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ORIGINAL RESEARCH article

Front. Pediatr., 27 June 2023
Sec. Pediatric Infectious Diseases

The impact of non-pharmaceutical interventions on premature births during the COVID-19 pandemic: a nationwide observational study in Korea

\r\nJi Young Lee,&#x;Ji Young Lee1,†Joonsik Park,&#x;Joonsik Park2,†Myeongjee Lee,&#x;Myeongjee Lee3,†Minkyung HanMinkyung Han3Inkyung JungInkyung Jung4Sung Min LimSung Min Lim1Jee Yeon BaekJee Yeon Baek1Ji-Man Kang,Ji-Man Kang1,5Min Soo Park,,,,&#x;Min Soo Park1,2,6,7,‡Jong Gyun Ahn,,&#x;
\r\nJong Gyun Ahn1,5,†*
  • 1Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 2Division of Neonatology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 3Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 4Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 5Institute for Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 6Pharmaceutical Medicine and Regulatory Science, Yonsei University Graduate School, Seoul, Republic of Korea
  • 7Department of Clinical Pharmacology, Severance Hospital, Seoul, Republic of Korea

Background: Non-pharmaceutical interventions (NPIs), such as social distancing and hand washing, have been associated with a decline in the preterm birth rate worldwide. We aimed to evaluate whether the preterm birth rate in Korea during the coronavirus disease 2019 lockdown has changed compared to that in previous years.

Method: A birth registry from the Korea Statistical Information Service, which is a nationwide official database, was used to include all births claimed to have occurred between 2011 and 2020. Newborns with gestational age (GA) less than 22 weeks and birth weight less than 220 g were excluded. The pre-NPI period was designated as January 2011 to January 2020, and the NPI period was defined as February 2020 to December 2020. We assessed the effect of NPI on the incidence of prematurity per 100 births using an interrupted time-series quasi-experimental design and implementing an autoregressive integrated moving average (ARIMA) model.

Results: From 2011 to 2020, a total of 3,931,974 live births were registered, among which 11,416 were excluded. Consequently, the final study population included 3,920,558 live births (both singleton and multiple births) among which 275,009 (7.0%) were preterm. The preterm birth rate was significantly higher during the NPI period (8.68%) compared to that in the pre-NPI period (6.92%) (P < 0.001). The ARIMA model showed that in all singleton and multiple births, except those in July (observed 9.24, expected 8.54, [95% prediction interval {PI} 8.13–8.96], percent difference 7.81%), September (observed 7.89, expected 8.35, [95% PI 7.93–8.76], percent difference −5.66%), and December (observed 9.90, expected 9.40, [95% PI 8.98–9.82], percent difference 5.2%), most observed values were within the 95% PI of the expected values and showed an increasing trend.

Conclusion: In this nationwide observational study, the trend in premature birth rate did not significantly change due to NPI implementation in Korea, as it had been increasing since 2011. The trend of Korea's birth rate appears to be unaffected by the implementation of NPIs; however, further studies with a longer follow-up period are needed.

1. Introduction

The coronavirus disease 2019 (COVID-19) pandemic has brought about unexpected changes in the global society. After the first quarter of 2020, most countries decided to implement non-pharmaceutical interventions (NPIs) to prevent the spread of COVID-19 (1). NPIs consist of frequent hand washing, isolating infected individuals, wearing masks, closing schools and public facilities, and canceling or postponing large gatherings (2). These interventions provided effective measures to control the contagious disease; however, they also led to unwanted and often unexpected public health consequences (3).

Preterm labor is defined as labor that starts before 37 weeks of pregnancy. The estimated global preterm birth rate in 2014 was 10.6%, and this was similar in Asia, where a 10.4% preterm birth rate was reported (4). In recent decades, there has been a trend of increasing preterm birth rates in developed countries (5). Several reports have noted the severe adverse effects of maternal COVID-19 and its associated negative perinatal outcomes for newborns; however, there have also been findings of a potentially decreased rate of preterm births during the pandemic (6).

Investigators in Tennessee first identified an association between NPI and preterm birth after the COVID-19 pandemic (7). Birth records in Tennessee showed a decline in preterm births after the state's stay-at-home order was put into place in 2020. A single center study from South Korea also suggested the possible preventative effects of NPI on preterm birth rates due to the mitigation effects of NPI. Similar phenomena were observed in three Scandinavian countries; however, statistically significant impact of NPI on preterm birth rates was not observed in these studies (8). However, recent studies investigating the effect of NPI on preterm birth rates have demonstrated inconsistent findings. An increased focus on hygiene, strict physical distancing, and home confinement have been suggested as possible reasons for the potential effects of NPI on preterm birth, which may have influenced the overall inflammatory state of pregnant women (9). Therefore, the objective of this study was to establish whether a correlation exists between preterm birth rates and the NPI period in Korea in 2020.

2. Materials and methods

2.1. Data source

Birth registry data from the Korean Statistical Information Service (an official national database) was used to include information on all births between 2011 and 2020 (10). Parents are required to register a newborn's birth with the Korean government within 1 month of birth, and the data includes not only information about the newborn but also parents’ personal information such as age, location of delivery, and educational level. Among preterm live births, both singleton and multiple births were included for analysis.

2.2. Study design

This was a retrospective, observational study that evaluated the change in preterm birth rates after the implementation of NPI. After the first confirmed case of COVID-19 in Korea on January 20, 2020, the government imposed mitigation measures, such as social distancing and restricted overseas travel, in February 2020. In this study, the NPI period was defined as January 2011 to January 2020 and the pre-NPI period as February 2020 to December 2020. Although only live births are meant to be registered, we observed 11,416 cases in the categories of gestational age (GA) less than 22 weeks and birth weight less than 220 g (Figure 1). These cases, generally regarded as medically nonviable, were excluded (11, 12).

FIGURE 1
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Figure 1. Flow chart of the selection of study population.

2.3. Definitions

As per the World Health Organization's definition, in this study, preterm birth was defined as births with a GA < 37 weeks (13). Subgroup analysis was conducted by further categorizing the data into the following GA groups: extremely preterm (22 to <28 weeks), very preterm (28 to <32 weeks), and moderate to late preterm (32 to <37 weeks). Small for gestational age (SGA) was defined as a birth weight of less than the 10th percentile for GA and large for gestational age (LGA) as a birth weight of more than the 90th percentile for GA (14).

2.4. Statistical analysis

Categorical variables were expressed as frequencies (%) and compared using the Chi-square test. Odds ratios of preterm births by birth types, such as singletons and multiples, and GA subgroups were calculated using multivariable logistic regression analyses between the defined pre-NPI and NPI periods after adjusting for maternal age, sex, maternal education, and birth order.

We assessed the effect of NPI on preterm birth rates and prematurity incidence per 100 births using an interrupted time-series quasi-experimental design (15). To account for seasonality and autocorrelation in preterm rates over time, an autoregressive integrated moving average (ARIMA) model was implemented in the data from the pre-NPI period. The optimal ARIMA parameters were identified based on an automated algorithm, specifically, auto.arima() in the forecast package in R (16). Using the optimal model selected for each outcome, we derived the expected preterm birth rates after NPI implementation and the percentage difference between the observed and expected preterm birth rates to evaluate the prediction effect. An “unexpected” outcome was defined as an observed value that was outside the expected 95% prediction interval (PI). As a sensitivity analysis, we implemented a standard interrupted time analysis with a segmented regression model allowing level and slope change to evaluate whether the trend in monthly prematurity birth rate incidence changed in the NPI period when compared to the pre-NPI period. A P-value < 0.05 was considered statistically significant. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R Statistical Software (version 4.1.2; R Core Team 2021).

Additionally, to compare the results using different statistical methods, segmented regression analysis was performed for statistical modeling of interrupted time series to evaluate whether the trend changed during the NPI period (17, 18). The results of this analysis are included in the supplementary material.

2.5. Ethics

This research was conducted ethically, in accordance with the World Medical Association and Declaration of Helsinki, and the institutional review board (No. 4-2021-0416) approved the study.

3. Results

The final study population included 3,920,558 births, of which 275,009 (7.0%) were preterm (Figure 1). A slight male predominance was observed (51.3%). The proportion of preterm births was significantly higher during the NPI period (8.48%) compared to that in the pre-NPI period (6.92%) (P < 0.001). Additionally, the proportion of low-birth-weight neonates, with birth weight under 2,500 g, especially in the subcategory of 1,500 g to less than 2,500 g (5.09% vs. 5.98%, respectively, P < 0.001), was higher in the NPI period compared to the pre-NPI period. Detailed demographic features of the study populations for both periods are shown in Table 1.

TABLE 1
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Table 1. Clinical characteristics of study population in the pre-NPI and NPI periods.

3.1. Preterm birth rate trends in the pre-NPI and NPI periods

The observed and expected preterm birth rates were plotted in Figure 2, by either birth type or GA subgroup. Overall, the preterm birth rates, including both singleton and multiple births, showed an increasing trend in all GA subgroups. (Figure 2, Supplementary Figure S1) However, based on the ARIMA model, NPI implementation was not associated with an immediate or further change in the preterm birth rate. For all singleton and multiple births, most observed values were within the 95% PI of the expected values, with an increasing trend (Figure 2A), except for those in July (observed 9.24, expected 8.54, [95% PI 8.13–8.96], percent difference 7.81%), September (observed 7.89, expected 8.35, [95% PI 7.93–8.76], percent difference −5.66%), and December (observed 9.90, expected 9.40, [95% PI 8.98–9.82], percent difference 5.2%) (Supplementary Table S1A). When preterm singleton births were separately analyzed, all the observed values were within the 95% PI (Supplementary Table S1B). For multiple births alone, most observed values were within the 95% PI, except for those in July (observed 3.39, expected 3.01 [2.68–3.35], percent difference 11.69%) and December (observed 3.61, expected 3.20 [95% PI 2.84–3.57], percent difference 11.94%) (Supplementary Table S1C).

FIGURE 2
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Figure 2. The observed values and expected monthly trend of the preterm birth rate (per 100 births) in the pre-NPI and NPI periods. (A) All births including singleton and multiple birhts, (B) Singleton births, (C) Multiple births The blue dots are observed values. The vertical green line denotes the period of NPI implementation. The black and red lines are trends for before and after NPI implementation, respectively. x-axis: incidence per 100 births, y-axis: year 2011–2021. NPI, non-pharmaceutical interventions.

3.2. Preterm birth rate and odds ratio of preterm births in the pre-NPI and NPI periods

Preterm births (including both singletons and multiple births) increased in the NPI period when compared to the pre-NPI period (odds ratio (OR) = 1.25, 95% CI, 1.23–1.27, P < 0.001) and a similar trend was observed in the multivariate analysis (OR = 1.18, 95% CI, 16–1.20, P < 0.001). (Table 2) When preterm births were separated into singleton and multiple birth groups and analyzed according to GA, both types of births showed similar trends with regards to preterm birth rates.

TABLE 2
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Table 2. Comparison of preterm births during the pre-NPI and NPI periods.

3.3. Global preterm birth rates during the pandemic

We summarized and compared the results of previous international studies on whether there was a change in the preterm birth rate due to NPI implementation (Table 3). Overall, there were nine international studies, and their defined lockdown periods ranged from 1 month to 12 months (1922). A heterogeneity in outcomes was noted; however, the majority reported a decline in preterm birth rates in either the extremely preterm or late preterm groups (20, 2327). There was also conflicting literature, that found no change in preterm births before and after NPI implementation in Spain, Sweden, and the United Kingdom (2830). The results and design of these studies are described in Table 3.

TABLE 3
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Table 3. Global comparison of preterm birth rates during coronavirus disease 2019 lockdown.

4. Discussion

In this study, we aimed to establish whether a correlation exists between preterm birth rates and the NPI period in Korea in 2020. Our findings showed that the preterm birth rate was increasing in the pre-NPI period, and this continued to increase after the implementation of such measures, suggesting an unclear impact of NPI implementation on the preterm birth rate.

Preterm births have been increasing in most developed countries, including South Korea. The percentage of preterm births in the United States increased from 9% in 1981 to 10.5% in 2021 (31, 32). Similar trends have also been observed in East Asian countries such as Taiwan and South Korea (33). Increased accessibility to medical services, increased number of survivors of chronic diseases which were previously fatal, and the development of assisted reproductive technologies have contributed to an overall increase in high-risk pregnancies such as twins or those of advanced maternal age (34).

The etiology of preterm delivery can be broadly categorized into three main groups: (1) spontaneous preterm labor; (2) maternal or fetal infections; and (3) premature preterm rupture of the membranes (9). Etiologies for preterm birth are generally unclear; however, environmental factors, such as viral infection and smoking exposure, are important risk factors for both ruptured and intact membrane preterm labor (35). NPI could change maternal environmental and habitual exposures, leading to a possible change in preterm birth rates. Bian et al. suggested that changes in the overall behavior of pregnant women during the pandemic might also have contributed to the above, as one-third of preterm births are iatrogenic (23, 36).

In contrast to our findings, many international data-based studies supported a negative association between NPI and preterm birth that were investigated up to the first quarter of 2020. In the United States, Gemmill et al. reported a decline in preterm birth rate during the pandemic, especially during the early and late 2020 (37). Oakley et al. observed a decrease in preterm births after NPI initiation until March 2020 in Norway, Sweden, and Denmark (8). Hedermann et al. also noted this phenomenon among the Danish population born before February 2020 (21). Bian et al. investigated births up to December 2020 in a single center study in Shanghai, China, and found a significant decrease in preterm birth rates (23). Kim et al., in a Korean single center study, reported a decrease in preterm labor after the NPI period (38). Serial works of published data that followed support similar associations of decreased preterm birth rates with the COVID-19 lockdown (Table 3).

4.1. Limitations

Owing to the lack of confirmed etiologies for preterm births, the decline in preterm births during pandemic lockdowns could simply be a coincidence. On the other hand, further investigating this potential association could lead to more effective measures to prevent preterm births. Cohort data from other countries with lockdown periods during the pandemic showed a potential decrease in preterm births during the pandemic; however, they only investigated a short period of time after the NPI, mostly the first three months of 2020. This contrasts with our study, with data collection over a large period, in which we found no significant relationships between NPI implementation and preterm birth. Another limitation to our study is the lack of individual patient data in our database. For instance, the database does not include information on the cause or type of preterm birth, such as an underlying maternal or fetal condition (“indicated preterm birth”) or preterm rupture of membranes or cervical dilatation (“spontaneous preterm birth”). Consequently, it is difficult to correlate NPI with a specific type of preterm birth. However, because NPI could affect the maternal or fetal environment in multifaceted ways, differentiating the type of birth in the analysis may not have necessarily provided additional helpful information. However, to improve the quality of the database, further collection of National Health Insurance Data and the Korean Developmental Survey Data is required in the future. As a result of these limitations, we cannot definitively conclude that a causal relationship between COVID-19 mitigation measures and preterm birth rate exists.

5. Conclusions

In conclusion, we were unable to establish a significant relationship between the NPI and pre-NPI preterm birth rates in South Korea. The overall South Korean preterm birth rate continues to increase, and this contributes to the country's disease burden. Future research should ideally aim to investigate whether there are more significant variables that could affect preterm birth rates, as well as how clinicians can reduce these factors and ultimately decrease the rate of preterm births.

Data availability statement

Birth registry data from the Korean Statistical Information Service (KOSIS) can be accessed from the KOSIS website. The raw data from the KOSIS is available at https://kosis.kr.

Ethics statement

The studies involving human participants were reviewed and approved by Yonsei University College of Medicine. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

Author contributions

JA and IJ had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version before submission. JL, ML, JP, IJ, MH, and JA contributed to the study's concept and design. JL, JP, ML, SL, JB, JK, IJ, and JA were involved in data acquisition, analysis, or interpretation. JL, JP, and JA drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. JL, JP, ML, MH, IJ, and JA performed the statistical analysis. JA and MP supervised the study and are the guarantors of this study. All authors contributed to the article and approved the submitted version.

Funding

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2022R1G1A100844111) and a faculty research grant from the Yonsei University College of Medicine (6-2021-0145). The study sponsor was not involved in the study design, analysis, and interpretation of data, the writing of the report, or the decision to submit the study results for publication.

Acknowledgments

The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2023.1140556/full#supplementary-material

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Keywords: COVID-19, lockdown, non-pharmaceutical intervention, prematurity, preterm birth

Citation: Lee JY, Park J, Lee M, Han M, Jung I, Lim SM, Baek JY, Kang J-M, Park MS and Ahn JG (2023) The impact of non-pharmaceutical interventions on premature births during the COVID-19 pandemic: a nationwide observational study in Korea. Front. Pediatr. 11:1140556. doi: 10.3389/fped.2023.1140556

Received: 9 January 2023; Accepted: 12 June 2023;
Published: 27 June 2023.

Edited by:

Valeriane Leroy, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by:

Balaji Govindaswami, Valley Medical Center Foundation, United States
Jennifer Zeitlin, Institut National de la Santé et de la Recherche Médicale (INSERM), France

© 2023 Lee, Park, Lee, Han, Jung, Lim, Baek, Kang, Park and Ahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jong Gyun Ahn amdhaG5AeXVocy5hYw==

These authors have contributed equally to this work and share last authorship

These authors have contributed equally to this work and share first authorship

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