Abstract
Introduction
SARS-CoV-2 can lead to a more severe infection during pregnancy. However, population-level data on COVID-19 disease and vaccine uptake in this population group are lacking, especially in South America.
Objective
We aimed to describe SARS-CoV-2 infection in pregnant women from a central region of Argentina.
Methodology
From March-2020 to March-2022, 2407 cases of pregnant women from Córdoba province with confirmed SARS-CoV-2 infection reported in the official records were analyzed. The infectivity and mortality rates were calculated; a control group of non-pregnant women infected with SARS CoV-2 was included. Sixty-six samples were subjected to variants of concern (VOC) detection by real time RT-PCR.
Results
The overall infection rate was 0.25%, and the number of infections mirrored the number of cases for general population. In September-2021 (when mass vaccination in pregnant women occurred) the infection rate decreased (0.35% in March 2020-September 2021 vs. 0.14% in October 2021-March 2022). The global fatality rate was 0.75% (18/2407). During March-2020 to September-2021 the fatality rate was higher than in the control group: 1.01% vs. 0.08% (p<0.05). Since then, no deaths were recorded in pregnant women (fatality rate 0% vs. 0.01% in the control group). The VOCs distribution was: Gamma: 56%, Delta: 20%, Omicron: 12%, Alpha: 3%, 9% of non-VOC lineages.
Conclusions
The fatality rate found was similar to that obtained for the entire country in this group, and higher than the control group. The frequency of VOCs reflected what happened in the general population. The decrease in cases and deaths since September-2021 correlated with the mass vaccination in this group.
Keywords: sars-cov-2, covid 19, embarazo, Argentina, epidemiología
Resumen
Introducción
El SARS-CoV-2 puede provocar una infección más grave durante el embarazo. Sin embargo, faltan datos a nivel poblacional sobre COVID-19 y la adopción de vacunas en este grupo de población, especialmente en América del Sur.
Objetivo
describir la infección por SARS-CoV-2 en mujeres embarazadas de la región central de Argentina.
Metodología
se analizaron 2.407 casos de gestantes de Córdoba entre marzo-2020 y marzo-2022 con infección confirmada por SARS-CoV-2 reportados en registros oficiales. Se calcularon tasas de infección y mortalidad; incluyéndose un grupo control de mujeres no embarazadas infectadas con SARS-CoV-2. Sesenta y seis muestras se sometieron a detección de variantes de preocupación (VOC) mediante RT-PCR en tiempo real.
Resultados
tasa de infección: 0,25%; el número de infecciones reflejó el número de casos de población general. En septiembre-2021 (momento de vacunación masiva en embarazadas) la tasa de infección disminuyó (0,35% en marzo-2020 septiembre-2021 vs. 0,14% en octubre-2021-marzo-2022). La tasa de letalidad global fue 0,75% (18/2407). Durante marzo-2020 a septiembre-2021 la tasa de letalidad fue mayor que en el grupo control: 1,01% vs 0,08% (p<0,05). Luego no se registraron muertes de embarazadas. Distribución de VOCs: Gamma: 56 %, Delta: 20 %, Omicron: 12 %, Alfa: 3 %, 9 % de linajes no VOC.
Conclusiones
La letalidad fue similar a la obtenida para todo el país en este grupo, y superior al grupo control. La frecuencia de VOC reflejó lo que sucedió en la población general. La disminución de casos y muertes desde septiembre de 2021 se correlacionó con la vacunación masiva en este grupo.
Palabras clave: sars-cov-2, covid 19, pregnancy, Argentina, epidemiology
Resumo
Introdução
O SARS-CoV-2 pode levar a uma infecção mais grave durante a gravidez. No entanto, faltam dados em nível populacional sobre a doença COVID 19 e a aceitação da vacina neste grupo populacional, especialmente na América do Sul.
Objetivo
Nosso objetivo foi descrever a infecção por SARS-CoV-2 em mulheres grávidas de uma região central da Argentina.
Metodologia
De março de 2020 a março de 2022, foram analisados 2.407 casos de mulheres grávidas da província de Córdoba com infecção confirmada por SARS-CoV-2 relatada nos registros oficiais. As taxas de infectividade e mortalidade foram calculadas; um grupo controle de mulheres não grávidas infectadas com SARS-CoV-2 foi incluído. Sessenta e seis amostras foram submetidas à detecção de variantes preocupantes (VOC) por RT-PCR em tempo real.
Resultados
A taxa geral de infecção foi de 0,25%, e o número de infecções refletiu o número de casos para a população em geral. Em setembro de 2021 (quando ocorreu a vacinação em massa em gestantes) a taxa de infecção diminuiu (0,35% em março de 2020-setembro de 2021 vs. 0,14% em outubro de 2021-março de 2022). A taxa de letalidade global foi de 0,75% (18/2407). Durante março de 2020 a setembro de 2021 a taxa de letalidade foi maior que no grupo controle: 1,01% vs. 0,08% (p<0,05). Desde então, nenhuma morte foi registrada em gestantes (taxa de letalidade 0% vs. 0,01% no grupo controle). A distribuição dos COVs foi: Gama: 56%, Delta: 20%, Ômicron: 12%, Alfa: 3%, 9% de linhagens não COV.
Conclusões
A taxa de letalidade encontrada foi semelhante à obtida para todo o país neste grupo, e maior que o grupo controle. A frequência de VOCs refletiu o que aconteceu na população em geral. A diminuição de casos e mortes desde setembro de 2021 correlacionou se com a vacinação em massa neste grupo.
Palavras-chave: sars-cov-2, covid 19, gravidez, Argentina, epidemiologia
KEY CONCEPTS
What is known about the subject?
Population-level data on COVID-19 disease and vaccine uptake in pregnant women are lacking, especially in South America. 2407 cases of pregnant women from Córdoba, Argentina, with confirmed SARS-CoV-2 infection were analyzed from March-2020 to March-2022. The overall infection rate was 0.25%, and the number of infections mirrored the number of cases for general population. A decrease in cases and deaths was recorded since September-2021, which correlated with the mass vaccination in this group. The VOCs distribution was: Gamma: 56%, Delta: 20%, Omicron: 12%, Alpha: 3%, 9% of non-VOC lineages.
What does this job provide?
We describe, for the first time, the epidemiology of SARS-CoV-2 infection in pregnant women from Argentina, showing an increased mortality rate in this population group when they are naturally infected (non-immunized). After mass immunization, no more deaths were registered in our region, evidencing the importance of this public health strategy, and showing that it must be continued over time.
Divulgation
We describe, for the first time, the epidemiology of SARS-CoV-2 infection in pregnant women from the central region of Argentina. The overall infection rate was 0.25%, and the number of infections mirrored the number of cases for general population. An increased mortality rate in this population group was registered when they were naturally infected (non-immunized) (1.01% in pregnant women vs.0.08% women from the general population). After mass immunization (started in September 2021), no more deaths were registered in our region in pregnant women, evidencing the importance of this public health strategy, and showing that it must be continued over time.
Introduction
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus, has spread rapidly worldwide, being declared as a global pandemic by the World Health Organization (WHO) in March 2020 1 . SARS-CoV-2 infection could affect all groups irrespective of age and gender. However, it has been associated with worse outcomes in several patient populations, including the elderly and those with chronic comorbidities, such as hypertension, diabetes, and cardiopulmonary problems 1 , 2 .
Pregnant women are more vulnerable to viral infections and therefore represent a potential risk group for severe outcomes in relation to viral infections 3 . Especially, they have an increased risk of severe pneumonia following infections with respiratory pathogens 4 . Little is known about the impact of pregnancy on COVID-19 and vice versa. It has been reported that pregnant women with COVID-19 are more likely to develop severe illness than non-pregnant women, with an increased rate of admission to the intensive care unit, need for supplemental oxygen, ventilation, and mortality 5 . Variations in clinical manifestations and severity compared to non-pregnant people could be due to numerous factors. Pregnant women represent a potential risk group for the occurrence of more severe symptoms 3 . The physiological and immunological changes that occur during pregnancy could explain the causes of the poor prognosis 6 . Among them, it is known that during pregnancy there is a physiological increase in the expression of the ACE2 receptor (receptor to which SARS-CoV-2 binds when it enters the host cell), which would lead to a higher risk of complications during the infection by this agent 2 . Added to this, there are some other factors: the presence of comorbidities (already mentioned), often not taken into account in studies about the severity of COVID-19 in this group, the presence of different viral variants (which changes according to the different introductions in each place and moment, and may influence the clinical presentation) 7 , and the characteristics of each population/region.
In Argentina, there is very little information about the impact of SARS-CoV-2 infection in pregnant women. Official data show mortality rates of 0.52% in 2020, 0.37% in 2021 and 0.21% in 2022 (data until March 14, 2022, the last official report in pregnant women) for the entire nation, with 233 deaths in total up to March 14th 2022 (when the last official report in pregnant women was published), with obesity, high blood pressure and diabetes being the main recorded comorbidities 8 . From the pregnant women who died, 7 (3%) had been immunized: 4 had 1 dose of the vaccine (applied more than 21 days before death) and 3 had 2 doses (applied more than 21 days before death). However, there are no studies that delve into epidemiological factors, nor studies by geographic regions, nor studies of variants/lineages of SARS-CoV-2 infecting this population and their possible correlation with the severity of the infection.
In this scenario, we aimed to describe SARS-CoV-2 infection in pregnant women from the central area of Argentina, including epidemiological features, the study of infecting variants and the impact of the introduction of the vaccine, in order to provide data on the impact of this virus in this group, which would serve to take control and preventive measures.
Materials and methods
Studied population
This is an anonymous, descriptive, retrospective, observational study, in which the data was collected from Sistema Integrado de Información Sanitaria Argentino (SISA) database. All cases of SARS-CoV-2 infection in pregnant women (sex female, age range: 15-49 years) from the province of Córdoba, in the central region of Argentina (31°25′00′′S, 64°11′00′′W; with 3,978,984 inhabitants) 9 notified in SISA system, were studied during the period March 2020 to March 2022. From the epidemiological records, the following data was collected: age, location, comorbidities, date of onset of symptoms, vaccination data, death.
All cases of SARS-CoV-2 infection in non-pregnant women between 15 and 49 years old (same age range as the population group under study) notified during the same period, residing in the province of Córdoba, were included as a control group.
The data for the general population (number of infected people) were obtained from the website of the Ministry of Health of the Province of Córdoba (https://prensa.cba.gov.ar/category/salud-2/).
Detection of variants of SARS-CoV-2
Sixty-six available SARS-CoV-2 RNA positive samples with Cts<30 obtained from oropharyngeal swabs from pregnant women between June and December 2021 were analyzed to screen variants of concern (VOC) mutations by real time RT-PCR 10 . The samples had originally been extracted with MegaBio plus Virus RNA Purification Kit II (BioFlux) on the GenePure Pro Nucleic Acid Purification System NPA-32P and amplified by real time RT-PCR using DisCoVery SARS-CoV-2 Nucleic Acid Detection Kit (sensitivity: 500 copies/mL; specificity: 100%).
Detection of the relevant mutations L452R, P681R, P681H, K417N and L452Q (within the S protein) was carried out by real time RT-PCR, using the TaqMan™ SARS-CoV-2 Mutation Panel (Applied Biosystems), following the strategy described by Castro et al. 2022. Each reaction was performed as multiplex, including probes detecting simultaneously the wildtype (wt) and the mutant nucleotide sequences. Briefly, 7µL RNA were added to 8µL of a mixture containing TaqPathTM 1-Step RT-qPCR Master Mix, CG (4X), TaqManTM SARS-CoV-2 Mutation Panel Assay (40X) and nuclease-free water.
Statistical analysis
All statistical analyses were conducted using R statistical software, version 4.0.5 (2021-03-31). The binom package and the Pearson-Kloper method was employed to calculate proportions and their associated 95% confidence intervals 11 .
The fatality rate was calculated for the entire study period and for two distinct intervals: March 2020 to September 2021, and October 2021 to March 2022. A Fisher's exact test was used to compare the fatality rate between pregnant women and the control group of non-pregnant women, with statistical significance set at p < 0.05. Power analysis was performed using base R functions to determine whether the sample size was sufficient to detect significant differences in outcomes between the groups. Additionally, a sensitivity analysis was conducted to assess the potential impact of unmeasured confounders on the observed associations. For this purpose, E-values were calculated using the EValue package 12 . Relative risk estimates were initially obtained to compute E-values using the epitools package 13 . When cell counts in contingency tables contained zeros, a Haldane-Anscombe continuity correction was applied by adding 0.5 to all cells 14 , 15 .
The distribution of variants of concern (VOCs) within the study population was analyzed by calculating the proportion of each VOC among the samples, and these proportions were compared to those observed in the general population during the same period.
Results
The first case of COVID-19 in a pregnant woman in Córdoba was registered on 18th March 2020 [epidemiological week (EW) 12, 2020]. From that date, the daily cases varied proportionally to the number of daily cases reported in the general population (Figure 1), with a total of 2407 cases being reported in pregnant people in the period studied. Table 1 shows maternal characteristics at the time of diagnosis, with the highest number of cases coming from the capital city of the province (in the central region, 48.57%) and in women between 25 and 36 years old (48.80%).
Figure N°1. Number of COVID-19 cases in general population (A) and in pregnant women (B) from Córdoba province, Argentina, between March 2020 and March 2022. Predominant SARS-CoV-2 circulating variants and start date of vaccination is also indicated.
Table N° 1. Maternal characteristics at diagnosis of COVID-19. Percentages are based on the total number of pregnant women with COVID-19 (n = 2407). %[95CI]: percentage of each maternal characteristic along with its 95% confidence interval .
|
Maternal characteristics |
N° of samples (%) |
|
Maternal age | |
|
<25 |
777 (32.28%) |
|
26-36 |
1175 (48.82%) |
|
>37 |
455 (18.90%) |
|
Geographic origin within the province | |
|
Center (capital city of Córdoba) |
1169 (48.57%) |
|
North |
271 (11.26%) |
|
East West |
506 (21.02%) 259 (10.76%) |
|
South |
202 (8.39%) |
|
Previous medical condition | |
|
Asthma |
111 (4.61%) |
|
Obesity |
72 (2.99%) |
|
Neurological disorder |
62 (2.57%) |
|
Hypertension |
47 (1.95%) |
|
Diabetes |
31 (1.29%) |
|
Renal insufficiency |
7 (0.29%) |
|
Tuberculosis |
6 (0.25%) |
|
Low weight |
5 (0.21%) |
|
Heart failure |
3 (0.12%) |
|
Oncological disease |
2 (0.08%) |
|
Chronic hepatitis |
2 (0.08%) |
The EW which registered the highest number of diagnoses of SARS-CoV-2 infection in this group was EW 25, 2021 (June 20th to 26th), with 144 reported cases, in accordance with the peak of the second wave of COVID-19 in Córdoba (Figure 1). The global infection rate (number of pregnant women infected with respect to the total number of infected individuals) was 0.25% [% confidence interval (CI) = 0.24-0.26]. In September 2021, this value decreased from 0.35% (%CI = 0.33-0.37) (March 2020-September 2021) to 0.14% (%CI = 0.13-0.15) (October 2021-March 2022), which coincides with an increase in the vaccination record in pregnant women (according to SISA database).
Of the total cases analyzed, 15.8% (380/2407) (%CI = 14.35-17.30) corresponded to hospitalized pregnant women, with the most common symptoms being fever, headache, myalgia, cough, dyspnea, sore throat and malaise.
The case fatality rate throughout the entire period was 0.75% (18/2407) (%CI = 0.44-1.18). The month with the highest number of registered deaths was July 2021 (with 6 deaths), while the last death was recorded in September 2021 (Figure 2). Until that date (period March 2020-September 2021), the fatality rate was significantly higher than that obtained for the control group of non-pregnant women: 1.01% (%CI = 0.60-1.60) vs. 0.08% (%CI = 0.06-0.09), respectively (p<0.05). Since then, no deaths in pregnant women were registered, and the case fatality rate in this second period (October 2021-March 2022) was 0% (vs. 0.01% in the control group) (p>0.05). From the 18 deaths registered (age range 21-48 years old), 8 individuals (44.4%) presented some comorbidity, such as obesity (33.3%, 6/18), asthma (5.6%, 1/18), diabetes (5.6%, 1/18) and arterial hypertension (5.6%, 1/18), and only 2 were vaccinated with one dose of the vaccine (Supplementary Table 1).
Supplementary Table N° 1. Characteristics of the pregnant women infected with SARS-CoV-2 who died during March 2020-March2022 in Córdoba, Argentina .
|
Sample ID |
Age (years) |
Comorbidities |
Variant of infection |
|
1 |
22 |
No |
No VOC |
|
2 |
38 |
Obesity |
ND |
|
3 |
25 |
Asthma |
ND |
|
4 |
43 |
Obesity |
ND |
|
5 |
36 |
No |
ND |
|
6 |
32 |
Diabetes, obesity |
Gamma |
|
7 |
30 |
No |
ND |
|
8 |
41 |
No |
ND |
|
9 |
25 |
Arterial hypertension |
ND |
|
10 |
37 |
No |
ND |
|
11 |
43 |
No |
ND |
|
12 |
41 |
Obesity |
ND |
|
13 |
33 |
Obesity |
ND |
|
14a |
37 |
No |
ND |
|
15 |
40 |
No |
Gamma |
|
16b |
35 |
Obesity |
Gamma |
|
17 |
48 |
No |
ND |
|
18 |
21 |
No |
Alpha |
ND: not determined.
aOne dose of Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector).
bOne dose of SARS-CoV-2 inactivated (Vero cells) vaccine.
Figure N° 2. Number of deaths in pregnant women infected with SARS-CoV-2 in Córdoba, Argentina, during March 2020-March 2022.
Proportions, confident intervals, power and E-values are summarized in Table 2. The relative high E-values indicate that a large degree of association between confounders and fatality-pregnancy is needed to explain the relationship.
Table N° 2. Result from the analysis of case fatality rate for both periods.
|
Period |
Fatality rate %[95CI] |
p-value |
Power |
Relative risk |
E-value |
|
|
Pregnant |
Non-pregnant |
|||||
|
Total |
0.75 [0.44-1.18] |
0.05 [0.04-0.05] |
< 0.05 |
0.99 |
16.560 |
32.62 |
|
First |
1.01 [0.60-1.60] |
0.08 [0.06-0.09] |
< 0.05 |
0.99 |
13.26 |
26.02 |
|
Second |
0 [0-0.58] |
0.01 [0.009-0.02] |
> 0.05 |
0.99 |
5.52 |
10.51 |
The distribution of VOCs found in the 66 samples analyzed was: 56% of Gamma (37/66), 20% of Delta (13/66), 12% of Omicron (8/66), 3% of Alpha (2/66) and 9% of non-VOC lineages (not typifiable by the methodology used). The proportion of VOCs circulating in pregnant women was similar to that obtained in the general population in the same period (Figure 3) 10 , 16 . Clinical data could not be obtained from these samples.
Figure N° 3. Proportion of infecting VOCs in pregnant women during June-December 2021 in Córdoba province, Argentina.
Conclusion
Between March 2020 and March 2022 (the period of study), the province of Córdoba, Argentina, experienced three waves of COVID-19: the first in September-October 2020, due to non-VOC SARS-CoV-2 strains, the second in June-July 2021, in which the major variant was Gamma, and the third wave in December 2021-January 2022, caused by the Omicron variant. During this period, SARS-CoV-2 infection rates in pregnant women closely mirrored those in the general population, when different SARS-CoV-2 variants predominated, as occurred in other countries 17 . In September 2021 the number of cases in pregnant women decreased drastically, which coincided with an increase in the number of vaccinated pregnant women, according to official SISA records. In Córdoba, vaccination for SARS-CoV-2 was carried out by government entities, and gradually in the different population groups 18 . The health team was the first group that was immunized, receiving the first dose in December 2020/January 2021. In February 2021, vaccination was gradually implemented in pregnant women in the province, starting with those with comorbidities, to later extend it to the entire group 18 , 19 . However, the cases registered in pregnant people in the following months, corresponded to non-immunized women, and, at the time of the second wave of COVID-19 in Córdoba, almost all pregnant people were still not vaccinated, which would indicate a low vaccination rate in this group at the beginning of the vaccination program. This could have occurred due to a delay in enabling vaccination in risk groups, a poor knowledge of the availability of the vaccine (by patients and physicians) or mistrust in it (for being new vaccine formulations). By September 2021 vaccination was registered in almost all pregnant women (according to SISA records).
The case fatality rate found in pregnant people from Córdoba (0.75%) was similar to that obtained for the entire country in this group (0.76%) 8 , and higher than non-pregnant control group, which is consistent with previous reports in other regions 20 , 21 , and shows, as previously documented, that pregnancy can lead to an increased susceptibility to infections 7 . Almost half of the pregnant women who died (44.4%) presented comorbidities, which is consistent with what has been recorded for other population groups or general population 22 , 23 . In September 2021 the last death in pregnant women due to COVID-19 was recorded (SISA records). It is notable that, at this point, the case fatality rate dropped considerably [1.01% until September 2021 vs. 0% in this second period (September 2021-March 2022)], coinciding with the massive vaccination in this population group. This highlights the efficacy of vaccines in preventing deaths, as reported in previous works 7 , 17 . There is also strong evidence that vaccines are protective of severe disease and pregnancy complications 20 , which affirms the importance of their application. It is worth mentioning that, unlike what happens in Europe or the United States, where anti-vaccine movements may influence the vaccine uptake 17 , in Argentina there are high levels of adherence to vaccines (not only for COVID-19, but for all vaccines), so practically the entire population attended was immunized during the pandemic. This explains why no more deaths by COVID-19 in pregnant women have been detected in our region since 2021.
The frequency of variants detected in this study correlated with that found in the general population at each moment. Therefore, no predominance of a particular VOC was observed in SARS-CoV-2 infections in pregnant women through the studied period in Córdoba. Some previous studies have described a correlation between the infecting variant and the severity of the infection. This is the case of VOC Delta, which has been associated with more severe disease in pregnant women 7 . However, our results do not show this trend. Particularly with VOC Delta, in the short period in which this variant was predominant, no deaths by COVID-19 were registered in pregnant women. Similarly, during the Omicron outbreak (with major circulation of this variant), no deaths were recorded in this population group. This could be due to a limited number of samples analyzed for VOC characterization during this study, the low circulation of VOC Delta in our region (VOCs Gamma and Omicron were more predominant, while VOC Delta has a predominantly fleeting circulation) and the introduction of the vaccine (with high adherence), which contributed to the occurrence of milder infections.
A limitation of our study was the lack of data in several of the samples analyzed, which hindered a thorough analysis of SARS-CoV-2 infections in pregnant women. Particularly not having the data on the trimester of pregnancy, which could be a factor that influences the severity and obstetric consequences of the infection 17 . Another limitation was the low number of samples analyzed for VOC detection, since only few quality samples were available for testing.
Our results show, for the first time, the epidemiology of SARS-CoV-2 infection in pregnant women from Argentina, showing an increased mortality rate in this population group when they are naturally infected (non-immunized). After mass immunization, no more deaths were registered in our region, evidencing the importance of this public health strategy, and showing that it must be continued over time.
Footnotes
Limitaciones de responsabilidad:
La responsabilidad del trabajo es exclusivamente de quienes colaboraron en la elaboración del mismo.
Conflicto de interés:
Ninguno.
Conflicto de interés:
La presente investigación no contó con fuentes de financiación.
Originalidad:
Este artículo es original y no ha sido enviado para su publicación a otro medio de difusión científica en forma completa ni parcialmente.
Cesión de derechos:
Quienes participaron en la elaboración de este artículo, ceden los derechos de autor a la Universidad Nacional de Córdoba para publicar en la Revista de la Facultad de Ciencias Médicas de Córdoba y realizar las traducciones necesarias al idioma inglés.
Contribución de los autores:
Quienes participaron en la elaboración de este artículo, han trabajado en la concepción del diseño, recolección de la información y elaboración del manuscrito, haciéndose públicamente responsables de su contenido y aprobando su versión final.
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