ABSTRACT

Objective:

This study aimed to examine the effects of infection with the Delta variant of coronavirus disease-2019 (COVID-19) on the clinical course, laboratory parameters, and neonatal outcome in pregnant women.

Material and Methods:

A total of 96 pregnant women who tested positive for the Delta variant of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causing COVID-19 were retrospectively examined. The pregnant women were divided into three groups: Asymptomatic; non-severe; and severe. Age, obstetric history, symptoms and findings, blood tests, medication and vaccination history, clinical course, and perinatal outcome of pregnant women were analyzed.

Results:

Pregnant women who tested positive for the Delta variant of SARS-CoV-2 had an intensive care unit (ICU) admission rate of 9.4% and a mortality rate of 5.2%. Pregnant women in the severe disease group had significantly higher rates of preterm birth and cesarean section compared with the non-severe and asymptomatic group. Pregnant women in the severe group had high C-reactive protein (CRP) levels at the time of admission. White blood cell count (WBC) and procalcitonin levels were increased in clinical follow-up in women in the severe group.

Conclusion:

The Delta variant of SARS-CoV-2 was found to increase mortality rates in pregnant women compared to pre-Delta variants of COVID-19. In pregnant women infected with the Delta variant, advanced gestational age at diagnosis, high CRP, WBC, and procalcitonin levels were significantly correlated with poor prognosis. Pregnant women infected with the Delta variant and with severe COVID-19 had an increased risk for preterm delivery and cesarean section. Although newborns of women with severe disease were found to have significantly higher rates of ICU admission, there was no significant difference in neonatal mortality rates. We recommend close monitoring of CRP, WBC, and procalcitonin levels, in addition to symptoms, in pregnant women infected with the Delta variant of SARS-CoV-2 and diagnosed in the third trimester.

Keywords:

COVID-19, pregnancy, delta variant

Introduction

Coronavirus disease-2019 (COVID-19) is a highly contagious infection caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and has so far resulted in nearly 300 million cases of COVID-19 and more than 5 million deaths worldwide (1,2). First detected in Wuhan, the capital of China’s Hubei province in December 2019, COVID-19 has since spread rapidly worldwide and was declared a pandemic by the World Health Organization (WHO) on March 11, 2020 (2). SARS-CoV-2 is an mRNA virus that acts mainly by binding to the angiotensin-converting enzyme 2 receptor, abundantly found in the respiratory and digestive tract and widely expressed during pregnancy (3,4). Similar to other RNA viruses, SARS-CoV-2 has genetically mutated over time, resulting in variants with different characteristics (5). WHO has classified SARS-CoV-2 variants into three groups based on the impact on public health, variation in transmissibility and virulence, and resistance to therapeutics and vaccines: variants of concern (VOCs), variants of interest (VOIs), and variants under monitoring. VOCs are the dominant group in the outbreak and comprise Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1,617.2) variants and Omicron (B.1.1.529) variant, which was added to the list on December 6, 2021. The Delta variant, first isolated in India in October 2020, was classified as a VOI on April 4, 2021, and as a VOC on May 11, 2021, due to its rapid spread worldwide (6). Data for November 2021 shows that the Delta variant has become the most common VOC, accounting for 99.7% of the variants isolated worldwide over the last 60 days (7).

Pregnancy comprises a unique immunological condition that is regulated by immune system mediating signals originating from the placenta (8,9,10,11,12). Pregnant women are at greater risk for viral infections than the normal population owing to the respiratory, circulatory, endocrine, immunological, and anatomical changes that occur during pregnancy (3,13,14). Pregnant women reportedly have higher rates of hospital admissions, pneumonia, requirement for ventilator support, and intensive care unit (ICU) admissions associated with COVID-19 than the non-pregnant population (15). Studies conducted with different subsets of population to compare the wild type (Wuhan) and the Alpha variant reported that the Delta variant had a higher virulence and was less affected by neutralizing antibodies induced by vaccination than other variants (16,17,18). However, few studies in the literature have examined the effect of this variant on the pregnant population. Furthermore, it is crucial to investigate the effects of the Delta variant on pregnant women, given that they are more severely affected by COVID-19 compared to the general population and have low vaccination rates worldwide (19). Therefore, the aim of the present study was to investigate the effect of the Delta variant of SARS-Cov-2 on the clinical course, laboratory parameters and neonatal outcome in pregnant women.

Material and Methods

The present study retrospectively assessed 96 pregnant women admitted to the University of Health Sciences Turkey, Gazi Yaşargil Training and Research Hospital, Clinic of Obstetrics and Gynecology after testing positive for the Delta variant of SARS-CoV-2 following a polymerase chain reaction (PCR) examination between April 2021 and September 2021. The study was approved by the Ethics Committee of the University of Health Sciences Turkey, Gazi Yaşargil Training and Research Hospital and conducted in accordance with the Helsinki Declaration of Ethical Principles (approval number: 917, date: 05.11.2021). Data of the patients included in the study were retrieved from the hospital archiving system and medical records. In PCR tests, the SL452R mutation, specific to the Delta variant, was detected using SARS-CoV-2 Emerging Plus kits (Bio-Speedy, İstanbul, Turkey). COVID-19 diagnosis was established through physical examinations, PCR tests from nasopharyngeal swabs, and X-ray and/or computed tomography (CT) to assess lung involvement in the presence of pneumonia. It was explained to pregnant women that chest CT can be performed safely in pregnancy, and after providing signed consent, symptomatic pregnant women underwent CT examinations (20). During the CT scan, the lower abdomen and pelvis of the pregnant woman were wrapped in protective aprons.

Among the 96 pregnant women, 49 were asymptomatic and 47 were symptomatic. Women were classified as asymptomatic or symptomatic. Asymptomatic pregnant women were admitted with obstetric indications. Symptomatic pregnant women were further divided into non-severe, and severe disease groups (21,22). Pregnant women with mild symptoms (fever, cough, and other upper respiratory symptoms), without abnormalities or with mild changes on chest CT (multiple areas of patch-like involvement and interstitial changes usually found in the outer zone of the lung and beneath the pleura) were included in the non-severe group. Patients were included in the severe group if they had at least one of the following: tachypnea (respiratory rate ≥30/minimum); hypoxia (SpO₂ <93%); the partial pressure of oxygen/fraction of inspired oxygen (PaO₂/FiO₂) ≤300 mmHg on blood gas analysis; respiratory or organ failure that required admission to the ICU; or the presence of shock.

There is no agreed and definitive treatment protocol for pregnant women with COVID-19. Low-molecular-weight heparin (LMWH) was used for thromboembolism prophylaxis. Steroids were used for a limited time (3-5 days) in pregnant women who demonstrated progressive deterioration of oxygen saturation, increased activation of a pro-inflammatory response, and rapid worsening of findings on chest imaging (23). Betamethasone was given to promote fetal lung maturation at or beyond 24 weeks of gestation in those who were at risk of preterm birth within 7 days. Antitussive agents and inhaled bronchodilators were used for supportive therapy. Also, patients were started on tocilizumab in the case of cytokine storm syndrome and broad-spectrum antibiotic therapy in the presence of concomitant suspected bacterial pneumonia (21,24).

Data items analyzed included age, obstetric history, symptoms and findings, blood tests, medication and vaccination history, clinical course, and perinatal outcomes. Postpartum hemorrhage was defined as blood loss of more than 1000 mL following cesarean delivery (25). IUGR was defined as estimated fetal weight <3^rd centile based on sonographic measurements of the fetus along with end-diastolic flow loss on Doppler examination (26). Blood tests were reported at three different time points to better predict the course of the disease; at the time of admission, during the hospital stay, and at discharge. The tests administered during the hospital stay in symptomatic pregnant patients, that is, at the second time point, (excluding 5 pregnant women who died) were taken at the time of clinical worsening (such as the onset of oxygen therapy or the introduction of steroid therapy for pregnant women who were already on oxygen therapy). In asymptomatic pregnant women, tests administered during the hospital stay were used. In the newborns, birth weight, Apgar scores, umbilical cord blood gas analysis, neonatal intensive care unit (NICU) admission, and mortality rates were analyzed.

Results

A total of 48.9% patients (n=47) were symptomatic pregnant women, of whom 72% (n=34) were categorized as non-severe and 28% (n=13) severe patients. There was no significant difference between the three groups in terms of mean age, gestational age, gravidity, parity, and abortus history. A significant majority of the symptomatic group consisted of pregnant women in the third trimester. There was no significant difference between symptomatic pregnant women in the non-severe and severe groups in terms of frequency of fever, cough, shortness of breath, diarrhea, and myalgia. The severe disease group had a significantly higher average heart rate and significantly lower average oxygen saturation than the non-severe disease group. A diagnosis of pneumonia based on physical examination findings was made in 91.1% of the pregnant women in the non-severe group and 100% of those in the severe group, and all of the symptomatic pregnant women underwent a CT scan of the chest. Radiological findings of pneumonia were detected in 50% of those in the non-severe group and 100% of those in the severe group. Steroid and LMWH use were significantly higher in the symptomatic group compared to the asymptomatic group. Furthermore, 19% of the symptomatic pregnant women (n=9) required ICU admission. Although all non-severe pregnant women were monitored in the clinic, 69% (n=9) of the pregnant women in the severe group were admitted to the ICU. Of the pregnant women admitted to the ICU, 55.5% (n=5) developed acute respiratory distress syndrome, and 33.3% (n=3) developed acute renal failure. A total of 55.5% (n=5) of the pregnant women in the ICU were intubated and all of the intubated patients died. The mortality rate in pregnant women was 5.2%. Of all the pregnant women who participated in the study, 46% (n=44) delivered their babies. The delivery rate in the severe disease group was 53.8%, and all deliveries were cesarean preterm deliveries owing to maternal conditions. Preterm delivery and cesarean section rates were significantly higher in the severe group compared to the non-severe and asymptomatic group (Table 1).

Table 1

The average gestational age and weight at birth, and APGAR scores at 1 and 5 minutes were significantly lower in the newborns of the severe group than those of the non-severe and asymptomatic groups. The NICU admission rate was calculated at 20.5% for all the groups combined. There was no significant difference in NICU admission rates between the non-severe and asymptomatic groups but this rate was significantly higher in the severe group. There was no significant difference in umbilical cord blood gas pH values of newborns across the three groups. There were no neonatal deaths in this study (Table 2).

Table 2

Blood samples collected from each patient at three different time points were evaluated to better predict the clinical course of the disease. There was no significant intergroup difference in the mean counts of white blood cell (WBC), neutrophils, platelets or lymphocytes, or in levels of hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, ferritin, and procalcitonin. WBC counts increased over time (p²=0.002) in the severe group, and the rate of increase in this group was significantly higher than that in the non-severe and asymptomatic groups (p³=0.001) (Graphic 1). Although the mean C-reactive protein (CRP) level was significantly higher in the severe group than in the non-severe and asymptomatic group, there was no significant increase in CRP levels in any of the three groups during clinical follow-up (Graphic 2). Procalcitonin levels appeared to increase significantly initially in the severe group and remained high on clinical follow-up (Graphic 3) (Table 3).

Table 3

Discussion

This study revealed that a more advanced gestational age at initial diagnosis was associated with a poorer prognosis when pregnancy was complicated by infection with the Delta variant of SARS-CoV-2. A total of 19% of all admissions were ICU admissions, of which 55.5% were intubated, and all intubated patients died. Worsening of the maternal clinical picture was found to cause a significant increase in cesarean delivery, preterm delivery, low birth weight, and NICU admission rates. High CRP values in pregnant women were significantly correlated with severe disease. Increasing WBC and procalcitonin levels during follow-up of pregnant women were significantly associated with poor prognosis. Reportedly, symptomatic disease, severe disease, and ICU admission rates are significantly higher in pregnant women infected with the Delta variant of SARS-CoV-2 than in those with pre-Delta variants but there was no significant change in maternal mortality rates (27). Furthermore, 62.3-84% of pregnant women infected with the Delta variant were reportedly symptomatic. Also, 48-79% of symptomatic pregnant women are in the non-severe group and 21-36% were in the severe disease group. Several studies have reported that 4.9-29% of pregnant women infected with the Delta variant were admitted to the ICU, 33.3-80% of those in the ICU are intubated, and the mortality rate was 0-2%. Moreover, advanced gestational age at the time of initial diagnosis has been reported to be significantly associated with poor prognosis (27,28,29). Our study found that advanced gestational age at the time of initial diagnosis was significantly associated with poor prognosis. ICU admission and intubation rates were similar to those published in the literature. However, our study found a mortality rate of 5.2% in pregnant women infected with the Delta variant. This rate is remarkably high compared to both the literature on pregnant women infected with the Delta variant, and also higher than previous mortality rates found in our clinic in pregnant women infected with the Delta variant (2.99%, n=15/501). Our study found that COVID-19-related deaths in pregnant women increased with the Delta variant. A large number of pregnant women with COVID-19-related severe disease are referred to our tertiary center. This may be another reason why we found increased mortality rates.

There is a paucity of information in the literature on symptomatology in pregnant women infected with the Delta variant of SARS-CoV-2. It has been reported that 71% of symptomatic pregnant women infected with this Delta variant have a cough, 44.7% have a fever, 42% have dyspnea, 37% have myalgia-malaise, and 10.5% have diarrhea (28). In pregnant women infected with the Delta variant, lymphocytopenia has been reported at a rate of 27.8%, elevated AST at 11.5%, and elevated ALT at 9.8% (28). No significant difference has been reported among asymptomatic, non-severe, and severe groups of pregnant women infected with the Delta variant in terms of blood test parameters (lymphocyte, leukocyte, blood urea nitrogen, creatinine, AST, and ALT) at the time of admission (27). Our study found significantly higher CRP levels in pregnant women in the severe group than in the non-severe and asymptomatic group. Clinical follow-ups showed that increasing WBC and procalcitonin levels were significant predictors of poor prognosis.

The rate of chest CT findings with an appearance consistent with pneumonia has been reported at 88% in symptomatic pregnant women infected with the Delta variant of SARS-CoV-2 (28). In our study, 64% of the symptomatic pregnant women had findings consistent with pneumonia on their chest CT scans, but this varied from 100% in the severe group to 50% in the non-severe group.

While Wang et al. (28) reported no significant difference between pregnant women infected with the Delta variant and those with pre-Delta variants of SARS-CoV-2 in terms of preterm delivery rates, fetal weight, and adverse neonatal outcomes (NICU admission, hypoxic-ischemic encephalopathy, sepsis, ventilator support, meconium aspiration, birth trauma, stillbirth, etc.), Seasely et al. (27) reported an association between infection with the Delta variant and statistically increased rates of preterm delivery and NICU admission (27,28). The rate of preterm delivery has been reported at 73% and the rate of NICU admission at 74% in pregnant women infected with the Delta variant (27). Comparisons of neonatal outcomes among pregnant women infected with the Delta variant in asymptomatic, non-severe, and severe groups found no significant difference in terms of preterm delivery and poor neonatal outcomes (28). Our study found no increase in the incidence of preterm delivery complications such as spontaneous abortion, threatened abortion, and hyperemesis gravidarum in symptomatic pregnant women infected with the Delta variant (30,31,32,33). However, we found significantly higher cesarean and preterm delivery rates in the severe group compared to the asymptomatic and non-severe groups. We believe that maternal clinical features are the main determinant of preterm delivery and cesarean section rates in symptomatic pregnant women. Our study found that the newborns of mothers in the severe group had significantly lower average gestational age at birth and birth weight, and significantly higher NICU admission rate compared to the newborns of mothers in the non-severe and asymptomatic group.

Conclusion

The Delta variant of SARS-CoV-2 leading to COVID-19 was found to result in increased mortality rates in pregnant women compared to pre-Delta variants. In pregnant women infected with the Delta variant, advanced gestational age at diagnosis, elevated CRP, WBC, and procalcitonin levels were found to be significantly correlated with poor prognosis. Pregnant women infected with the Delta variant of SARS-Cov-2 were also found to be at increased risk for preterm delivery and cesarean section in the presence of severe disease. Although intensive care admissions were found to be significantly higher in the newborns of pregnant women in the severe disease group, no significant difference was found in neonatal mortality rates. We recommend close monitoring of CRP, WBC, and procalcitonin levels in addition to symptoms, particularly in pregnant women infected with the Delta variant in the third trimester. We believe that swift decision-making for the delivery of the fetus can improve neonatal outcomes in case of impaired maternal oxygenation.

Statistical analysis

SPSS, version 20.0, was used to evaluate the data collected during the study (IBM SPSS, Armonk, NY, USA). Statistical significance was set at p-value <0.05. Based on the Shapiro-Wilk normality test results, multiple groups of continuous variables were compared with the non-parametric Kruskal-Wallis analysis test, and in case of significant differences, Dunn’s multiple comparisons test was used to identify the groups that created the difference. As for descriptive statistics, letter indices were placed on grouped data for the results tabled in median values (minimum-maximum), and the differences between the groups were displayed. The chi-square and Fisher’s exact test results were used to evaluate the distribution of categorical variables based on groups, and the results were expressed in frequency distributions and percentages. The repeated measures ANOVA model was used to explain the measurements taken at three different time points for the three independent groups, investigating also the main effect groups, and time as well as interaction terms.

Study Limitations

The main limitation of this study is its retrospective design. Despite this, the present study is important due to the scarcity of data in the literature on the effects of the Delta variant of SARS-CoV-2 on pregnancy outcomes. We believe that the current study is strengthened by the inclusion and analysis of blood parameters at three different time points to better predict the course of the disease.

References

Oğlak SC, Obut M. The risk of vicarious trauma among front-line and non-front-line midwives and nurses: Vicarious traumatization among medical staff. Aegean J Obstet Gynecol 2020; 2: 1-4.

World Health Organization. [homepage on the Internet]. Coronavirus disease (COVID-19) [Accessed Feb 2022]. Available from: www.who.int/health-topics/coronavirus

Li W, Yu N, Kang Q, Zeng W, Deng D, Chen S, et al. Clinical manifestations and maternal and perinatal outcomes with COVID-19. Am J Reprod Immunol 2020; 84: e13340.

Tunç Ş, Göklü MR, Oğlak SC. COVID-19 in pregnant women: An evaluation of clinical symptoms and laboratory parameters based on the 3 trimesters. Saudi Med J 2022; 43: 378-85.

Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19) [Updated 2022 Jan 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/

World Health Organization [homepage on the Internet]. Tracking SARS-CoV-2 variants [updated 3 Feb 2022; cited 21 Feb 2022]. Available from: www.who.int/en/activities/tracking-SARS-CoV-2-variants

Bian L, Gao Q, Gao F, Wang Q, He Q, Wu X, et al. Impact of the Delta variant on vaccine efficacy and response strategies. Expert Rev Vaccines 2021; 20: 1201-9.

Simsek Y, Ciplak B, Songur S, Kara M, Karahocagil MK. Maternal and fetal outcomes of COVID-19, SARS, and MERS: a narrative review on the current knowledge. Eur Rev Med Pharmacol Sci 2020; 24: 9748-52.

Behram M, Oğlak SC. The expression of angiogenic protein Cyr61 significantly increases in the urine of early-onset preeclampsia patients. J Contemp Med 2021; 11: 605-9.

Oğlak SC, Tunç Ş, Ölmez F. First Trimester Mean Platelet Volume, Neutrophil to Lymphocyte Ratio, and Platelet to Lymphocyte Ratio Values Are Useful Markers for Predicting Preeclampsia. Ochsner J 2021; 21: 364-70.

Behram M, Oğlak SC, Başkıran Y, Süzen Çaypınar S, Akgöl S, Tunç Ş, et al. Maternal serum IL-22 concentrations are significantly upregulated in patients with preterm premature rupture of membranes. Ginekol Pol 2021; 92: 631-6.

Ölmez F, Oğlak SC, Gedik Özköse Z. Increased maternal serum aquaporin-9 expression in pregnancies complicated with early-onset preeclampsia. J Obstet Gynaecol Res 2022; 48: 647-53.

Agolli A, Agolli O, Velazco DFS, Ahammed MR, Patel M, Cardona-Guzman J, et al. Fetal Complications in COVID-19 Infected Pregnant Woman: A Systematic Review and Meta-Analysis. Avicenna J Med 2021; 11: 200-9.

Tunç Ş, Göklü MR. Burn-Out Syndrome Among Healthcare Professionals Facing The Novel Coronavirus Disease 2019 (Covid-19) Pandemic. Journal of Harran University Medical Faculty 2021; 18: 375-83.

Mamun MMA, Khan MR. COVID-19 Delta Variant-of-Concern: A Real Concern for Pregnant Women With Gestational Diabetes Mellitus. Front Endocrinol (Lausanne) 2021; 12: 778911.

Public Health England [homepage on the Internet]. Effectiveness of covid-19 vaccines against hospital admission with the Delta (B.1.617.2) variant. [updated Jun 2021; cited Feb 2022]. Available from: khub.net/web/phe-national/public-library/document_library/ v2WsRK3ZlEig / view/ 479607266

Khandelwal N, Chander Y, Kumar R, Nagori H, Verma A, Mittal P, et al. Studies on Growth Characteristics and Cross-Neutralization of Wild-Type and Delta SARS-CoV-2 From Hisar (India). Front Cell Infect Microbiol 2021; 11: 771524.

Kislaya I, Rodrigues EF, Borges V, Gomes JP, Sousa C, Almeida JP, et al. Comparative Effectiveness of Coronavirus Vaccine in Preventing Breakthrough Infections among Vaccinated Persons Infected with Delta and Alpha Variants. Emerg Infect Dis 2022; 28: 331-7.

Rangchaikul P, Venketaraman V. SARS-CoV-2 and the Immune Response in Pregnancy with Delta Variant Considerations. Infect Dis Rep 2021; 13: 993-1008.

Wang CL, Liu YY, Wu CH, Wang CY, Wang CH, Long CY. Impact of COVID-19 on Pregnancy. Int J Med Sci 2021; 18: 763-7.

Can E, Oğlak SC, Ölmez F. Abnormal liver function tests in pregnant patients with COVID-19 - a retrospective cohort study in a tertiary center. Ginekol Pol 2022; 93: 151-7.

Can E, Oğlak SC, Ölmez F, Bulut H. Serum neutrophil gelatinase-associated lipocalin concentrations are significantly associated with the severity of COVID-19 in pregnant patients. Saudi Med J 2022; 43: 559-66.

Parasher A. COVID-19: Current understanding of its Pathophysiology, Clinical presentation and Treatment. Postgrad Med J 2021; 97: 312-20.

Nana M, Nelson-Piercy C. COVID-19 in pregnancy. Clin Med (Lond) 2021; 21: e446-50.

Oglak SC, Obut M, Tahaoglu AE, Demirel NU, Kahveci B, Bagli I. A prospective cohort study of shock index as a reliable marker to predict the patient's need for blood transfusion due to postpartum hemorrhage. Pak J Med Sci 2021; 37: 863-8.

Oğlak SC, Bademkıran MH, Obut M. Predictor variables in the success of slow-release dinoprostone used for cervical ripening in intrauterine growth restriction pregnancies. J Gynecol Obstet Hum Reprod 2020; 49: 101739.

Seasely AR, Blanchard CT, Arora N, Battarbee AN, Casey BM, Dionne-Odom J, et al. Maternal and Perinatal Outcomes Associated With the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta (B.1.617.2) Variant. Obstet Gynecol 2021; 138: 842-4.

Wang AM, Berry M, Moutos CP, Omere C, Clark SM, Harirah HM, et al. Association of the Delta (B.1.617.2) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with pregnancy outcomes. Obstet Gynecol 2021; 138: 838-41.

Adhikari EH, SoRelle JA, McIntire DD, Spong CY. Increasing severity of COVID-19 in pregnancy with Delta (B.1.617.2) variant surge. Am J Obstet Gynecol 2022; 226: 149-51.

Massalska D, Zimowski JG, Bijok J, Pawelec M, Czubak-Barlik M, Jakiel G, et al. First trimester pregnancy loss: Clinical implications of genetic testing. J Obstet Gynaecol Res 2017; 43: 23-9.

London V, Grube S, Sherer DM, Abulafia O. Hyperemesis gravidarum: a review of recent literature. Pharmacology 2017; 100: 161-71.

Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 188: Prelabor rupture of membranes. Obstet Gynecol 2018; 131: e1-14.

Locatelli A, Lambicchi L, Incerti M, Bonati F, Ferdico M, Malguzzi S, et al. Is perinatal asphyxia predictable? BMC Pregnancy Childbirth 2020; 20: 186-93.

The course of infection with the Delta variant of COVID-19 in pregnancy: analysis of clinical, laboratory, and neonatal outcomes