland multidisciplinary concern. By early April 2021, more than 159 million people in the world had been infected with SARS-COV-2,¹some of them reinfected despite the natural immunity acquired after the first infection. SARS-CoV-2 was the leading cause of almost 2 million severe illness and3.3 million deaths globally.¹

Vaccination against SARS-COV-2 should offer a way to sustain protection and end the COVID-19pandemicif a global immunization is obtained. Starting from the model of influenza epidemics that are controlled by vaccination, the development of an effective and available to everyone COVID-19 vaccine is a global health top priority. Vaccination is destined to be part of a multi-faceted public health response to this epidemic that seems never to end.

Since January 2020, Romania has developed a surveillance network national program for SARS-CoV-2.² By 12 May 2021, 3,672,354 persons have received at least one vaccine dose, representing 16.63% of the Romanian population.³ Vaccines have been shown to be powerful and protective against SARS-CoV-2 infection transmission, avoiding the occurrence of severe cases of disease requiring intensive care therapy hospitalization.^4-6In the clinical trials that studied population vaccinated with Pfizer-BioNTech and Moderna vaccines, 142 individuals need to be vaccinated to reduce one case of COVID-19 infection.⁷

Viral pandemics threaten the general population, and severe forms of the disease are found mainly in "vulnerable” population categories.⁸ The delay in introducing special measures for pandemics for the general and especially for the at-risk population was associated with overcrowding the proportion of intensive care units (ICU) admissions in hospitals; also, the increased number of deaths associated with the COVID-19 pandemicmay be related to delaying general protective measures.⁹

Pregnant women represent a high-risk population for viral infection. Physiological respiratory changes occur in pregnancy, leading to reduced functional residual respiratory volumes, diaphragm muscle elevation, hyperventilation. This physiological respiratory system adaptation contributes to worsening prognosis.¹⁰

Vaccination in pregnancy with inactivated viral vaccines is permitted¹¹e.g., influenza vaccine,^12,13 tetanus vaccine and pertussis vaccine.¹⁴Protective antibodies to the fetus and infant were found after vaccines were administered to the mother.^15,16

This work aims to present the current state of knowledge about COVID-19 vaccines administered during pregnancy based upon the reported cases. For the cases search, we used last year’s available data on PubMed and Cochrane databases, using the following search terms: "COVID-19", "SARS-CoV-2”, "vaccination” and "pregnancy” in the title of the article.

Pregnancy and COVID-19 infection

Pregnancy represents a unique immunological state in which the maternal immune tolerance has to balance adaptation to the semiallogeneic fetus with paternal antigens and against any external environmental microbial threats. Maternofetal immune tolerance is essential to maintain pregnancy.HLA expression pattern which includes HLA-E, -F, -G, and -Cis important in maternal tolerance to the semiallogeneicfetusand fetal growth.¹⁷

Different immunological mechanisms combined with different ratios among various populations of immune cells in the maternal-fetal interface may occur to modulate pregnancy-related pathologies, including diabetes mellitus, preeclampsia, and metabolic syndrome.^18,19Recent studies have demonstrated that pregnant women have the same risk as non-pregnant women for SARS-CoV-2 infection,²⁰ and pregnant women are more susceptible to respiratory diseases. The mortality risk and severe forms of COVID-19 associated with pregnancy are found mainly in patients with comorbidities, like obesity, diabetes mellitus or arterial hypertension.^21-23

In a systematic review of 2567 pregnancies, Khalil et al.²¹ have calculated that one in fiveinfected pregnant women will experience no symptoms, but symptomatic patients are at high risk of morbidity and mortality. Forty-three maternal deaths were reported from the 2567 studied cases, and 7% of cases were admitted in intensive care units and 3.4% required mechanical ventilation.

A recent multicentric prospective randomized study from the INTERGROWTH-21^st global network (the INTERCOVID study) by Vilar et al. analyzing a sample of 706 pregnant women positive for COVID-19 has reported a maternal mortality rate of 1.6%. Overall, 44.0% of women with an RT-PCR test positive for SARS-CoV-2 were asymptomatic, 19% presented two symptoms, and 30% presented three or more symptoms. Demographic characteristics, including BMI ≥25 was similar in the two groups, women with COVID-19 and without COVID-19 in pregnancy, but diabetes and chronic respiratory disease were more frequent among COVID-19 pregnant females. A percentage of 3.7% from the group of pregnancy with COVID-19 diagnosis presented preexistent hypertension when compared with 2.1% in the group of pregnancy without infection. However, a higher proportion of gestational hypertension and its complications were found in the group with COVID-19, with a relative risk of 1.76 for preeclampsia and eclampsia. In this report, 0.4% of infected women presented a history of tuberculosis, compared with 0.2% of non-infected women. There are more risks for pregnancy complications when symptoms persist more than five days, especially respiratory symptoms. ICU admission and the need for a higher level of care were reported in patients diagnoses with COVID-19.²⁴

Pregnant women requirefrequentvisits to the general practitioner and the maternity for prenatal care visits, ultrasound or laboratory tests.Many infected asymptomatic women have children who go to kindergarten and nursery, so there is a high risk of spreading the virus. Moreover, healthcare and frontline pregnant women are at higher risk for SARS-CoV-2 infections.

Given all of the above, it seems common sense that during pregnancy women need to be vaccinated, as a population vulnerable for complicated forms of COVID-19.

Evidence about vaccination during pregnancy, including COVID-19 vaccines

Because the is no yet available data about the effect of COVID-19 vaccines on mother and infants from the ongoing clinical trials, we know about use of vaccines in real-life,²⁵ mostly in healthcare pregnant women or in women who did not know they were pregnant at the time of vaccination.

However, taking into account more benefits than risks, global authorities, including the Romanian Society of Obstetrics and Gynecology (SOGR), have issued updated guidelines about the recommendation of vaccines in obstetrics.^26-29 SOGR has stipulated that COVID-19 vaccines can be used in pregnancy if the patient agrees after the doctor has informed her of the risks and benefits.²⁶

In 2013, the National Institutes of Health’s National Institute of Allergy and Infectious Diseases organized a series of conferences for establishing an expert panel of scientists that developed general recommendations and practical principles to prove coherence, safety and guidance on the assessment of vaccination, including pregnant population persons in clinical trials registers.³⁰

Evidence base for optimal counseling regarding safety on COVID-19 vaccines during pregnancy is needed. Also, if fetal teratogenic consequences are found after early vaccination in pregnancy for women who were not known to be pregnant at the time of vaccination, this need to be registered.

The first mass COVID-19 vaccination program started on 27 December 2020 in Romania.^31,32 As of April2021, the global COVID-19 vaccine research and global development reports include vaccine candidates in various development and research stages. They are based on different technologies: viral nucleic acid (DNA and RNA), virus-like particle, peptide, viral vector (replicating and non-replicating), recombinant antigenic protein, live attenuated virus and inactivated virus approaches.³³Fourteen vaccines are authorized in the world by different national regulatory authoritiesfor public use: twoRNA vaccines (Pfizer-BioNTech tozinameranandModerna mRNA 1273), five conventionalinactivated vaccines, fiveviral vector vaccines(Sputnik Light,Gam-Covid Vac,Oxford AstraZeneca,AD5-NCO andJohnson & Johnson), and two peptide antigens subunit vaccines(EpiVacCoronaandRBD-Dimer). By 12 May 2021, from Belgium and Denmark, 2 trials (from 29) about COVID-19 and different types of vaccines evaluation in pregnant and lactating population ≥18 years were found on the site of EU Clinical Trials Register.³⁴

In Romania, there are four vaccines authorized by the European Medicines Agency(EMA): Pfizer-BioNTech (authorized in 21 December 2020), Moderna (authorized in 6 January 2021), Oxford-AstraZeneca (authorized in 29 January 2021) andJohnson & Johnson (authorized in 11 March 2021).³⁵

Moderna's mRNA-1273 vaccine is administered in a deltoid muscle as two 100-microgram doses given 28 days apart. Pfizer's vaccine is administered intramuscularly as two doses of 30 micrograms given 21 days apart. Oxford-AstraZeneca’s vaccine is administered as two doses of 0.5 mL given 4 and 12 weeks (28 to 84 days) after the first dose. Johnson & Johnson’s vaccine is administered as a single dose of 0.5 mL. Oliaro et al. have calculated recently an absolute risk reduction of COVID-19 in the general population to 0.84% for the Pfizer-BioNTech vaccine, 1.2% for the Moderna vaccine, 1.3% for the Oxford-AstraZeneca vaccine, and 1.2% for the Johnson & Johnson vaccine.³⁶

Reported cases of pregnancy issues in case of COVID-19 vaccination during pregnancy

Animal studies on COVID-19 vaccination in females and during pregnancy showed no adverse malformative effects during fetal or embryonic stages of development or on female capacity of reproduction.³⁷

Khalil et al. have found an increased rate of spontaneous abortion in patients infected with SARS-CoV-2. Getting vaccinated before pregnancy could lower the rate of spontaneous abortion associated with SARS-CoV-2 infection.³⁸

A very large report from USA on the outcomes of 827 pregnancy in COVID-19 vaccinated women have found 86.1% live birth, 0.1% stillbirth and 12.6% spontaneous abortion. The majority of abortions occurred in the first trimester of pregnancy, before 13 weeks of pregnancy. Newborn antibodies related to maternal

SARS-CoV-2 infection were detected in fetal cord blood after the third trimester, as passive maternal immunization. This suggests transplacental transfer of IgG SARS-CoV-2 antibodies after maternal COVID-19 vaccination during the end of pregnancy.

Maternal vaccination near term might provide an effective level of protection to the neonate, but we do not know for how long will last.³⁹ Other studies have to outline newborn antibodies to SARS-CoV-2 detected in fetal and infant cord blood after the first dose of third-trimester maternal vaccination,^40-42 begging the question on antibody transfer and on the protective level for infants relative to the mother’s timing of vaccination.

Similar to non-pregnant women, obesity, hypertension, diabetes, cardiovascular disease are pathologies that can add the risk for the occurrence of severe form of COVID-19 disease during pregnancy.⁴³

The reported side effects after mRNA vaccines were similar to side effects in the general population: muscle pain, fever, fatigue, headache, chills. Pyrexia (38°C or higher) occurred in 3.7% of responders with a positive pregnancy test at the time of vaccination after the first dose and 15.8% after the second dose of the Pfizer-BioNTech mRNA vaccine.⁴⁴ Fever that occurred in pregnancy may be responsible for vaccine hypersensitivity,⁴⁵maternal infections, spontaneous abortion, premature birth, and/or fetal demise, congenital birth defects adverse outcomes.⁴⁶ Given the vaccine reactogenicity, including fever (38°C or higher), vaccination in the first trimester may be responsible for birth defects, including neural tube and brain development abnormality.⁴⁷

The AstraZeneca vaccine was associated with a risk of thrombosis after a few reported cases of this severe complication and death.⁴⁸ Pregnant women have a higher risk of thrombosis and thromboembolism. So it is deemed sage to avoid Astra-Zeneca vaccines during pregnancy since trial data will be more conclusive. Pregnant women are recommended to get a COVID-19 vaccination^26,28 using mRNA vaccines BioNTech-Pfizer and Moderna vaccines.²⁷ Nevertheless, the decision is left to the patient after proper framing of information.^26,28 COVID-19 vaccination during pregnancy is shown to be safe and effective. But many questions remain for future research. One of the important ones is about the optimal time to get vaccinated.There is still limited evidence about in uteroinfection and early positive fetal and neonatal testing.

In conclusion, this review of published data and studies of COVID-19 and pregnancy can serve as a basis for discussion for doctors and patients put in a position to decide the vaccine they will be getting. While the body of literature regarding the safety and effectiveness calculation on COVID-19 vaccines immunization is growing, two clinical trials are already registered, including pregnant women. Further research canshed some light on this question.

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