Antihypertensives in pregnant women with mild chronic hypertension.Paulino Vigil-De Gracia, MD.Complejo Hospitalario Dr. AAM Caja de Seguro Social. Investigador distinguido del Sistema Nacional de Investigación, SENACYT Panamá, e-mail: [email protected]: ¨The authors report no conflict of interest¨Funding: NOWord count: Abstract: 94 Main Text: 1085Running Title: Treatment of pregnancy with chronic hypertension.AbstractPregnant women with chronic hypertension have increased worldwide and with it more maternal and perinatal complications such as hypertensive crisis, preeclampsia, placental abruption, growth restriction, prematurity, perinatal mortality. In addition to correct diagnosis and strict follow-up during the pregnancy, antihypertensive drugs have been controversially used. An adequate randomized controlled study recently published shows the benefit of antihypertensives. The antihypertensive drug used seems to be the explanation why previous studies were not conclusive in denoting benefits. The drugs that have shown benefits are beta-blockers (labetalol), calcium channel blockers (nifedipine, amlodipine) and with minimal effectiveness methyldopa.Keywords: Chronic hypertension, pregnancy, antihypertensive drugs, labetalol, methyldopa.Pregnant women with chronic hypertension increase considerably in the world. This group of patients and especially the black population have a higher risk of presenting obstetric complications such as preeclampsia, placental abruption, growth restriction, prematurity, perinatal mortality. In addition, there are more maternal risks such as acute pulmonary edema, kidney damage, heart failure, stroke and death.1,2. The management of the patient with chronic hypertension requires follow-up, evaluations and the main management focuses on giving antihypertensive drugs. When these patients become pregnant or chronic hypertension is diagnosed for the first-time during pregnancy, there was no convincing evidence on the usefulness and necessity of giving antihypertensive treatments if the hypertension is not severe, which is usually defined as a blood pressure of <160/110 mm Hg. A recently published study shows convincing evidence on the need to give antihypertensive drugs in this population group.3. Until before this study 3, a Cochrane systematic review (CSR) 4 including in the meta-analysis 58 studies (5909 women) showed controversial results that prevented a clear recommendation, also a randomized study5 of adequate quality published in 2015, in which strict blood pressure control was done or not, it failed to prove benefits in perinatal or maternal outcomes, except less severe hypertension in the group with strict control of blood pressure. The findings of the CSR 4 and the study by Tita et al.3 show that the possible explanation for the controversial findings is the drugs used to treat hypertension.Most of the randomized studies examining the effectiveness of drugs in the management of pregnant women with non-severe chronic hypertension have small numbers of patients. There are only 4 studies that have evaluated at least 300 patients, two of them analyzed in CSR4 (one in the USA in 1990 with 300 women and the other in Pakistan in 2016 with 314 women), the study by Magge et al.5 published in 2015 with 981 women and the study by Tita et al. 3 published in the year 2022 with 2408 pregnant women. The study by Magee et al. 5, used antihypertensives in both groups, without randomization to the type of antihypertensives and therefore is not analyzed in the CSR4 and the study by Tita et 3 was published after the CSR 4. We currently have three big studies: a systematic review with 5909 women, a randomized study with 981 patients using antihypertensives in both groups, and a randomized study with 2408 women comparing using versus not using antihypertensives. Due to the relevance of the topic and the findings of these three studies, a narrative description and comments are necessary.The outcomes of maternal and perinatal complications according to the medication used to manage hypertension are described according to the findings of each of the three studies, table 1.Hypertensive crisis (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥ 110 mmHg): The reduction in hypertensive crises using antihypertensives was demonstrated in the CSR 4 and in the two big and randomized studies already mentioned3,5. The study by Magee et al. 5, for the strict control of hypertension, labetalol was used as the main antihypertensive, however, methyldopa was used in more than 40% of the population studied. The findings show that there is a significant decrease in hypertensive crises. The CSR 4 showed a decrease in hypertensive crises independent of the antihypertensive used, but a better result is observed when using beta-blockers. In addition, the CRS shows that in two studies (310 women) with methyldopa, hypertensive crises were also reduced. The Tita et al study3 shows a significant decrease in hypertensive crises and they used labetalol, nifedipine and amlodipine in 99% of patients in the treatment group, methyldopa was only used in 0.3%. The results of these investigations suggest benefits in avoiding hypertensive crises using beta-blockers, calcium channel blockers and methyldopa.Preeclampsia/severe preeclampsia and premature birth: The study by Tita et 3 shows significant decrease in severe preeclampsia and births before 35 weeks and the CSR 4 showed a decrease in preeclampsia only when using beta-blockers and a slight increase is observed when using calcium channel blockers, this systematic review does not find a decrease in preterm deliveries. The study by Magee et al. 5 showed no benefit in those outcomes. The findings of these studies show us that using methyldopa as an antihypertensive does not reduce preeclampsia or prematurity.Placental abruption, fetal/perinatal death: The CSR 4and the other two randomized studies 3,5 did not find any change in these findings, so there seems to be no benefit for these variables when antihypertensives are used in pregnant women with mild/moderate chronic hypertension. Nevertheless, the Tita et al study3 shows a significant decrease when adding both findings as a component of the set of primary results.Neonatal complications (respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage grade 3 or 4, hypoglycemia, bradycardia, seizure, hypotension): The study by Tita et al 3 does not show differences in these variables when giving you antihypertensive treatment, nor did the study by Magee et al. 5. The CSR 4 shows similar results to the two randomized studies, except that less respiratory distress syndrome is observed at the expense of the group that received antihypertensive treatment with beta-blockers.Small for gestational age: This is a result that has been questioned as a possible adverse effect of antihypertensives, however, the CSR4 and the two randomized studies 3,5they found no change in fetal growth.Cesarean section: Cesarean births did not vary significantly in the two randomized studies 3,5, however, in a sub-analysis of the CSR 4 shows that there is a significantly higher chance of cesarean section if the antihypertensive used is methyldopa, this emerges from the analysis of 13 studies with 1330 women.Conclusion: Antihypertensives generate benefits in pregnant women with mild chronic hypertension. The main antihypertensives used in these patients are labetalol, nifedipine, amlodipine, and methyldopa; these drugs reduce severe hypertension. Preeclampsia and especially severe preeclampsia is reduced by beta-blockers and calcium channel blockers. Using methyldopa there is no decrease in preeclampsia, there is a greater possibility of cesarean section and there are side effects such as sedation, depression, dizziness. In addition, the randomized controlled trial that includes the largest number of pregnant women with mild chronic hypertension, demonstrating several benefits with antihypertensives, did not use methyldopa. Methyldopa should not be considered as an antihypertensive in pregnant women with mild chronic hypertension due to its minimal usefulness and the existence of other more effective drugs.Table 1.Antihypertensives used in chronic hypertension without hypertensive crisis

Coronavirus Disease 2019 and messenger RNA Vaccination in Pregnant Women.Paulino Vigil-De Gracia, MD.Complejo Hospitalario Dr. AAM Caja de Seguro Social. Investigador distinguido del Sistema Nacional de Investigación, SENACYT Panamá, e-mail: [email protected] its appearance in December of 2019, the SARS-CoV-2 infection has been associated with greater severity in patients with pre-existing pathologies. With the progression of the disease and adequate studies in pregnant women, it has been shown that this group of the population is associated with a higher risk and severity of the disease1. About 10% of pregnant women evolve severely, there is a higher risk of admission to the intensive care unit (ICU), the need for mechanical ventilation, maternal deaths, a higher risk of pre-eclampsia, premature births, and neonatal complications2-4. Vaccines based on an mRNA platform have become one of the safest and most widely used alternatives for combatting SARS-CoV-2 5 infections.Pregnant women with SARS-CoV-2Pregnant women with COVID-19 are 3-5 times more likely to enter the ICU compared to non-pregnant women of reproductive age or pregnant women without the disease. In addition, there is a fatality percentage between 0.6 to 1.6%, which is highly significant 2,3. Another finding that worsens the prognosis is the association between COVID-19 and pre-eclampsia. This association has been observed in a longitudinal study 3 and in a systematic review4. Pregnant women infected with SARS-CoV-2 have a significant 62% greater likelihood of developing pre-eclampsia than those without infection, including a higher risk of presenting the worst conditions of pre-eclampsia in its severe form, HELLP syndrome and eclampsia, according to the findings of a systematic review4.As pregnant women are at high risk when infected with SARS-CoV-2, said prognosis worsens, as it is associated with pre-eclampsia/eclampsia. They are two diseases with poor maternal and perinatal prognosis.Neonatal complications, prematurity, and NICU stay are higher in those born to mothers with COVID-19 1,3. In addition to these findings, the frequency of cesarean sections is significantly higher in pregnant women with severe COVID-19. Therefore, neonatal results seem to be influenced more by the diagnosis of disease severity than the presence of the maternal infection itself.Vaccination before pregnancy and in the first weeks of pregnancyMessenger RNA vaccines are not live, attenuated, inactivated virus vaccines, nor do they use an adjuvant. These vaccines do not enter the nucleus and do not alter human DNA. As a result, mRNA vaccines cannot cause any genetic changes. Animal studies performed with the Moderna vaccine, evaluating perinatal and postnatal toxicity, show no alterations to embryonic, fetal or postnatal development after use of this type of vaccine. Pregnant women were not included in the original studies where the usefulness of these vaccines was confirmed. Therefore, there are no randomized studies that show benefits (or complications) in pregnant women.After the acceptance of the emergency use of the COVID-19 vaccine, several studies have been completed that show results associated with pregnancy. A report in the UK shows us that in the vaccinated women who were part of the original randomized studies, the number of unplanned pregnancies was the same in both groups (vaccine or placebo); furthermore, there were no differences in loss percentages in the first trimester of pregnancy 6.More recently, a preprint 5 vaccination report from the United States shows us the results of 2,456 pregnant women and the risk of spontaneous abortion between 6 and 19 weeks when these women were vaccinated in the pre-conception period or before the first 20 weeks of pregnancy. This study does not show a higher incidence of spontaneous abortions in the population vaccinated with mRNA vaccines, compared to the reference standard.Vaccination according to trimester of pregnancyThere are no randomized controlled studies proving the benefit of SARS-CoV-2 vaccines in pregnant women, however, there are several reports on its benefits and safety regardless of the trimester of pregnancy in which it has been used. A large cohort 7shows us that of 3,958 vaccinated pregnant women, 28.6% were vaccinated in the first trimester of pregnancy and 43.3% in the second trimester. According to the findings of this study in the United States7 and another in Israel 8, mass vaccination of the population occurs in all trimesters of pregnancy and the follow-up study of the population that has finished their pregnancy shows that there was no evidence of an increase in: abortions, malformations, fetal or neonatal death, premature birth, or restricted growth. In addition, there is a series of cases that shows that vaccination in the third trimester does not cause placental disorders9.Evidence of protectionTwo large retrospective cohorts have evaluated the effect of mRNA vaccines in vaccinated pregnant women. The study carried out in the USA7 with 3,958 pregnant women shows us that the possibility of infection 14 days after the first dose is 0.3%. Furthermore, the study carried out in 7,530 vaccinated pregnant women in Israel 8 compared to 7,530 unvaccinated (paired) women shows that between 11 and 28 days after the first dose, there is a significant decrease in infection when compared to the unvaccinated group. This difference becomes greater with the increase of the number of days post vaccination until a follow-up of 70 days.Another important finding with maternal vaccination is the possible fetal and neonatal protection. Breast milk was tested in a cohort of 84 vaccinated mothers with at least two doses of mRNA vaccine10. This study found a robust secretion of specific IgG and IgA antibodies against SARS-CoV-2 in breast milk for 6 weeks after vaccination. These results suggest the potential protective effect against SARS-CoV-2 in infants of vaccinated or infected breastfeeding mothers.On the other hand, the transplacental transfer of IgG antibodies has been evaluated in mothers who have received mRNA vaccine in the third trimester 11. The studies show that if 16-21 days have passed since the first dose by the time of birth, there will already be a large amount of IgG antibodies present in the umbilical cord and the greatest amount of passive immunity will be obtained 3-4 weeks after the first dose of mRNA vaccine administered to the mother. By that time, the amount of antibodies in the umbilical cord are similar to those existing in maternal blood 11.Other studies 12 have performed analyzes on both pregnant and lactating women and their results show that maternal antibodies generated by vaccines are transported to the child through umbilical cord blood and breast milk.SummaryPregnant women represent a group at high risk of infection by SARS-CoV-2. There are greater levels of admission to ICU, more death, more pre-eclampsia and prematurity,Vaccines with the mRNA platform have been shown to be effective and safe in pregnant women and there is no evidence of fetal or neonatal damage in any trimester of pregnancy.Vaccination against COVID-19 in pregnant women has been delayed in the world due to the non-inclusion in the original randomized studies; despite the absence of valid scientific elements demanding their exclusion. 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Background: The optimal duration of magnesium administration postpartum for prevention of eclampsia has not yet been established. Objective: To investigate the effect of early discontinuation of postpartum magnesium on the rates of postpartum eclampsia when compared to continuation for 24-hour postpartum. Search Strategy: Searches were performed using keywords related to “preeclampsia” and “magnesium sulfate” from inception of database until March 2019. Selection Criteria: Randomized controlled trials of women with preeclampsia receiving magnesium prior to delivery randomized to early discontinuation of magnesium postpartum. The control group was 24-hours of magnesium postpartum. Data Collection and Analysis: The primary outcome was the rate of postpartum eclampsia. Main Results: Eight RCTs with 2,183 women were included with five different magnesium administration time-frames. Eclampsia rates were not different between the two groups (5/1,088 (0.5%) after early discontinuation, versus 2/1,095 (0.2%) in the 24-hour group; RR 2.25, 95% CI 0.5-9.9, I2=0%, 8 studies, 2,183 participants). A number needed to treat was calculated; 370 women would need to receive 24-hours of magnesium postpartum to prevent one episode of postpartum eclampsia. The early discontinuation group had a significant decrease in time to ambulation and breastfeeding. Conclusions: Compared to continuation of magnesium for 24 hours postpartum, early magnesium discontinuation postpartum does not significantly increase the rate of postpartum eclampsia. The largest proportion of women did not receive magnesium postpartum after receiving at least 8 grams intrapartum, thus it is reasonable to consider discontinuation of magnesium postpartum if a woman has received similar adequate dose prior to delivery.

Objective: To review studies published with pregnant women infected with SARS-CoV-2 and analyze the evolution of them and also of the newborn in order to learn about this pathology in pregnant women. Search strategy: Systematic review in the PUBMED and GOOGLE Scholar databases until March 30, 2020. This research was extended to the references of such articles. Selection criteria: Observational studies that examined maternal and perinatal outcomes of pregnant women with SARS-CoV-2 are published. Data collection and analysis: Data about study characteristics, maternal y perinatal outcomes variable extracted. Main results: We found 14 publications regarding a total of 83 pregnant women with SARS-CoV-2 and results of 84 newborns. The average gestational age was 37 weeks. The most common symptom was fever, and 30% of the pregnant women had lymphopenia on admission to hospital. Cesarean section was performed in 89% of the patients; 70% of them were indicated by SARS-CoV-2. The most common obstetric complication was premature rupture of membranes in 9.6% of them. The need for ventilation support was low. The use of antivirals, corticosteroids, and drugs for the pathology management was scarce, except for antibiotics. Preterm birth was 25%, perinatal mortality was low, and there was no maternal death. There was no evidence of vertical transmission. Conclusion: Maternal and perinatal morbidity-mortality is lower than in other known respiratory diseases. Currently, it appears to be no benefit from antivirals and other drugs, beyond the general support of the disease, and vertical transmission of the virus has not been demonstrated.