As you are working in your Primary Care office, a woman comes in looking to get care. She mentions she had a positive pregnancy test at home and wanted to confirm at the doctor’s office. The test in the office is positive and you ask the patient about scheduling future appointments, and getting some immunizations for this visit. She mentions she has gotten the COVID vaccine last year, but has not gotten the newest booster. She asks if there will be any adverse effects with her or her unborn child if she got the booster now, or if she could wait to get the booster until after she gave birth.

Search Question:

For pregnant women, does administration of the COVID-19 vaccine lead to maternal-fetal complications as opposed to not administrating the vaccine or administrating the vaccine after birth?

Question Type: What kind of question is this? (boxes now checkable in Word)

☐Prevalence                             ☐Screening                  ☐Diagnosis

☐Prognosis                              ☐Treatment                 ☒Harms

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices.

– If meta-analysis or systematic review are not available, randomized controlled clinical trials will also offer great supporting evidence as they are carefully planned experiments, reduce the potential for bias, and allow for comparison between intervention and control groups.

– Cohort studies could also be used since they allow to follow the patients who have already received a particular treatment forward over time. This is not as reliable as randomized controlled clinical trials since patients might differ in ways other than in the variable that is being observed.

PICO search terms:

P	I	C	O
Pregnant women	Covid-19 Vaccination	Unvaccinated patients	Maternal outcomes during pregnancy
Pregnant people	Covid-19 Vaccine	Vaccination after delivery	Maternal outcomes after pregnancy
	Covid-19 Booster		Neonatal outcomes

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
Explain how you narrow your choices to the few selected articles.

Results found:

TRIP Database

• Pregnant women AND Covid-19 vaccination – 58
• Pregnant women AND Covid-19 vaccination AND maternal and neonatal outcomes – 15

PubMed

• Pregnant women AND Covid-19 vaccination (last 10 years) – 1,297
• Pregnant women AND Covid-19 vaccination (last 10 years) – 292

Google Scholar

• Pregnant women AND Covid-19 vaccination (last 10 years) – 41,700
• Pregnant women AND Covid-19 vaccination AND maternal and neonatal outcomes (last 10 years) – 28,300

The articles I chose were a mixture of two systematic review and meta-analysis’ and two retrospective cohort studies that dealt with my topic. Thankfully, my PICO is very topical, so finding articles were not a very big issue. Lots of the studies I found, however, looked at vaccine hesitancy for pregnant women across the United States, and what could be done to combat that. I also found many articles from overseas (like Japan, China, Sweden, Israel) that fit perfectly with my PICO, but I wanted to keep my PICO situated in the US and North America.

Citation: Marchand, G., Masoud, A.T., Grover, S. et al. Maternal and neonatal outcomes of COVID-19 vaccination during pregnancy, a systematic review and meta-analysis. npj Vaccines 8, 103 (2023). https://doi.org/10.1038/s41541-023-00698-8

Type of article: Systematic Review and Meta-analysis

Abstract   Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with increased pregnancy complications. Despite effective vaccination strategies for the general population, the evidence on the safety and efficacy of Coronavirus disease 2019 (COVID-19) vaccinations in pregnancy is limited due to a lack of well-powered studies. The present study compares the maternal, neonatal, and immunological outcomes between vaccinated pregnant and unvaccinated pregnant women using a systematic review and meta-analysis approach. We included 37 studies with a total of 141,107 pregnant women (36.8% vaccinated) spread across all outcomes. Our evidence indicates a higher rate of cesarean section in the 1898 vaccinated pregnant women compared to the 6180 women who did not receive vaccination (OR = 1.20, CI = (1.05, 1.38), P = 0.007, I2 = 45%). Regarding immunological outcomes, the risk of SARS-CoV-2 infection during pregnancy or postpartum was significantly reduced in 6820 vaccinated pregnant women compared to 17,010 unvaccinated pregnant women (OR = 0.25, CI = 0.13–0.48, P < 0.0001, I2 = 61%), as evident from qualitative assessment indicating significantly higher postpartum antibody titers compared to that observed in both unvaccinated mothers and mothers who have recently recovered from a SARS-CoV-2 infection. Our analysis represents high quality evidence showing that COVID-19 vaccination effectively raises antibody titers against SARS-CoV-2. This may confer protection against infection during pregnancy and the postpartum period. In addition to being protective against SARS-CoV-2, the vaccine was associated with decreased odds of preterm delivery. Furthermore, COVID-19 vaccination may also be associated with higher odds of cesarean section.

Key Points: – This systematic review and meta-analysis included 37 studies from the PubMed, Cochrane, Web of Science and Scopus databases – There were 141,107 pregnant women who were included in this study with the median age between 30-35 years old36.8% of the women were vaccinated – The odds (OR = 1.20) were significantly higher for the vaccinated women to get C-sections than the women who were not vaccinated. There were no other adverse maternal outcomes for vaccinated women  – Concerning neonatal outcomes, the odds (OR = 0.71) were significantly lower of preterm birth for vaccinated women than unvaccinated women – There was significantly reduced incidence of SARS-CoV-2 infection in vaccinated pregnant women compared to unvaccinated pregnant women (OR = 0.31) – Maternal IgG antibodies from vaccinated women were passed on to their children, and antibodies were still found up to 6 months in those babies protecting them from the virus

Why I chose it: I chose this article because it had a very large data set and it directly answered my PICO question. I was surprised to see that there were more C-sections done for vaccinated women than those who were not, but the authors did not really have a reason on why it was happening. This article also showed that maternal immunity was passed down from vaccinated mother to neonate, and the baby was protected for over 6 months with its mothers IgG antibodies. I was also pleased to see that vaccinated pregnant mothers had much less preterm births due to COVID than women who chose not to be vaccinated.

Citation: Juliá-Burchés, C., & Martínez-Varea, A. (2023). An Update on COVID-19 Vaccination and Pregnancy. Journal of personalized medicine, 13(5), 797. https://doi.org/10.3390/jpm13050797

Type of article: Systematic Review and Meta-analysis

Abstract Pregnant women are more prone to experience severe COVID-19 disease, including intensive care unit (ICU) admission, use of invasive ventilation, extracorporeal membrane oxygenation (ECMO), and mortality compared to non-pregnant individuals. Additionally, research suggests that SARS-CoV-2 infection during pregnancy is linked to adverse pregnancy outcomes, such as preterm birth, preeclampsia, and stillbirth, as well as adverse neonatal outcomes, including hospitalization and admission to the neonatal intensive care unit. This review assessed the available literature from November 2021 to 19 March 2023, concerning the safety and effectiveness of COVID-19 vaccination during pregnancy. COVID-19 vaccination administered during pregnancy is not linked to significant adverse events related to the vaccine or negative obstetric, fetal, or neonatal outcomes. Moreover, the vaccine has the same effectiveness in preventing severe COVID-19 disease in pregnant individuals as in the general population. Additionally, COVID-19 vaccination is the safest and most effective method for pregnant women to protect themselves and their newborns from severe COVID-19 disease, hospitalization, and ICU admission. Thus, vaccination should be recommended for pregnant patients. While the immunogenicity of vaccination in pregnancy appears to be similar to that in the general population, more research is needed to determine the optimal timing of vaccination during pregnancy for the benefit of the neonate.

Key Points: – This systematic review and meta-analysis looked 37 studies that were found using the PubMed database – Throughout these 37 studies, vaccinated women have not had any significant adverse events related to the vaccines such as miscarriage, preterm birth, fetal growth restriction, preeclampsia/eclampsia, stillbirth, or placental abruption – During an acute COVID-19 infection, 2.6% of vaccinated pregnant women needed oxygen therapy versus 16.2% of the pregnant women who were not vaccinated – No vaccinated pregnant women needed to be admitted to the ICU in contrast to almost 4% of unvaccinated pregnant women due to increased severity of symptoms – With vaccinated pregnant women there was a significant decrease in total preterm births <37 weeks (5.1% vs. 9.2%), spontaneous preterm birth (2.4% vs. 4.0%), and iatrogenic preterm birth (2.7% vs. 5.2%), in comparison with unvaccinated pregnant women – Vaccinated pregnant women decreased the risk of their infant being hospitalized with COVID-19 for up to 4-6 months of age, as opposed to unvaccinated pregnant women who gave no support to their child after birth

Why I chose it: I chose this article because it gave a lot of different information in regards to multiple adverse effects for pregnant women who were not vaccinated. Unvaccinated women needed higher levels of oxygen therapy due to an acute COVID-19 infection. They also had higher percentages of preterm births. I also was pleased to read neonates born to vaccinated women had much longer immunity to COVID-19. I was also interested in reading that pregnant women who were vaccinated during their third trimester gave the most immunity to their children reducing the risk of neonatal adverse outcomes, including multisystem inflammatory syndrome in children, protection against low Apgar scores, and admission to neonatal intensive care units.

Citation: Jorgensen SCJ, Drover SSM, Fell DB, et al. Newborn and Early Infant Outcomes Following Maternal COVID-19 Vaccination During Pregnancy. JAMA Pediatr. 2023;177(12):1314–1323. doi:10.1001/jamapediatrics.2023.4499

Type of article: Retrospective Cohort Study

Abstract Importance: The study team previously showed that maternal mRNA COVID-19 vaccination during pregnancy confers protection against SARS-CoV-2 infection and COVID-19–related hospital admission in newborns and young infants. In this study, the study team evaluated newborn and early infant safety outcomes following maternal messenger RNA (mRNA) COVID-19 vaccination during pregnancy, for which there is limited comparative epidemiological evidence. Objective: To determine if maternal mRNA COVID-19 vaccination during pregnancy is associated with adverse newborn and early infant outcomes. Design, Setting, and Participants: This population-based retrospective cohort study took place in Ontario, Canada, using multiple linked health administrative databases. Singleton live births with an expected delivery date between May 1, 2021, and September 2, 2022, were included. Data were analyzed from January 2023 through March 2023. Exposure: Maternal mRNA COVID-19 vaccination (1 or more doses) during pregnancy Main Outcomes and Measures: Severe neonatal morbidity (SNM), neonatal death, neonatal intensive care unit (NICU) admission, neonatal readmission, and hospital admission up to 6 months of age. The study team calculated inverse probability of treatment weighted risk ratios (RRs) and fit weighted Cox proportional hazards regression models comparing outcomes in infants of mothers who received COVID-19 vaccination during pregnancy with those who received no COVID-19 vaccine doses before delivery. Results: In total, 142 006 infants (72 595 male [51%]; mean [SD] gestational age at birth, 38.7 [1.7] weeks) were included; 85 670 were exposed to 1 or more COVID-19 vaccine doses in utero (60%). Infants of vaccinated mothers had lower risks of SNM (vaccine exposed 7.3% vs vaccine unexposed 8.3%; adjusted RR [aRR], 0.86; 95% CI, 0.83-0.90), neonatal death (0.09% vs 0.16%; aRR, 0.47; 95% CI, 0.33-0.65), and NICU admission (11.4% vs 13.1%; aRR, 0.86; 95% CI, 0.83-0.89). There was no association between maternal vaccination during pregnancy and neonatal readmission (5.5% vs 5.1%; adjusted hazard ratio, 1.03; 95% CI, 0.98-1.09) or 6-month hospital admission (8.4% vs 8.1%; adjusted hazard ratio, 1.01; 95% CI, 0.96-1.05). Conclusions and Relevance: In this population-based cohort study in Ontario, Canada, maternal mRNA COVID-19 vaccination during pregnancy was associated with lower risks of SNM, neonatal death, and NICU admission. In addition, neonatal and 6-month readmissions were not increased in infants of mothers vaccinated during pregnancy.

Key Points: – This retrospective cohort study looked at 142,006 infants 85,670 patients were exposed to one or more COVID-19 vaccine doses in utero – The risks of severe neonatal morbidity, neonatal death and neonatal ICU admission was significantly lower for vaccinated women during pregnancy as compared with unvaccinated pregnant women (11.4% to 13.1 %) – There were no statistical significances with neonatal readmission for 28 days or 6 months after birth for either vaccinated or unvaccinated mothers – The number of vaccine doses also was not statistically significant for the vaccinated pregnant women and the immunity that the neonates acquired from them

Why I chose it: I chose this article because it showed real world data from a North American hospital, and the data set was very large. As mentioned in other articles, neonates greatly benefit (for at least 4-6 months) from their mothers who have taken a COVID-19 vaccine. I was also very surprised to see that whether a vaccinated mother got one dose of the COVID-19 vaccine or she got multiple doses (including the booster), her infant benefited regardless.

Citation: Piekos, S. N., Hwang, Y. M., Roper, R. T., Sorensen, T., Price, N. D., Hood, L., & Hadlock, J. J. (2023). Effect of COVID-19 vaccination and booster on maternal-fetal outcomes: a retrospective cohort study. The Lancet. Digital health, 5(9), e594–e606. https://doi.org/10.1016/S2589-7500(23)00093-6

Type of article: Retrospective Cohort Study

Abstract Background: COVID-19 in pregnant people increases the risk for poor maternal–fetal outcomes. However, COVID-19 vaccination hesitancy remains due to concerns over the vaccine’s potential effects on maternal–fetal outcomes. Here we examine the impact of COVID-19 vaccination and boosters on maternal SARS-CoV-2 infections and birth outcomes. Methods: This was a retrospective multicentre cohort study on the impact of COVID-19 vaccination on maternal–fetal outcomes for people who delivered (n=106 428) at Providence St Joseph Health across seven western US states from Jan 26, 2021 to Oct 26, 2022. Cohorts were defined by vaccination status at delivery: vaccinated (n=35 926; two or more doses of mRNA-1273 Moderna or BNT162b2 Pfizer–BioNTech), unvaccinated (n=55 878), unvaccinated propensity score matched (n=16 771), boosted (n=10 927; three or more doses), vaccinated unboosted (n=13 243; two doses only), and vaccinated unboosted with propensity score matching (n=4414). We built supervised machine learning classification models, which we used to determine which people were more likely to be vaccinated or boosted at delivery. The primary outcome was maternal SARS-CoV-2 infection. COVID-19 vaccination status at delivery, COVID-19-related health care, preterm birth, stillbirth, and very low birthweight were evaluated as secondary outcomes. Findings: Vaccinated people were more likely to conceive later in the pandemic, have commercial insurance, be older, live in areas with lower household composition vulnerability, and have a higher BMI than unvaccinated people. Boosted people were more likely to have more days since receiving the second COVID-19 vaccine dose, conceive earlier in the pandemic, have commercial insurance, be older, and live in areas with lower household composition vulnerability than vaccinated unboosted people. Vaccinated pregnant people had lower rates of COVID-19 during pregnancy (4·0%) compared with unvaccinated matched people (5·3%; p<0·0001). COVID-19 rates were even lower in boosted people (3·2%) compared with vaccinated unboosted matched people (5·6%; p<0·0001). Vaccinated people were also less likely to have a preterm birth (7·9%; p<0·0001), stillbirth (0·3%; p<0·0002), or very low birthweight neonate (1·0%; p<0·0001) compared with unvaccinated matched people (preterm birth 9·4%; stillbirth 0·6%; very low birthweight 1·5%). Boosted people were less likely to have a stillbirth (0·3%; p<0·025) and have no differences in rates of preterm birth (7·6%; p=0–090) or very low birthweight neonates (0·8%; p=0·092) compared with vaccinated unboosted matched people (stillbirth 0·5%; preterm birth 8·4%; very low birthweight 1·1%). Interpretation: COVID-19 vaccination protects against adverse maternal–fetal outcomes, with booster doses conferring additional protection. Pregnant people should be high priority for vaccination and stay up to date with their COVID-19 vaccination schedule.

Key Points: – This retrospective cohort study looked at 106,428 patients across seven states who were part of the Providence St. Joseph Health network. – There were different cohorts that were looked at including vaccinated pregnant women with two or more doses (35,926), vaccinated pregnant women with only one dose (13,243), and unvaccinated pregnant women (55,878) – Unvaccinated pregnant women were significantly more likely to have COVID-19 during pregnancy compared with vaccinated pregnant women. – Boosted (or multiple dosed) pregnant women had the least number of COVID-19 infections during their pregnancy. – The overall proportion of people with COVID-19 during pregnancy was significantly lower in the vaccinated cohort (RR 0.75) compared with the unvaccinated cohort – Three maternal deaths in the unvaccinated cohort, all of whom had COVID-19, were observed – There were no statistically significant differences in COVID-19-related hospitalization rates, supplemental oxygen rates, or vasopressor rates between all three cohorts – The vaccinated cohort had significantly lower rates of stillbirth (RR 0.50) and preterm births (RR 0.84), compared with unvaccinated cohort – The boosted cohort had significantly lower rates of stillbirth (RR 0.60) compared with vaccinated cohort, but showed no differences in rates of preterm births or birth weights

Why I chose it: I chose this article because it was one of the largest retrospective cohort studies that looked at the effects of COVID-19 vaccination and boosters on maternal-fetal outcomes regarding delivery. I also enjoyed the different types of cohorts that were looked at (unvaccinated, vaccinated, boosted). I was not really surprised that pregnant women who were given the COVID-19 boosters faired the best out of all three groups, but I was surprised how well the vaccinated group (that did not get the boosters) do overall. This was also the first study that I saw talk about how vaccination prevented infants from being born with low birthweight and very low birthweights.

What is the clinical “bottom line” derived from these articles in answer to your question?

As the COVID-19 vaccination started rolling out late 2020/early 2021 many pregnant women were very wary about taking a new vaccine that they did not know much about, as well as taking the first mRNA vaccine that was ever offered. As time went on, more practitioners saw that the vaccine was protective of the pregnant women and the neonate to come. COVID-19 antibodies persisted in the neonates protecting them from the virus for up to 6 months. In women who were vaccinated, lowered instances of maternal adverse effects were observed like miscarriage, preterm birth, preeclampsia/eclampsia, stillbirth, or placental abruption. If asked, I would say pregnant women should be vaccinated against COVID-19 and stay up to date with their vaccination schedule (in reference to vaccine boosters).