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Epidemiological and clinical characteristics of pregnant women and neonates with COVID‐19 in Northwest Mexico

Abstract Introduction The SARS‐CoV‐2 virus, which causes COVID‐19, has spread quickly worldwide, causing millions of cases and thousands of deaths. Some risk factors in the general population are related to the development of severe COVID‐19 or death, but in pregnant women and neonates, the information is limited. Objective To determine the epidemiological and clinical characteristics of pregnant women and neonates diagnosed with COVID‐19 by RT–PCR and serological tests, and analyze the relationship between the influenza vaccination and COVID‐19 symptoms in infected pregnant women in Sinaloa state. Methods We collected samples from 116 pregnant women and 84 neonates from the Women´s Hospital of Sinaloa. They were diagnosed with COVID‐19 by RT–PCR and serological tests (IgG), and sociodemographic, clinical and laboratory parameters were recorded. Results A total of 11.2% (13/116) of the pregnant women were RT–PCR+, 25% (29/116) were IgG+ and 4.3% (5/116) were positive for both tests. Symptoms such as rhinorrhea (P = .04), cough (P = .02) and polypnea (P = .04) in pregnant women were related to COVID‐19, also leukocyte index was higher in pregnant women with COVID‐19 (P = .03), but the associations were lost after the Bonferroni correction. No laboratory parameters or underlying diseases were associated with COVID‐19, and most infected pregnant women had mild cases. We found an association between the influenza vaccine and less common COVID‐19 symptoms in pregnant women who were infected (P = .01). A total of 7.2% (6/84) of neonates were RT–PCR+, 35.7% (30/84) were IgG+, and there were no symptoms or underlying diseases associated with neonates who were infected. In conclusion, this work demonstrated that some symptoms were related to COVID‐19, most pregnant women and neonates had mild cases, and the influenza vaccine could decrease the severity of COVID‐19 cases in pregnant women.


INTRODUCTION
The emerging novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the International Committee on Taxonomy of Viruses. 1  risk factors related to severe cases of COVID-19, such as sex, age, and underlying diseases, but due to physiological changes during pregnancy, such as reduced functional residual volumes, diaphragm elevation, and altered cell immunity, unfortunately, the impact of COVID-19 on pregnant women is still poorly understood. 4 Few studies have demonstrated that pregnant women infected with SARS-CoV-2 could be asymptomatic patients or symptomatic patients with respiratory complications, such as requiring mechanical ventilation, and these alterations could occur until the pregnant woman's death. 5 Pregnant women not only develop alterations in their body such as preeclampsia, but fetuses also can present alterations by COVID- 19. COVID-19 is related to the risk of preterm birth, low birth weight, and the need for neonatal hospitalization in a neonatal intensive care unit, as well as the risk of fetal malformations, and intrauterine growth restriction 6, . 7 The changes that neonates can present from COVID-19 could be related to the vertical transmission of the virus from the mother to neonate. Some studies showed that neonates became RT-PCR positive for SARS-CoV-2 from their mothers with COVID-19 in their first hours of life, a phenomenon that suggests possible vertical transmission, which could represent a significant public health issue. 8 On the other hand, mothers infected with SARS-CoV-2 can also protect the fetus due to vertical transmission of IgG from the mother to fetus. 9 To avoid complications of COVID-19, the timely diagnosis of this virus is important, and there are some tests than can achieve it. The gold standard is RT-PCR, which performs the direct detection of virus-specific nucleic acids. This virus is isolated from the nasopharynx of infected patients. RT-PCR had high sensitivity (95%) to identify SARS-CoV-2 in the acute stage of infection 10 . Other techniques to diagnose infection by SARS-CoV-2 are serological tests, which are indirect methods for the detection of infections because antibodies against SARS-CoV-2, such as IgM and IgG, are identified from peripheral blood, and serological tests present high sensitivity in the late states of infection. 10,11 On the other hand, before of apparition of vaccines anti-  to prevent this disease, options to help to combat the ravages caused by the SARS-CoV-2 were needed, and different research have demonstrated that influenza virus and coronavirus share some features, 12 due to similarities between viruses the vaccination against influenza confers some level of protection against SARS-CoV-2 due to epitopes cross-reactivity or common immunological pathways involved and some works demonstrated it, because influenza vaccine have reduced risk of SARS-CoV-2 infection, also it has increased the survival rate of infected patients. 4,13 Mexico is one of the countries that has been more affected by COVID-19, and Sinaloa is within the 10 states with the most cases in Mexico. Additionally, in Sinaloa, a large proportion of the population suffers from chronic diseases, such as obesity, type 2 diabetes or hypertension, which can cause pregnant women to suffer severe COVID-19. 14,15 The vertical transmission mechanism(s)of COVID-19 in pregnant women and neonates is still unclear. In this comprehensive study, we investigated the prevalence of SARS-CoV-2 in pregnant women and neonates who tested positive by RT-PCR and serological tests in Sinaloa state, located in Northwest Mexico. We also analyzed the associations between the symptoms and underlying diseases of pregnant women and neonates with COVID-19. Finally, we analyzed the relationship between influenza vaccination and COVID-19 symptoms in infected pregnant women.

Population of study and procedures
In this study, pregnant women and neonates from the Women's Hos-

Ethical approval
The subjects were informed about the investigation and signed informed consent forms agreeing to participate in the study.

Statistical analyses
Fisher's exact test was used to assess differences between the groups and categories (symptoms, clinical outcome, comorbidities, clinical severity, laboratory parameters and vaccination history). A P value ≤.05 was considered to indicate statistical significance, moreover Bonferroni correction was applied to avoid alpha error 1. The data were analyzed using the statistical package SPSS Statistics version 24 (IBM Corp., Armonk, NY, USA).

Concomitant diagnosis for SARS-CoV-2 by RT-PCR and serological tests in pregnant women
From August 2020 to December 2020, a total of 116 pregnant women who attended the prenatal care outpatient clinic, and the obstetric emergency department were analyzed to identify those who were positive for SARS-CoV-2 by RT-PCR or by detecting IgG antibodies; of the pregnant women, 11.2% (13/116) were positive for SARS-CoV-2 by PCR, while 25% (29/116) of them were positive for IgG antibodies, as shown in Table 1 Table 1. Most of them were housewives, living in free union, aged between 21 and 25 years, and had completed secondary school. The higher prevalence of women positive for RT-PCR or IgG tests was in urban areas compared with rural areas. All of the women were obstetric hospitalized, and none were treated with intensive therapy (Table 1). SARS-CoV-2 and IgG positivity were more prevalent in women with multiple pregnancies, as well as women with only one product, than in those with multiple pregnancies or abortions (Table 1).

Clinical characteristics and laboratory parameters of pregnant woman who had positive RT-PCR and IgG tests for SARS-CoV-2
Pregnant women who were positive for COVID-19 or IgG antibodies reported many symptoms, which are shown in Table 2. The most prevalent symptoms that were reported, regardless of whether the women were positive by RT-PCR or IgG tests, were abdominal pain, headache, vomiting, rhinorrhea, cough, and dyspnea, among others ( Table 2). No symptoms were related to the 13 women who were positive according to the RT-PCR test, while rhinorrhea (P: .04), cough (P: .02) and polypnea (P: .04) were associated with pregnant women who were positive for IgG antibodies compared with those who were negative, but the association was lost after to apply the Bonferroni correction ( Years of duration by degree of education. Elementary school: 6 years; Secondary school: 3 years; Technical school: 3 years; High school: 3 years; University: 5 years; Postgraduate: Master's degree 2 years, PhD degree: 5 years. Obstetric hospitalization: Women who go to hospital to give birth.
Anthropometrical and laboratory parameters related to COVID-19, such as weight, BMI, oxygen saturation, breathing frequency, and temperature, were also analyzed ( Table 3). The only laboratory parameter related to pregnant women with COVID-19 RT-PCR positivity was the leukocyte index, in comparison with those with test negativity (Table 3). Although pregnant women who were positive for SARS-CoV-2 and IgG antibodies had higher BMIs than those who were negative, no associations were found. Most of the parameters were normal in the pregnant women who were positive for RT-PCR or IgG tests, except leukocyte index which was significant higher in women positive to RT-PCR in comparison with those negative (3.3 vs 1.6, respectively, P: .03), but after to Bonferroni correction the association was lost (

The clinical outcomes in pregnant women with COVID-19 (RT-PCR) and IgG positivity
Some underlying diseases, such as hypertension, gestational diabetes, obesity, cardiovascular diseases, cancer and asthma, were detected in the pregnant women with COVID-19 (RT-PCR) or IgG positivity ( Table 5). The pregnant women with COVID-19 (RT-PCR positive) presented only hypertension (30.7%) and obesity (23%), while women with IgG antibodies presented most of the diseases except cancer (Table 5).
However, the pregnant women who were negative by RT-PCR and IgG tests presented a higher prevalence of underlying diseases than those who were positive. Therefore, no associations were found among the underlying diseases and pregnant women with COVID-19, IgG positivity or both.

Influenza vaccination and symptoms in pregnant women who tested positive for COVID-19
The influenza vaccination history and presence of common COVID-19 symptoms in pregnant women were analyzed (  Table 5. This indicates that pregnant women with a previously influenza vaccination had less common COVID-19 symptoms.

3.5
The RT-PCR and IgG tests of newborns born to mothers diagnosed with or without COVID-19:

Symptoms and clinical outcomes
The probability of neonates being infected intrahospital, by their mothers with COVID-19, or the mother transferring antibodies to the neonates is high; therefore, the neonates born in the Women's Hospital were also analyzed. Two groups of neonates were examined in this study: twenty-two neonates from the mothers included in this study and 62 neonates from mothers who were not included in this study (Table S1). In Group 1, three neonates (RT-PCR-and IgG-) from mothers who were RT-PCR+ and IgG-, 4 neonates (one who was RT-PCRand IgG-, one who was RT-PCR+ and IgG+, and 2 who were RT-PCRand IgG+) from mothers who were RT-PCR-and IgG+, three neonates (RT-PCR+ and IgG-) from mothers who were RT-PCR-and IgG-and 12 neonates (RT-PCR-and IgG-) from mothers who were also negative for both tests, were included (Table S1). Group 2 included 23 neonates RT-PCR-and IgG+ and 2 who were RT-PCR+ and IgG+, and the rest of the neonates were negative for both tests (Supplementary Table 1).
Symptoms such as phlegm, dyspnea, polypnea, and fatigue, among others, were found in the neonates who were studied. Regarding Fisher's exact test was performed to check for statistical significance. Bonferroni correction was applied to P value corrected.   12 (11.6) . Fisher's exact test was performed to check for statistical significance. Bonferroni correction was applied to p value corrected.

TA B L E 6
Relationship between pregnant women who tested positive for COVID-19 and influenza vaccination and symptoms Fisher's exact test was performed to check for statistical significance. Bonferroni correction was applied to p value corrected.

P value noncorrected P value corrected
neonates who were RT-PCR positive, none presented any symptoms related to COVID-19 (Table 6). Regarding IgG positivity, symptoms such as dyspnea, polypnea, conjunctivitis and poor general health were found, but neonates who were negative for the IgG test presented a higher prevalence of symptoms (Table 6). Therefore, no associations were found.
Finally, associations among the underlying diseases with neonates who were RT-PCR and IgG positive were examined. Respiratory distress syndrome, sepsis, congenital malformations, heart diseases and jaundice were the underlying diseases that were found in neonates, but as for symptoms, PCR-positive neonates did not have any underlying diseases (Table 6). Respiratory distress syndrome, sepsis and congenital malformations were found in IgG-positive neonates, but the prevalence was similar to that in IgG-negative neonates.

DISCUSSION
Since 2019, SARS-CoV-2 has spread around the world and has caused many deaths, but currently, we know that some characteristics in subjects, such as age, sex, and underlying diseases, are important to whether patients develop severe COVID-19 4 , but the information available for pregnant women and their neonates with COVID-19 is very scarce. In this study, we showed that 11.2% of the pregnant women were diagnosed with SARS-CoV-2 by RT-PCR tests and 25% were diagnosed by serological tests (IgG). Most of the women had nonsevere cases without alterations in most clinical parameters. However, rhinorrhea, cough and polypnea were symptoms that were related to It is estimated that in the USA, more than 208, 937 COVID-19 cases have been reported in pregnant women 18 . The prevalence of COVID-19 in pregnant women varies depending on the country. In northern California, a COVID-19 prevalence of 2.5% was found in pregnant women. 19 In Brazil, of 195 pregnant women, 1.02% of them were diagnosed with COVID-19 by RT-PCR tests, and 8.7% were diagnosed with serological tests. 20 These studies are in contrast with our results because we found a higher prevalence, but the pregnant number ana-lyzed in this study was lower in comparison with other study in Mexico City. 21,22 More studies are needed to determine the prevalence of COVID-19 in pregnant women, because there are only few reports which show the pregnant women prevalence with SARS-CoV-2. 23,24 In this work, RT-PCR and serological tests were used to diagnose the study subjects. RT-PCR has been considered the gold standard to diagnose SARS-CoV-2; however, the sensitivity of RT-PCR as a serological test can change depending on the infection time period. RT-PCR is the gold standard in acute infection with specificity of > 99%, 25 but a previous study demonstrated that after five days of infection, the sensitivity of RT-PCR could decrease to 82%, and as the days after infection increase, the sensitivity decreases to 38%. This is in comparison with serological tests, which, in acute infection, present a low sensitivity of approximately 34%, but as the days after infection increase, the sensitivity increases; after 10 days post-infection, the sensitivity increases from 75% to 95% after 17 days. 10 It is very important to correctly use and interpret both tests to diagnose patients, provide ideal strategies and avoid severe COVID-19.
In the general population, some symptoms have been associated with COVID-19, such as cough, fever, myalgias, poor general health, and dyspnea 4 . In this study, cough, rhinorrhea and polypnea were related to IgG positivity in pregnancy women, but these associations were lost after Bonferroni correction, nevertheless other studies are match with our results. Chen L et al (2020) showed that fever, cough and chest tightness were the symptoms more prevalent in pregnant women infected. 26 46 Another study demonstrated the presence of the SARS-CoV-2 genome in umbilical cord blood and in at-term placentas, suggesting the vertical transmission of the infection. 8 However, there are studies that declared no association between vertical transmission and SARS-CoV-2 infection from mothers to neonates. 47,48 In this study, neonates with IgG antibodies and/or SARS-CoV-2 infections were found, and both could probably transfer from mothers to neonates, as previously mentioned. However, three SARS-CoV-2positive neonates were identified from mothers who were negative by RT-PCR and IgG tests, and there was a high probability that these

CONCLUSION
This study provides evidence that pregnant women from northwestern Mexico suffer mild to moderate COVID-19 disease, and some symptoms are associated with this population. In addition, we found possible protection of the influenza vaccine in pregnant women, decreasing the symptoms of this disease. Finally, a possible vertical transmission of infection or protection from mothers with SARS-CoV-2 to neonates was observed. Although we found few severe COVID-19 cases in this study, more studies are needed to monitor the behavior of SARS-CoV-2 in pregnant women and neonates, and new variants of this virus are emerging, such as the beta, delta or gamma variants, which could have a larger impact in this population. Continuous monitoring could help to detect factors that affect pregnant women and neonates; in this way, we could create strategies to avoid severe cases and deaths caused by SARS-CoV-2.