Four Waves of the COVID-19 Pandemic: Comparison of Clinical and Pregnancy Outcomes

Abstract

During the last two and a half years, clinical manifestations, disease severity, and pregnancy outcomes have differed among pregnant patients with SARS-CoV-2 infection. These changes were preceded by the presence of new variants of SARS-CoV-2, known in the literature as variants of concern. The aim of this study is to describe the differences between maternal clinical characteristics and perinatal outcomes among pregnant women with COVID-19 during four waves of the COVID-19 epidemic in Serbia. This retrospective study included a series of 192 pregnant patients who were hospitalized due to the severity of their clinical status of SARS-CoV-2 infection. During four outbreaks of COVID-19 infection in Serbia, we compared and analyzed three sets of variables, including signs, symptoms, and characteristics of COVID-19 infection, clinical endpoints, and maternal and newborn parameters. During the dominance of the Delta variant, the duration of hospitalization was the longest (10.67 ± 1.42 days), the frequency of stillbirths was the highest (17.4%), as well as the frequency of progression of COVID infection (28.9%) and the requirement for non-invasive oxygen support (37%). The dominance of the Delta variant was associated with the highest number of prescribed antibiotics (2.35 ± 0.28), the most common presence of nosocomial infections (21.7%), and the highest frequency of corticosteroid therapy use (34.8%). The observed differences during the dominance of four variants of concern are potential pathways for risk stratification and the establishment of timely and proper treatments for pregnant patients. Early identification of the Delta variant, and possibly some new variants with similar features in the future, should be a priority and, perhaps, even an opportunity to introduce more accurate and predictive clinical algorithms for pregnant patients.

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Citation: Mihajlovic, S.; Nikolic, D.;
Santric-Milicevic, M.; Milicic, B.;
Rovcanin, M.; Acimovic, A.;
Lackovic, M. Four Waves of the
COVID-19 Pandemic: Comparison of
Clinical and Pregnancy Outcomes.
Viruses 2022,14, 2648. https://
doi.org/10.3390/v14122648
Academic Editors: Justin C. Konje
and Badreldeen Ahmed
Received: 29 October 2022
Accepted: 24 November 2022
Published: 27 November 2022
Publisher’s Note: MDPI stays neutral
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Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
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Attribution (CC BY) license (https://
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4.0/).
viruses
Article
Four Waves of the COVID-19 Pandemic: Comparison of
Clinical and Pregnancy Outcomes
Sladjana Mihajlovic 1,2, Dejan Nikolic 2,3, Milena Santric-Milicevic 4,5 , Biljana Milicic 6, Marija Rovcanin 7,
Andjela Acimovic 1and Milan Lackovic 1, *
1Department of Obstetrics and Gynecology, University Hospital “Dragisa Misovic”, 11000 Belgrade, Serbia
2Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
3
Department of Physical Medicine and Rehabilitation, University Children’s Hospital, 11000 Belgrade, Serbia
4Institute of Social Medicine, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
5Center-School of Public Health and Health Management, Faculty of Medicine, University of Belgrade,
11000 Belgrade, Serbia
6Department of Medical Statistics and Informatics, School of Dental Medicine, University of Belgrade,
11000 Belgrade, Serbia
7Clinic for Gynecology and Obstetrics “Narodni Front”, 11000 Belgrade, Serbia
*Correspondence: milan.lackovic@dragisamisovic.bg.ac.rs
Abstract:
During the last two and a half years, clinical manifestations, disease severity, and pregnancy
outcomes have differed among pregnant patients with SARS-CoV-2 infection. These changes were
preceded by the presence of new variants of SARS-CoV-2, known in the literature as variants of
concern. The aim of this study is to describe the differences between maternal clinical characteristics
and perinatal outcomes among pregnant women with COVID-19 during four waves of the COVID-19
epidemic in Serbia. This retrospective study included a series of 192 pregnant patients who were
hospitalized due to the severity of their clinical status of SARS-CoV-2 infection. During four outbreaks
of COVID-19 infection in Serbia, we compared and analyzed three sets of variables, including signs,
symptoms, and characteristics of COVID-19 infection, clinical endpoints, and maternal and newborn
parameters. During the dominance of the Delta variant, the duration of hospitalization was the longest
(10.67
±
1.42 days), the frequency of stillbirths was the highest (17.4%), as well as the frequency of
progression of COVID infection (28.9%) and the requirement for non-invasive oxygen support (37%).
The dominance of the Delta variant was associated with the highest number of prescribed antibiotics
(2.35
±
0.28), the most common presence of nosocomial infections (21.7%), and the highest frequency
of corticosteroid therapy use (34.8%). The observed differences during the dominance of four variants
of concern are potential pathways for risk stratification and the establishment of timely and proper
treatments for pregnant patients. Early identification of the Delta variant, and possibly some new
variants with similar features in the future, should be a priority and, perhaps, even an opportunity to
introduce more accurate and predictive clinical algorithms for pregnant patients.
Keywords:
pregnancy; COVID-19; variants of concern; pandemic waves; maternal and pregnancy
outcomes
1. Introduction
Since the official outbreak of the COVID-19 pandemic in China in December 2019 [
1
],
pregnant women, as well as all other vulnerable population groups, have lived in a vicious
cycle of ever-emerging new waves of the pandemic. Serbian authorities officially reported
the first COVID-19 case in March 2020 [
2
]. The initial shock of the unknown was mixed
with mandatory strict and restrictive social measures, culminating in a governmental
lockdown announcement [
3
]. In general, hospital capacities for non-COVID patients have
been limited, medical professionals have transferred to newly formed COVID hospitals,
and changes in healthcare systems have culminated in limited maternal and prenatal
Viruses 2022,14, 2648. https://doi.org/10.3390/v14122648 https://www.mdpi.com/journal/viruses

Viruses 2022,14, 2648 2 of 12
care and resources worldwide [
4
]. According to the World Health Organization (WHO)
data, as of 17 November 2022, there were 2,415,439 confirmed cases of COVID-19 and
17,326 deaths attributed to COVID-19 in Serbia; moreover, there were 6,717,622 doses of
vaccines administrated as of 4 September 2022 [5].
In the last two and a half years, different strategies and approaches have been intro-
duced in order to prevent and reduce perinatal morbidity and neonatal mortality related
to limited antenatal care (ANC) access, since ANC is recognized as the most cost-effective
mechanism of prevention [
6
,
7
]. Over time, our patients have embraced different models
of ANC, such as scheduled appointments, home visiting, self-quarantine, community
clinics, and hybrid models [
8
]. In the meantime, the clinical manifestations and disease
severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have
also changed, shifting from asymptomatic to life-threatening conditions, such as acute
respiratory distress syndrome (ARDS), respiratory failure, and death [1].
New variants of SARS-CoV-2 have emerged since its genome is prone to mutations [
9
],
showing us that the virus is continuously evolving and challenging our therapeutic strate-
gies. Several routes of transmission have been speculated, including contact via droplets
and airborne transmission [
10
]. Furthermore, in aerosols, the SARS-CoV-2 half-life median
estimate time is approximately 1.1–1.2 h [
10
]. Even though many variants of the virus have
quickly vanished, selected advantages have enabled the Alpha, Beta, Gamma, Delta, and
Omicron variants of the virus to surpass other variants globally [
11
]. In September 2020,
Alpha was first detected in the United Kingdom; in May 2020, Beta was detected in South
Africa; Gamma was detected in Brazil in November 2020; Delta was detected in October
2020 in India; and Omicron was detected in November 2021 [12].
Increased risks for hospitalization, admission to intensive care units (ICU), and mor-
tality have been reported among patients infected with Alpha, Beta, Gamma, and Delta
variants compared to the wild type virus. All four variants have different degrees of risk,
especially among vulnerable groups. Therefore, Delta was most commonly associated
with the risk of admission to ICU and mortality, while hospitalization was most commonly
indicated among patients infected with the Beta variant [13].
Delta became the dominant variant in May 2021 [
14
]. It is reported to be 60% more
contagious than the Alpha variant and it has 23 more mutations compared to the Alpha
variant [15].
The discovery of the Omicron variant was announced by the officials of multiple
countries at the same time. Omicron has led to trajectory changes of the pandemic once
again; even though it appears that Omicron causes less severe clinical presentations among
infected patients [
16
], its potential to infect a larger number of people, leading to long-term
consequences and symptoms, has raised concerns [
17
]. Upper respiratory tract infection
symptoms, such as a cough, sore throat, fever, headache, and chills, are most commonly
associated with the Omicron variant [18].
The aim of this study was to describe the differences between the clinical characteristics
and perinatal outcomes among pregnant women with COVID-19 during four waves of the
COVID-19 epidemic in Serbia.
2. Materials and Methods
2.1. Study Design and Sample
The retrospective observational study included 192 pregnant patients who were hos-
pitalized due to the severity of the clinical status of SARS-CoV-2 infection at the tertiary
health care level at the University Hospital “Dr. Dragisa Misovic”. The admission criteria
to the hospital were established based on an adapted version of the Modified Early Ob-
stetric Warning Score (MEOWS) [
19
]. No patients from the study group were vaccinated
against COVID. Exclusion criteria were multiple pregnancies and a negative PCR test for
SARS-CoV-2.
The institutional Review Board of the University Hospital “Dr. Dragisa Misovic”,
Belgrade, Serbia, approved the study protocol in August 2020.

Viruses 2022,14, 2648 3 of 12
2.2. Study Setting
During the time of the COVID-19 epidemic in 2020 and 2021, in Serbia, the University
Hospital “Dr. Dragisa Misovic” was transformed into a COVID-19 hospital. As such,
it served as the Serbian referral center for severely ill pregnant patients infected with
COVID-19.
Based on the admission and discharge dynamics of our patients, there were four
outbreaks of COVID-19 infection in 2020 and 2021 in Serbia, which coincided with the
dominance of Alpha, Beta, Gamma, and Delta variants of SARS-CoV-2 [
12
]. The first wave
of the pandemic lasted from March to August 2020, the second wave lasted from October
to December 2021, the third wave lasted from February to May 2021, and the fourth wave
from September to November 2021. The first wave coincided with the dominance of the
Beta variant of concern (VOC), the second wave with the dominance of the Alfa VOC,
the third wave with the dominance of the Gamma VOC, and the fourth wave with the
dominance of the Delta VOC.
2.3. Study Variables
There were three sets of variables: signs, symptoms, and characteristics of COVID-19
infection (the first set), clinical endpoints (the second set), and maternal and newborn
parameters, as well as obstetrical characteristics (the third set).
2.4. Signs, Symptoms, and Characteristics of the COVID-19 Infection
Upon hospitalization, patients were interviewed, and the presence or absence of the
following signs and symptoms were collected: red or irritated eyes, sore throat, cough,
difficulty breathing or shortness of breath, headache, loss of smell or taste, tiredness or
diarrhea, antibiotic use before the beginning of hospitalization, as well as the number of
days from symptom onset until hospitalization.
2.5. Clinical Endpoints
Clinical endpoints were extracted from each patient’s medical chart; they included ra-
diology imaging findings (X-ray and computerized tomography (CT) scan results), D-dimer
values, data regarding requirements for non-invasive mechanical ventilation, number of
days of non-invasive oxygen requirements, progression of the COVID-19 infection, the
day of hospitalization when the peak of deterioration occurred, the number of prescribed
antibiotics during hospitalization, the potential use of corticosteroid therapy (methyl-
prednisolone), antiviral drugs (lopinavir/ritonavir or remdesivir), low-molecular-weight
heparin (LMWH), and the presence or absence of nosocomial infections as well as acute
respiratory distress syndrome (ARDS), severe inflammatory response syndrome (SIRS),
shock, multi-organ failure (MOF), pulmonary embolism, and ultimately maternal mortality.
2.6. Maternal, Newborns Parameters, and Obstetrical Characteristics
From the maternal parameters, we collected the gestational age at admission to the
hospital (calculated in days), delivery mode, parity, and presence of co-morbidities in
pregnancy, including gestational diabetes mellitus, gestational hypertension, preeclampsia
and anemia in pregnancy, premature rupture of the membrane (PROM), and abnormal
uterine bleeding. Maternal anthropometric parameters, pre-pregnancy weight, and body
height were collected from the primary health service reports of the patients and pre-
pregnancy body mass index (BMI) ranges were calculated.
Additionally, on the first day of hospitalization, ultrasonography parameters were
observed, including the amniotic fluid index (AFI), placental maturity grade, intrauterine
growth restriction (IUGR), and large for gestational age (LGA).
Newborn parameters included the infants’ Apgar scores in the first and fifth min
of life, the incidence of prematurity, and data regarding fetal antenatal maturation with
dexamethasone.

Viruses 2022,14, 2648 4 of 12
2.7. Statistical Analysis
The results are presented as absolute (n) numbers and percentages (%), as well as
mean values (MV) and standard deviation (SD). Furthermore, a 95% of confidence interval
(CI) was calculated for the continuous variables. Comparisons among the tested groups of
patients between the different waves were conducted by the Kruskal
−
Wallis and ANOVA
test for continuous variables, and the Chi
−
square test for categorical variables. Statistical
significance was set at p< 0.05.
3. Results
There were no significant differences in the mean values of age between the COVID-19
pandemic waves in the tested pregnant women (p= 0.199). The frequencies of the different
values of BMI significantly differed between pandemic waves (p< 0.001); in the first three
waves, overweight pregnant women were most frequently affected (63.9%, 55.3%, and
48.9%, respectively); in the fourth wave, obese (39.1%) and normal weight pregnant (41.3%)
women had similar percentages. Gestational age at admission significantly differed between
the four waves (p= 0.011), as well as the frequencies of prematurity (
p= 0.002
), presence of
gestational diabetes (p= 0.010), PROM (p< 0.001), pregnancy outcome (
p= 0.019
), amniotic
fluid index (0.049), placental maturity degree (p= 0.013), and fetal antenatal maturation
(0.004) (Table 1). Gestational age was the highest during the first wave (266.64
±
5.05)
and the lowest during the third wave (244.80
±
10.21). Term infants were most frequently
present in the first three waves (81.4%, 78.9%, and 81.4%, respectively), while in the fourth
wave, preterm and term infants made up 50% of each. Gestational diabetes was most
frequent in the third wave (17%), while PROM was in the second wave (28.9%). The highest
frequencies of stillbirth (17.4%) and fetal antenatal maturation (29.5%) were noticed during
the fourth wave. The highest placental maturity grade was in the second wave (
2.66 ±0.13
),
while the lowest was in the fourth wave (2.21 ±0.12) (Table 1).
Table 1.
Distribution of maternal and newborn parameters, and obstetrical characteristics regarding
the epidemic wave.
Wave 1
n= 61
Wave 2
n= 38
Wave 3
n= 47
Wave 4
n= 46 p-Value
Age, MV ±SD
(95% CI)
29.62 ±5.87
(28.12–31.13)
31.47 ±4.29
(30.07–32.88)
31.60 ±5.33
(30.03–33.16)
30.52 ±5.28
(28.95–32.09) 0.199 *
BMI, N (%)
Normal weight 14 (23%) 8 (21%) 12 (25.5%) 19 (41.3%)
<0.001 **
Overweight 39 (63.9%) 21 (55.3%) 23 (48.9%) 9 (19.6%)
Obese 8 (13.1%) 9 (23.7%) 12 (25.5%) 18 (39.1%)
Parity
1 31 (50.8%) 20 (52.7%) 20 (42.6%) 21 (45.7%)
0.442 **
2 21 (34.4%) 11 (28.9%) 23 (48.9%) 13 (28.3%)
3 8 (13.1%) 6 (15.8%) 3 (6.4%) 11 (23.9%)
4 1 (1.6%) 1 (2.6%) 1 (2.1%) 1 (2.1%)
Gestational age
at admission
MV ±SD (95% CI)
266.64 ±5.05
(256.55–276.73)
252.53 ±10.39
(231.48–273.57)
244.80 ±10.21
(224.23–265.37)
254.7 ±4.99
(244.63–264.78) 0.011 ***
Prematurity
Preterm 11 (18.6%) 8 (21.1%) 7 (16.3%) 22 (50%)
0.002 **
Term 48 (81.4%) 30 (78.9%) 35 (81.4%) 22 (50%)
Postterm 0 (0%) 0 (0%) 1 (2.3%) 0 (0%)

Viruses 2022,14, 2648 5 of 12
Table 1. Cont.
Wave 1
n= 61
Wave 2
n= 38
Wave 3
n= 47
Wave 4
n= 46 p-Value
Gestational
hypertension
Yes 5 (8.2%) 4 (10.5%) 5 (10.6%) 8 (17.4%) 0.513 **
No 56 (91.8%) 34 (89.5%) 42 (89.4%) 38 (82.6%)
Preeclampsia Yes 1 (1.6%) 2 (5.3%) 3 (6.4%) 5 (10.9%) 0.241 **
No 60 (98.4%) 36 (94.7%) 44 (93.6%) 41 (89.1%)
Gestational
diabetes
Yes 0 (0%) 3 (7.9%) 8 (17%) 3 (6.5%) 0.010 **
No 61 (100%) 35 (92.1%) 39 (83%) 43 (93.5%)
Anemia in
pregnancy
Yes 22 (36.1%) 14 (36.8%) 19 (40.4%) 16 (34.8%) 0.949 **
No 39 (63.9%) 24 (63.2%) 28 (59.6%) 30 (65.2%)
PROM Yes 2 (3.3%) 11 (28.9%) 3 (6.5%) 2 (4.5%) <0.001 **
No 53 (86.9%) 25 (65.8%) 41 (89.1%) 41 (93.2%)
Pregnancy
outcome, N (%)
Livebirth 58 (96.7%) 37 (97.4%) 44 (93.6%) 38 (82.6%)
0.019 **
Stillbirth 1 (1.7%) 1 (2.6%) 1 (2.1%) 8 (17.4%)
Miscarriage 1 (1.7%) 0 (0%) 2 (4.3%) 0 (0%)
Abnormal uterine
bleeding
Yes 1 (1.6%) 1 (2.6%) 0 (0%) 1 (2.6%) 0.767 **
No 60 (98.4%) 37 (97.4%) 61 (100%) 37 (97.4%)
Amniotic fluid
index
MV ±SD (95% CI)
117.38 ±4.39
(108.59–126.16)
109 ±5.35
(98.37–120.06)
116.25 ±5.96
(104.24–128.26)
126 ±5.18
(116.44–137.37) 0.049 ***
Placental maturity
grading
MV ±SD (95% CI)
2.45 ±0.10
(2.25–2.66)
2.66 ±0.13
(2.39–2.93)
2.44 ±0.14
(2.15–2.73)
2.21 ±0.12
(1.97–2.45) 0.013 ***
Intrauterine growth
restriction
Yes 4 (6.6%) 1 (2.6%) 1 (2.2%) 2 (4.7%) 0.681 *
No 57 (93.4%) 37 (97.4%) 44 (97.8%) 41 (95.3%)
Large for
gestational age
Yes 1 (1.6%) 2 (5.3%) 1 (2.2%) 1 (2.3%) 0.733 *
No 60 (98.4%) 36 (94.7%) 44 (97.8%) 42 (97.7%)
Fetal antenatal
maturation
Yes 6 (9.8%) 2 (5.3%) 4 (8.9%) 13 (29.5%) 0.004 *
No 55 (90.2%) 36 (94.7%) 41 (91.1%) 31 (70.5%)
Delivery mode
Spontaneous 6 (10%) 4 (10.5) 5 (10.9%) 7 (16.3%)
0.200 *
Stimulated 22 (36.7%) 15 (39.5%) 17 (37%) 14 (32.6%)
Induction of
labor 9 (15%) 3 (7.9%) 0 (0%) 6 (14%)
Elective
Cesarean
Section
12 (20%) 2 (5.3%) 11 (23.9%) 3 (7%)
Emergency
Cesarean
Section
8 (13.3%) 10 (26.3%) 11 (23.9%) 12 (27.9%)
Assisted birth 2 (3.3%) 2 (5.3%) 1 (2.2%) 1 (2.3%)
Apgar score 1st min
MV ±SD (95% CI)
8.25 ±0.22
(7.8–8.7)
7.63 ±0.41
(6.8–8.46)
7.53 ±0.45
(6.62–8.44)
7.02 ±0.49
(6.04–8.01) 0.262 ***
Apgar score 5th min
MV ±SD (95% CI)
9.23 ±0.25
(8.74–9.72)
8.79 ±0.43
(7.93–9.65)
8.53 ±0.49
(7.54–9.52)
7.95 ±0.54
(6.86–9.05) 0.215 ***
* ANOVA test; ** Pearson Chi-Square test; *** Kruskal–Wallis test.

Viruses 2022,14, 2648 6 of 12
The number of days of hospitalization (p= 0.007), ICU duration (p= 0.014), the number
of days on oxygen therapy (p< 0.001), the peak of deterioration from the beginning of
hospitalization (p< 0.001), and the number of prescribed antibiotics (p< 0.001) significantly
differed between the four different COVID-19 pandemic waves. Performed CT (p= 0.019),
progression of COVID infection (p= 0.043), administration of corticosteroids (p< 0.001),
antiviral drugs (p= 0.045), low-molecular-weight heparin (p< 0.001), and nosocomial
infection (p= 0.028) significantly differed between pandemic waves (Table 2). The highest
frequency of antiviral drugs was in the first wave (9.8%), while the use of low-molecular-
weight heparin was in the third wave (95.7%). The longest duration in the ICU was in
the second wave (0.82
±
0.52 days). The highest frequency of the performed CT was in
the third wave (34%). During the fourth wave, the duration of patient hospitalizations
was the longest (10.67
±
1.42 days), the frequency of X-ray-confirmed pneumonia (57.8%)
and the requirement for non-invasive oxygen support (37%) were the highest, as well
as the longest duration of non-invasive oxygen therapy (5.68
±
1.45 days), the most
frequent progression of COVID infection (28.9%), the longest peak of deterioration from the
beginning of hospitalization (7.52
±
5.61 days), the highest number of prescribed antibiotics
(2.35
±
0.28), the use of corticosteroids (34.8%), and the presence of nosocomial infections
(21.7%).
Table 2.
Distribution of clinical characteristics in pregnant COVID-19 patients regarding the epidemic
wave.
Wave 1
n= 61
Wave 2
n= 38
Wave 3
n= 47
Wave 4
n= 46 p-Value
Number of days of hospitalization MV
±SD (95% CI)
5.16 ±0.36
(4.45–5.88)
6.26 ±0.80
(4.65–7.88)
6.23 ±0.55
(5.13–7.34)
10.67 ±1.42
(7.82–13.53) 0.007 *
Number of days in intensive care unit
MV ±SD (95% CI)
0.34 ±0.23
(0.11–0.80)
0.82–0.52
(0.23–1.86)
0.68 ±0.35
(0.03–1.39)
3.65 ±1.27
(1.09–6.22) 0.014 *
X-ray confirmed
pneumonia
Yes 10 (16.4%) 8 (21.1%) 19 (40.4%) 26 (57.8%) <0.001 **
No 51 (83.6%) 30 (78.9%) 28 (59.6%) 19 (42.2%)
CT performed Yes 7 (11.5%) 12 (31.6%) 16 (34%) 15 (32.6%) 0.019 **
No 54 (88.5%) 26 (68.4%) 31 (66%) 31 (67.4%)
Non-invasive oxygen
therapy requirement
Yes 3 (4.9%) 6 (15.8%) 9 (19.1%) 17 (37%) <0.001 **
No 58 (95.1%) 32 (84.2%) 38 (80.9%) 29 (63%)
Number of days of non-invasive oxygen
MV ±SD (95% CI)
0.26 ±0.201
(0.14–0.66)
1.24 ±0.609
(0.00–2.47)
1.52 ±0.663
(0.19–2.86)
5.68 ±1.45
(2.75–8.61) <0.001 *
Progression of COVID
infection
Yes 5 (8.2%) 7 (18.4%) 7 (14.9%) 13 (28.9%) 0.043 **
No 56 (91.8%) 31 (81.6%) 40 (85.1%) 32 (71.1%)
The peak of deterioration from begging
of hospitalization (day)
3.16 ±2.57
(2.51–3.82)
6.78 ±4.97
(5.13–8.44)
7.51 ±3.68
(6.43–8.59)
7.52 ±5.61
(5.86–9.19) <0.001 *
Number of prescribed antibiotics
MV ±SD (95% CI)
1.26 ±0.114
(1.03–1.49)
1.68 ±0.239
(1.20–2.17)
1.74 ±0.179
(1.39–2.10)
2.35 ±0.28
(1.79–2.91) <0.001 *
Corticosteroids Yes 2 (3.3%) 4 (10.5%) 3 (6.4%) 16 (34.8%) <0.001 **
No 59 (96.7%) 34 (89.5%) 44 (93.6%) 30 (65.2%)
Antiviral drugs Yes 6 (9.8%) 0 (0%) 0 (0%) 3 (6.5%) 0.045 **
No 55 (90.2%) 38 (100%) 46 (100%) 43 (93.5%)
Low-molecular-weight
heparin
Yes 20 (32.8%) 32 (84.2%) 45 (95.7%) 36 (78.3%) <0.001 **
No 41 (67.2%) 6 (15.8%) 2 (4.3%) 10 (21.7%)

Viruses 2022,14, 2648 7 of 12
Table 2. Cont.
Wave 1
n= 61
Wave 2
n= 38
Wave 3
n= 47
Wave 4
n= 46 p-Value
Nosocomial infection Yes 3 (4.9%) 4 (10.5%) 3 (6.4%) 10 (21.7%) 0.028 **
No 58 (95.1%) 34 (89.5%) 44 (93.6%) 36 (78.3%)
ARDS N (%) Yes 4 (6.6%) 2 (5.3%) 1 (2.1%) 5 (10.9%) 0.375 **
No 57 (93.4%) 36 (94.7%) 46 (97.9%) 41 (89.1%)
SIRS N (%) Yes 1 (1.6%) 2 (5.3%) 2 (4.3%) 2 (4.3%) 0.778 **
No 60 (98.4%) 36 (94.7%) 45 (95.7%) 44 (95.7%)
Shock Yes 1 (1.6%) 2 (5.3%) 1 (2.1%) 2 (4.3%) 0.705 **
No 60 (98.4%) 36 (94.7%) 46 (97.9%) 44 (95.7%)
MOF Yes 1 (1.6%) 2 (5.3%) 1 (2.1%) 2 (4.3%) 0.705 **
No 60 (98.4%) 36 (94.7%) 46 (97.9%) 44 (95.7%)
Pulmonary embolism Yes 0 (0%) 0 (0%) 1 (2.2%) 1 (2.2%) 0.554 **
No 60 (100%) 34 (100%) 44 (97.8%) 45 (97.8%)
Lethal outcome Yes 0 (0%) 1 (2.6%) 2 (4.3%) 4 (8.7%) 0.121 **
No 61 (100%) 37 (97.4%) 45 (95.7%) 42 (91.3%)
* Kruskal–Wallis test; ** Pearson Chi-Square test.
The number of days from symptom onset to hospitalization (p< 0.001), frequencies of
loss of smell (p< 0.001) and taste (p< 0.001), and tiredness (p= 0.010) significantly differed
between the four COVID-19 pandemic waves (Table 3).
Table 3.
Distribution of symptoms before hospitalization in pregnant COVID-19 patients with regard
to pandemic waves.
Wave 1
n= 61
Wave 2
n= 38
Wave 3
n= 47
Wave 4
n= 46 p-Value
Number of days from symptom onset to
hospitalization
MV ±SD (95% CI)
3.07 ±0.582
(1.90–4.23)
5.16 ±0.63
(3.88–6.43)
5.64 ±0.55
(4.52–6.75)
5.63 ±0.84
(3.94–7.32) <0.001 *
Antibiotics used before
hospitalization N (%)
Yes 17 (27.9 %) 23 (60.5%) 35 (74.5%) 28 (60.9%) 0.847 **
No 44 (72.1%) 15 (39.5%) 12 (25.5%) 18 (39.1%)
Red or irritated eyes N (%) Yes 5 (8.2%) 0 (0%) 0 (0%) 2 (4.3%) 0.076 **
No 56 (91.8%) 38 (100%) 47 (100%) 44 (95.7%)
Sore throat N (%) Yes 13 (21.3%) 7 (18.4%) 6 (12.8%) 14 (30.4%) 0.206 **
No 48 (78.7%) 31 (81.6%) 41 (87.2%) 32 (69.6%)
Cough N (%) Yes 21 (34.4%) 16 (43.2%) 26 (55.3%) 25 (54.3%) 0.096 **
No 40 (65.6%) 21 (56.8%) 21 (44.7%) 21 (45.7%)
Difficulty breathing or
shortness of breath N (%)
Yes 9 (14.8%) 7 (18.4%) 9 (19.1%) 14 (30.4%) 0.241 **
No 52 (85.2%) 31 (81.6%) 38 (80.9%) 32 (69.6%)
Headache N (%) Yes 6 (9.8%) 10 (26.3%) 6 (12.8%) 6 (13%) 0.138 **
No 55 (90.2%) 28 (73.7%) 41 (87.2%) 40 (87%)
Loss of smell N (%) Yes 10 (16.4%) 23 (60.5%) 9 (19.1%) 15 (32.6%) <0.001 **
No 51 (83.6%) 15 (39.5%) 38 (80.9%) 31 (67.4%)

Viruses 2022,14, 2648 8 of 12
Table 3. Cont.
Wave 1
n= 61
Wave 2
n= 38
Wave 3
n= 47
Wave 4
n= 46 p-Value
Loss of taste N (%) Yes 7 (11.5%) 23 (60.5%) 9 (19.1%) 14 (30.4%) <0.001 **
No 54 (88.5%) 15 (39.5%) 38 (80.9%) 32 (69.6%)
Tiredness N (%) Yes 18 (29.5%) 16 (42.1%) 27 (57.4%) 26 (56.5%) 0.010 **
No 43 (70.5%) 22 (57.9) 20 (42/6%) 20 (43.5%)
Diarrhea N (%) Yes 1 (1.6%) 2 (5.3%) 1 (2.1%) 2 (4.3%) 0.705 **
No 60 (98.4%) 36 (94.7%) 46 (97.9%) 44 (95.7%)
* Kruskal–Wallis test; ** Pearson Chi-Square test.
Loss of smell (60.5%) and loss of taste (60.5%) were the most frequent in the second
wave, while tiredness was the most frequent in the fourth wave (56.5%). The longest
duration from symptom onset to hospitalization was in wave 3 (5.64 ±0.55) (Table 3).
4. Discussion
During the four waves of the COVID-19 epidemic in Serbia in 2020–2021, we hospital-
ized and treated 192 severely or critically ill pregnant patients infected with SARS-CoV-2.
In the pregnant patients, the frequency of common early symptoms related to the
COVID-19 infection, such as red or irritated eyes, sore throat, cough, difficulty breathing,
headache, and diarrhea, unlike tiredness and loss of taste and smell, was similar during the
four waves of the epidemic. Tiredness was the most frequently observed early symptom
among patients in the third and the fourth groups of patients, while loss of smell and
taste were the more frequently observed symptoms of infection in the second group of
patients, meaning that Delta and Gamma VOCs were associated more commonly with
systemic manifestations of infection compared to the Alpha VOC. Globally, the Delta VOC
has resulted in substantially higher rates of cases of hospitalization and deaths [
12
], which
raises the necessity for early clinical assessment, specific monitoring, and surveillance of
these patients. Based on the results from the United Kingdom, the proportion of pregnant
patients who experienced progression of disease severity has significantly increased during
the dominance of Alpha and Delta VOCs; 35.8% of all pregnant women experienced severe
disease during the dominance of the Alpha VOC compared to 45.0% during the Delta
period [
20
]. Results from the United States confirmed that the Delta VOC was associated
with a more common progression of infection as well as with the rising proportions of
patients requiring hospitalization [
21
]. Our results undoubtedly confirm these statements.
During the dominance of the Delta VOC (the fourth wave), we observed that the average
duration of hospitalization was nearly double compared to the other three waves. We
observed a similar pattern of distribution in the likelihood of the progression of COVID-19
infection during the Delta wave. Patients had up to three times longer average durations of
ICU and were more likely to depend on various modes of mechanical ventilation. In the
first group of patients, during the dominance of the Beta wave, the peak of deterioration
occurred (on average) on the third day from the symptom onset, and it overlapped with
the beginning of hospitalization. In the remaining three groups, the peak of deterioration
occurred on the seventh day, and hospitalizations were, on average, initiated on the fifth
day. Additionally, Ong et al. concluded that compared to Delta and Alpha, the Beta VOC
was less likely to lead to the development of pneumonia or a severe form of COVID-19
infection [22].
Patients treated during the Beta wave also had less frequently used antibiotics before
hospitalization. These findings suggest the need for the analysis of whether antibiotics were
effective in preventing or developing a severe form of COVID-19 infection. Furthermore, in
this group of patients, nosocomial infections were less present, which is a constant reminder

Viruses 2022,14, 2648 9 of 12
that the rational use of antibiotics is a safe and proven way of preventing hospital-acquired
infections [23].
During the four waves of the COVID-19 epidemic, several different therapeutic strate-
gies were applied in Serbia and the rest of the world [
24
]. Corticosteroid therapy was
initiated in cases of severe maternal infection. Every third patient during the Delta wave
was treated with corticosteroid therapy. The recent meta-analysis has proven the effective-
ness of corticosteroid therapy among critically ill patients [
25
], and among the majority
of authors, methylprednisolone was designated as the therapy of choice for pregnant
women [26].
The initiation of any type of antiviral drug therapy during pregnancy remains con-
troversial [
27
]. In our hospital, we initiated this type of therapy in selected cases; the
decisions for the initiations were made by perinatologists in coordination with intensive
care medicine specialists, pulmonologists, and infectologists. Antiviral drugs were pre-
scribed during the first and fourth waves of the pandemic. Lopinavir and ritonavir are
protease inhibitors, and they have low placental transfer [
28
]. They were administered
during the first wave of the pandemic, and remdesivir was administered during the fourth
wave of the pandemic. These patients were under constant monitoring. We did not detect
any adverse reactions or side effects, but due to the low number of patients, our findings
remain inconclusive, as do other authors’ results and systemic reviews [29].
Prior to the Royal College of Obstetrics and Gynecology (RCOG) recommendations,
which introduced the widely adopted routine administration of low-molecular-weight
heparin (LMWH) therapy [
30
], we administrated LMWH therapy primarily based on
laboratory values of D-dimer. Measurements of D-dimer combined with imaging testing
were part of the diagnostic algorithm for the diagnosis of pulmonary embolisms [
31
].
LMWH is not contraindicated during pregnancy, it has comparable efficiencies compared
to unfractionated heparin, which has fewer major bleeding complications [
32
]. Less than
a third of patients during the first wave of the pandemic received LMWH, while during
the remaining three waves of the pandemic, it was administrated almost regularly, with
the highest incidence of 95.7% during the third wave of the pandemic. Patients infected
with SARS-CoV-2 during the third wave of the pandemic had the lowest average values
of D-dimer, a finding that initially encouraged us to believe that routine administration
of LMWH is an effective therapeutic strategy for the prevention of pulmonary embolism.
Unfortunately, this has not proven to be true, since one of the two cases of pulmonary
embolism was observed during the dominance of the Gamma VOC in the third wave of
the pandemic; once again, the low sensitivities and specificities of D-dimer tests during
pregnancy were confirmed [
33
]. These findings emphasize the importance of clinical
algorithms, such as the pregnancy-associated YEARS diagnostic algorithm in the diagnosis
of pulmonary embolism [34].
During the dominance of Alpha, Beta, and Gamma VOCs, based on pre-pregnancy
BMI values, the majority of patients in this study group were overweight. However, results
from our study showed that from the first to the fourth wave there was a decrease in the
percentage of overweight pregnant patients and an increase in the percentage of obese preg-
nant patients. During the Delta wave, the obese and normal-weight groups of patients had
similar distributions. The pre-pregnancy BMI weight range classified nearly 40% of these
patients as obese. Such findings might lead to the possible assumption that in the different
waves of COVID-19 infections, pregnant women could have different susceptibilities with
regard to their pre-pregnancy BMIs. Obesity is a well-known risk factor for the progression
and severity of COVID-19 infection [
35
,
36
]. The high incidence of obese patients during
the Delta wave might be an explanation for the often worse clinical outcomes among
patients during this wave of the epidemic, since certain metabolic phenotypes, as well
as obesity, raise susceptibility to poor COVID-19 outcomes [
37
]. Obesity is a risk factor
commonly associated with co-morbidities in pregnancy [
38
]. Even though the incidence of
gestational diabetes differed between the compared groups, it was more frequent during
the dominance of the Gamma VOC; even though the incidence of gestational hypertension

Viruses 2022,14, 2648 10 of 12
and preeclampsia did not differ between the four compared groups, during the Delta wave,
the likelihood of gestational hypertension was 30% higher. Co-morbidities in pregnancy
are by now very well-known risk factors for adverse maternal and pregnancy outcomes
among pregnant COVID-19 patients [39–41].
The majority of observed patients in this study group were in the late third trimester
of pregnancy, a finding which is consistent with other results and confirms that women are
at higher risk of COVID-19 infection during the third trimester of pregnancy [42].
Prematurity has increased globally and it was considered to be the leading cause of
neonatal morbidity and mortality in the last two decades [
43
]. Based on recent official
reports, the incidence of prematurity in Serbia has reached 12% [
44
]. Unfortunately, the
severity of infection has led to higher rates of prematurity, especially iatrogenic prematurity;
these conclusions are supported by other authors’ findings as well [
45
]. Prematurity affected
half of the patients during the Delta wave of the pandemic. The remaining three groups
had approximately the same range of premature (20%). This discrepancy in the prematurity
rate also explains the difference in the frequency of antenatal corticosteroid maturation
therapy between the four compared groups.
Aside from the higher rates of prematurity, during the Delta wave, we observed a
devastating incidence of stillbirths that rose to nearly 20%. DeSisto et al. reported a stronger
positive connection between the Delta VOC and stillbirth compared to other VOCs [
46
],
which makes a further analysis of the impact of the Delta VOC on fetal well-being essential.
This study has several limitations, including the sample size and the fact that all par-
ticipants in this study belonged to the Serbian population. The study method is descriptive
and, therefore, it is not possible to analyze the cause–effect of patients’ features on the
outcomes of pregnancy.
5. Conclusions
During the dominance of the Delta VOC, we observed differences in the likelihood
of progression of the clinical presentation of COVID-19 infection, raising concerns about
the development of a severe form of COVID-19 infection as well as the risk of adverse
maternal and pregnancy outcomes. The observed differences during the dominance of the
four VOCs (Alpha, Beta, Gamma, and Delta) are potential pathways for risk stratification
and the establishment of timely and proper treatments for pregnant patients. Therefore,
early identification of the Delta VOC, and possibly some new VOCs with similar features
in the future, should be priorities, and perhaps even opportunities for the introduction of
more accurate and predictive clinical algorithms for pregnant patients.
Author Contributions:
Conceptualization, S.M., D.N., M.L. and M.S.-M.; methodology, S.M., D.N.,
M.L., M.S.-M., B.M., M.R. and A.A.; data curation, B.M., M.R. and A.A.; writing—original draft
preparation, S.M., D.N., M.L., M.S.-M., B.M., M.R. and A.A.; supervision, S.M., D.N., M.L. and M.S.-M.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
The study was approved by the Institutional Review Board
(decision no. 01-8816, 3 August 2020).
Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement:
All data are presented in this study. Original data are available upon
reasonable request from the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.
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