COVID-19 Quarantine is a Risk Factor for Poor Pregnancy Outcomes in GDM Patients: A Retrospective Study

Aims: This study was to evaluate the effects of the home quarantine on pregnancy outcomes of gestational diabetes mellitus (GDM) patients during the COVID-19 outbreak. Methods: Thecomplete electronic medical records of GDM patients with home quarantine history were collected and classied into the home quarantine group from 24 February 2020 to 24 November 2020. The same period of GDM patients without home quarantine historywas included in the control group from 2018 and 2019. Results: A total of 1358 GDM patients were included in the analysis, including 484 in 2018, 468 in 2019, and 406 in 2020. GDM patients with home quarantine in 2020 had higher glycemic levels and worse pregnancy outcomes than 2018 and 2019, including higher cesarean section rate,lower Apgar scores, and higher incidence of macrosomia and nuchal cord. More importantly, the second trimester of home quarantine had brought a broader impactto pregnant women and fetuses. Conclusion: Home quarantine has aggravated the condition of GDM pregnant women and brought more adverse pregnancy outcomes during the COVID-19 outbreak. Therefore, we suggested that governments and hospitals should strengthen lifestyle guidance, glucose management, and antenatal care for GDM patients with home quarantine during public health emergencies.


Introduction
A new coronavirus that caused severe acute respiratory syndrome (SARS-CoV-2, COVID-19) emerged in late 2019, which has caused over 184 million infections and more than 3984000 deaths (https://covid19.who.int). COVID-19 can directly cause severe complications, including cough, fevers, myalgia, pharyngitis, dyspnea, pneumonia, even acute respiratory distress syndrome (ARDS), and multisystem organ failure [1,2]. The rapid spread of the epidemic around the world not only brought suffering and life threats to the infected individuals and their families but also seriously affected the economy and health of uninfected people. Varying degrees and types of lockdowns are effectively used to prevent the widespread of COVID-19, which has signi cantly changed the daily lifestyle of the people, including sports activities decreased, sleep time increased, increased intake of high-calorie food, and so on [3,4]. Lockdown made them more vulnerable to over-eating and sedentary that leading to further weight gain and increased cardiovascular risk [5]. These changes have indirectly brought a threat to uninfected people, such as the worsening of sleep quality, increased risk of adolescent psychiatric disorder, impaired immune function, and increased risk of infections and autoimmunity [6][7][8][9].
Gestational diabetes mellitus (GDM) is a typical metabolic disorder closely associated with diet and exercise [10]. Numerous evidences showed that active exercise is bene cial to weight control, glycemic control, reduce the risk of large for gestational age (LGA) and postpartum depression of GDM patients [11,12]. In contrast, GDM patients with high fat, high carbohydrate, high energy, and low brous diet will lead to impaired gut microbiota which can be transmitted to the offspring and further increasing the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in GDM patients and their offspring lastly [13][14][15][16]. The retrospective studies of GDM patients during the COVID-19 pandemic lockdown also showed that the reduced physical activity, modi ed dietary habits, and anxiety exacerbated the glycemic out of control [17,18]. Although these studies showed that home quarantine has changed the lifestyle of GDM patients and further affected their health, it is still unclear whether home quarantine has an impact on pregnancy outcomes.
During the outbreak of COVID-19 in China, Chongqing has been taken strict home quarantine from 24 January 2020 to 20 April 2020. During the lockdown, only essential activities were allowed, and mobility of most people was limited to the acquisition of food and medicines; living at home was compulsive. Therefore, a retrospective cohort study was conducted on women diagnosed with GDM during the lockdown, aiming to study the effects of lifestyle change on GDM patients and newborns. This study was hopeful to guide antenatal care and clinical decision-making of GDM patients during public health emergencies.

Study design and participants
This was a single-center retrospective cohort study; information about the subjects was collected in The First A liated Hospital of Chongqing Medical University, which is a Grade and Grade A hospital with an average of 10000 births per year. Only participants with complete clinical information were included in the analysis, and all participants were clinically diagnosed with GDM, according to the Chinese OGTT biochemical criterion. Moreover, venous plasma glucose that is analyzed, and that at least one glucose threshold value must be equaled or exceeded to de ne the patient as having gestational diabetes. All participants who attended the clinic visit were offered a 75 g oral glucose tolerance test (OGTT) after 8-10 h of overnight fasting. With GDM diagnosed from venous samples according to the IADPSG/WHO 2010 criteria (fasting plasma glucose ≥ 5.1 mmol/L, 1 h plasma glucose ≥ 10.0 mmol/L or 2 h plasma glucose ≥ 8.5 mmol/L) (IADPSG), which was the clinical guideline in use during the study [19]. Subjects were excluded if they had chronic medical conditions, including hypertension, type 2 diabetes mellitus, and heart or kidney diseases. The time of home quarantine of the GDM patients was inferred from their gestational weeks and delivery date, and who with at least one month home quarantine was included in the analysis. It is worth noting that none of the patients during the COVID-19 pandemic were diagnosed with the SARS-CoV2 infection. Since the strict epidemic lockdown is from 24 January 2020 to 20 April 2020 in Chongqing, China, therefore, the complete clinical information of patients from 24 February 2020 to 24 November 2020 was collected and classi ed into the home quarantine group, and the data of the same period in 2018 and 2019 were also collected and classi ed into the control group (Fig. 1). Then, these GDM patients were further divided into three groups according to different periods of pregnancy during home quarantine to explore the effects of home quarantine in different periods on pregnancy outcomes (Fig. 1). This study was approved by the ethics committee of the First A liated Hospital of Chongqing Medical University (ID: 20200501).

Data collection
All data were collected from hospital electronic medical records, including maternal characteristics, management, and maternal and fetal outcomes.

Statistical analyses
All statistical analyses were performed using the SPSS software program, version 22.0 (IBM, Armonk, NY, USA). Continuous variables were presented as mean ± SD, and categorical variables were presented as percentage and count. Chi-square or Fisher's exact test was used for categorical variables including the incidence of GDM, and one-way analysis of variance was used to compare basic characteristics of the pregnant woman of different groups. Post hoc analysis involving pairwise comparisons was performed if there are ≥ 3 independent groups, using L-S-D correction results, and results with signi cant differences between two groups have been shown in tables.
Multiple logistic regression was used to compare the outcomes of pregnant women and fetuses and obstetric complications, such as placental factors, umbilical factors, and macrosomia of different groups. Potential covariates that may be associated with the outcomes of pregnant woman and fetus, abnormal placentation, macrosomia, and other obstetric complications were adjusted in the model, including age, parity, gestational age, and fetal number. In addition, multiple logistic regression was used in pregnancy BMI, one-minute Apgar scores, delivery pattern, OGTT biochemical criterion, and obstetric complications. Thus, other variables are considered as continuous variables such as neonatal weight, body length, placental weight, and length. Results are presented as OR or Adjusted OR with 95% CI.

Results
Clinical characteristics of GDM patients in 2018, 2019, and 2020.
The labor complications were further analyzed to evaluate the effects of home quarantine on fetal outcomes. Multivariate logistic regression was used to control for the following covariates, age, gravidity, parity, gestational age, fetal number, as well as pre-pregnancy BMI; the data showed that the incidence of fetal macrosomia in 2020 was higher than in 2018 (AOR: 0.82, 95% CI, 0.71-0.98, P = 0.046; Table 4). Besides, the incidence of the nuchal cord has also increased in 2020 (AOR: 0.63, 95% CI, 0.44-0.90, P = 0.003; Table 4). Macrosomia is typically de ned as a birth weight above the 90th percentile for gestational age or > 4,000 g. These 1358 GDM patients were further divided into three groups according to different periods of pregnancy during home quarantine, including 1st, 2nd, and 3rd trimester. The data showed that a signi cant difference in pre-pregnancy BMI (P = 0.002) in the 2nd trimester in 2018 and 2020, 2019, and 2020 (Supplemental Table 1 Table 2).

Discussion
Until now, COVID-19 is still raging around the world, and numerous countries are forced to adopt varying degrees and forms of lockdown to prevent the broader spread of the virus effectively. These lockdowns have brought many challenges to the economic development and lives of people, which have dramatically changed the diet and exercise of people, even aggravated the symptoms of many diseases, especially for metabolic diseases [20][21][22]. Therefore, this retrospective study of GDM patients was used to investigate the impacts of home quarantine on pregnant women and their pregnancy outcomes during the COVID-19 outbreak. The data showed that delivery volume from February 2020 to November 2020 was signi cantly lower than that in the same period of 2018 and 2019, while no signi cant difference was observed in the incidence of GDM. It has been reported that a signi cant increase in the number of GDM patients during the lockdown [17]. By interviewing doctors and women, we speculated that there might be the following reasons: 1) Fertility intention of women were inhibited because of the decreased income during home quarantine; 2) Although the better medical conditions of The First A liated Hospital of Chongqing Medical University will attract more pregnant women, the epidemic led more pregnant women chose to deliver nearby that resulting in a decline in hospitalization rate; 3) The detection rate of GDM decreased since a signi cant number of pregnant women changed their antenatal examination plans without the permission of their doctors due to the fear of infection; 4) During the epidemic outbreak, online consultation was widely carried out in hospitals, which may lead to a further decline in the detection rate of GDM. Therefore, multicenter data is needed to determine whether home quarantine would lead to a change in GDM incidence.
Although the increase of GDM incidence was not observed, the data indicated that the 0 min OGTT of GDM patients in 2020 was signi cantly higher than that in 2018 and 2019. Further clinical data from different trimesters showed that home quarantine increased the 0 min OGTT of GDM patients, especially in the second trimester. In addition, the home quarantine group had thicker and heavier placenta than GDM patients of 2018 and 2019, which will lead to macrosomia in most GDM patients [23]. These ndings suggested that home quarantine may aggravate the condition of GDM patients.
According to the analysis of pregnancy outcomes, the cesarean section rate of GDM patients in 2020 was signi cantly higher than that in 2018 and 2019; meanwhile, signi cant increases were also observed in fetal head circumference, body length, and incidence of macrosomia in GDM patients of 2020. The high-fat and high-calorie diet will not only increase the occurrence of GDM but also increase the probability of macrosomia, while the increase of depression, anxiety, and stress during the lockdown will make pregnant women more inclined to a highcalorie or high-fat diet [24][25][26]. Thus, we speculated that anxiety or other factors during the lockdown made the maternal diet style change, resulting in excessive nutrient transport to the fetus and placenta which further leading to fetal macrosomia. Studies have found that moderate exercise is helpful to improve GDM condition, especially bene ting from walking [27][28][29]. The light regulation of circadian rhythm has also been found to be essential for fetal development. On the one hand, home quarantine had greatly limited the exercise of GDM patients; on the other hand, the residential structure and climate in Chongqing greatly limited the light exposure of pregnant women. These might also be the reasons for the decline of various clinical indicators in GDM pregnant women and increased incidence of macrosomia.
Macrosomia will cause postpartum bleeding and vaginal lacerations and lead to an increased risk of fetal dystonia, collarbone fracture, and brachial plexus injury, which further increases the rate of admission to the neonatal intensive care unit [30]. Thus, pregnant women with macrosomia generally adopted the cesarean section in clinical treatment, which gives a possible explanation for the increase of cesarean section rate in 2020. Moreover, the data con rmed that one-min Apgar scores in 2020 were signi cantly lower than in 2018 and 2019, and the incidence of the nuchal cord increased signi cantly. Clinically Apgar score is widely used to evaluate various neonatal indexes, such as hypotonia, pulse, skin color, respiration, breath, response to stimulation, and so on [31]. Previous studies have shown that the nuchal cord could cause breathing di culties and distress in newborns [32], which may cause the decrease in Apgar scores in 2020.

Conclusions
In conclusion, our ndings suggested that home quarantine will aggravate the condition of GDM pregnant women and further bring more adverse pregnancy outcomes, such as macrosomia and nuchal cord. More importantly, the analysis of the different trimesters showed that home quarantine in the second trimester would bring more extensive adverse effects on GDM patients compared to the rst and third trimester, including neonatal weight, body length, placental weight, placental size, amniotic uid volume, and the risk of placental implantation. Comprehensive current research and our research, we proposed that the GDM patients should actively adjust their emotions, have a proper diet, and exercise moderately during home quarantine, especially those in the 2nd trimester. Besides, all hospital levels should intensify movement guidance and dietary management for pregnant women during the pandemic lockdown.

Declarations
Author Contributions.
were involved in the data analysis, interpreted the ndings, and wrotethe manuscript. Y.Y., L.R., X.L. and T.L. reviewed and edited the manuscript.All authors gave nal approvalfor publication. T.L. is the guarantor of thiswork and, as such, had full access to all of the data in the study and takesresponsibility for the integrity of the data and the accuracy of the data analysis.  The total delivery and GDM patients in 2018, 2019, and 2020.