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Maternal magnesium sulfate administration increases early-onset hyperkalemia risk in premature infants: A propensity score-matched, case-control study

Open AccessPublished:September 17, 2022DOI:https://doi.org/10.1016/j.pedneo.2022.06.011

      Abstract

      Background

      Magnesium sulfate (MgSO4) is a common substance administered to pregnant women with preeclampsia or eclampsia to prevent and treat seizures or gestational hypertension. This study aimed to evaluate whether administering maternal magnesium sulfate increased the risk of early-onset hyperkalemia in preterm infants.

      Methods

      This single-center, propensity score-matched, case–control study examined preterm infants born within 24–36 weeks of gestation using electronic medical records between January 2015 and June 2019, in the Saitama City Hospital, Japan. We categorized infants according to their maternal MgSO4 administration status. After adjusting for perinatal information and maternal treatment, we compared the incidence of the variables, including neonatal hyperkalemia, within 24 h after birth between the matched cohorts. All infants in Model 1 were analyzed separately, while in Model 2 infants with birth weight of less than 1000 g were excluded.

      Results

      We enrolled 421 infants (maternal MgSO4 group, 124; control group, 297). Ninety-five infants in Model 1 and 86 in Model 2 were matched in each group using propensity scores, respectively. In the matched cohorts of both models, infants in the maternal MgSO4 group had a higher hyperkalemia incidence than did those in the control group (42.1% vs. 7.4% in Model 1, 44.2% vs. 5.8% in Model 2, respectively; p < 0.0001). However, there was no relationship between the duration of intrauterine exposure to MgSO4 and early-onset neonatal hyperkalemia incidence.

      Conclusion

      Our study demonstrated that maternal MgSO4 administration, even for a short period of time, may increase the risk of early-onset hyperkalemia in preterm infants. Accordingly, physicians should be cautious when administering serum potassium to infants born to mothers administered MgSO4, especially within 24 h after birth.

      Key Words

      Abbreviations

      Cr
      creatinine
      EMRs
      electronic medical records
      FENa
      fractional sodium excretion
      GFR
      glomerular filtration rate
      K
      potassium
      MgSO4
      magnesium sulfate
      NOHK
      non-oliguric hyperkalemia

      1. Introduction

      Magnesium sulfate (MgSO4) is frequently administered to pregnant women with preeclampsia or eclampsia to prevent and treat seizures or gestational hypertension.
      • Berhan Y.
      • Berhan A.
      Should magnesium sulfate be administered to women with mild pre-eclampsia? A systematic review of published reports on eclampsia.
      Furthermore, the Ministry of Health, Labour and Welfare of Japan approved MgSO4 as a tocolytic agent covered by public health insurance. Hence, MgSO4 is also administered to pregnant women at risk of premature labor due to uterine contractions in Japan.
      MgSO4 also affects fetal neuroprotection, especially in preterm infants.
      • Doyle L.W.
      Antenatal magnesium sulfate and neuroprotection.
      ,
      • Edwards J.M.
      • Edwards L.E.
      • Swamy G.K.
      • Grotegut C.A.
      Effect of cord blood magnesium level at birth on non-neurologic neonatal outcomes.
      However, previous studies have indicated that intrauterine MgSO4 may increase the risk of early complications, such as hypotonia, respiratory failure, feeding intolerance, intraventricular hemorrhage, cardiac failure, and patent ductus arteriosus, in newborns.
      • Abbassi-Ghanavati M.
      • Alexander J.M.
      • McIntire D.D.
      • Savani R.C.
      • Leveno K.J.
      Neonatal effects of magnesium sulfate given to the mother.
      • del moral T.
      • Gonzalez-Quintero V.H.
      • Claure N.
      • Vanbuskirk S.
      • Bancalari E.
      Antenatal exposure to magnesium sulfate and the incidence of patent ductus arteriosus in extremely low birth weight infants.
      • Numoto S.
      • Kakita H.
      • Takeshita S.
      • Ueda H
      • Kondo T
      • Kurahashi H
      • et al.
      Effects of maternal magnesium sulfate treatment on newborns.
      Although many reports have examined the morbidity of infants born to mothers administered MgSO4, to the best of our knowledge, there are only three reports regarding this matter written in English,
      • Yada Y.
      • Ohkuchi A.
      • Otsuki K.
      • Goishi K
      • Takahashi M
      • Yonemoto N
      • et al.
      Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: a Japanese nationwide retrospective cohort study.
      • Tanaka K.
      • Mori H.
      • Sakamoto R.
      • Matsumoto S
      • Mitsubuchi H
      • Nakamura K
      • et al.
      Early-onset neonatal hyperkalemia associated with maternal hypermagnesemia: a case report.
      • Aoki K.
      • Akaba K.
      Characteristics of nonoliguric hyperkalemia in preterm infants: a case-control study in a single center.
      including one case report on the serum potassium (K) levels of premature newborns exposed to intrauterine MgSO4. Nevertheless, the effects of MgSO4 on newborns remain unclear. Therefore, we conducted a retrospective case–control study to determine whether antenatal MgSO4 administration increased the risk of early-onset neonatal hyperkalemia in preterm infants. Moreover, we used propensity score-matching to eliminate the effects of confounders and hypothesized the mechanisms of MgSO4 underlying the increase in the aforementioned risk by measuring serum and urine electrolyte samples.

      2. Materials and methods

      2.1 Study design and participants

      We screened the Saitama City Hospital's electronic medical records (EMRs) for infants born at 24–36 weeks of gestation between January 2015 and June 2019. We observed 997 premature infants who were hospitalized in the neonatal intensive care unit or stepdown neonatal units during the study period (Fig. 1). The exclusion criteria were as follows: 1) the presence of samples in which hemolysis was suspected or those with a lack of at least two-point blood sampling; as in most cases with only single serum potassium data-assessing blood samples, the samples were taken immediately after birth, and the subsequent course could not be followed (n = 502); 2) infants born in and transferred from another hospital after birth due to various missing perinatal data (n = 46); 3) congenital malformations, including chromosomal abnormalities, congenital anomalies of the kidneys and urinary tract, and complex congenital heart diseases (n = 9); 4) infants requiring thoracotomy or laparotomy (n = 3); 5) persistent severe acidemia and/or hypothermia (n = 3); 6) hyperinsulinic hypoglycemia (n = 1); 7) mortality within 28 days of birth (n = 2); and 8) infants deemed to be inappropriate due to other issues (n = 10). The infants were categorized into either the MgSO4 (n = 124) or control (n = 297) group, according to whether maternal MgSO4 was administered.
      Fig. 1
      Figure 1Flowchart representing infant selection and the exclusion processes in the study.

      2.2 Clinical evaluation of neonates and mothers

      Mothers in the MgSO4 group were administered a routine loading infusion of 4 g of MgSO4 over 30 min, followed by a maintenance dose rate of 1–2 g/h (equivalent to 0.2–0.4 g/h of Mg).
      • Yokoyama K.
      • Takahashi N.
      • Yada Y.
      • Koike Y
      • Kawamata R
      • Uehara R
      • et al.
      Prolonged maternal magnesium administration and bone metabolism in neonates.
      ,
      • Mitani M.
      • Matsuda Y.
      • Shimada E.
      Perinatal Research Network Group in Japan
      Short- and long-term outcomes in babies born after antenatal magnesium treatment.
      MgSO4 administration was at a maximum dose of 2 g/h and continued until at least 4 h before delivery.
      • Okusanya B.O.
      • Oladapo O.T.
      • Long Q.
      • Lumbiganon P
      • Carroli G
      • Qureshi Z
      • et al.
      Clinical pharmacokinetic properties of magnesium sulphate in women with pre-eclampsia and eclampsia.
      Neonatal hyperkalemia was defined as a serum K level of >6.0 mmol/L, with onset defined as the first time of recording such a measurement.
      • Aoki K.
      • Akaba K.
      Characteristics of nonoliguric hyperkalemia in preterm infants: a case-control study in a single center.
      ,
      • Wright C.
      • Posencheg M.
      • Seri I.
      • Evans J.
      Fluid, electrolyte, and acid–base balance.
      ,
      • Vemgal P.
      • Ohlsson A.
      Interventions for non-oliguric hyperkalaemia in preterm neonates.
      We considered the peak serum K level within 24 h of birth as the highest serum K level because hyperkalemia in infants born to mothers with MgSO4 was unexceptionally recognized within 24 h of birth in our preliminary study. From EMRs, we collected the perinatal information of the mothers and infants; the infants’ vital signs, clinical symptoms, and urine volume; and laboratory data, including maternal serum electrolytes and urinary electrolytes. Additionally, we measured maternal serum Mg levels directly before, and on the delivery day. Infant urine output was measured by weighing wet diapers. Data are expressed in g/kg/h.

      2.3 Statistical methods

      Continuous variables are presented as mean ± standard deviation or median (interquartile range, IQR), and categorized data are presented as n (%). We compared the means between both groups using Student's t-test for normal distributions and the Mann–Whitney U-test for non-normal distributions. The Shapiro–Wilk test was performed to analyze the normality distribution of each variable. Fisher's exact test was performed to compare categorical data.
      To overcome the bias regarding the different distribution of covariates among patients in both groups, we performed a propensity-score-matched analysis with 1:1 matching using a multiple logistic regression model to predict patient probability (Model 1). Propensity score matching was also performed on Model 2, excluding infants with a birth weight of less than 1000 g, since non-oliguric hyperkalemia is common in such infants.
      We matched each case to a control having the most similar calculated propensity score with a caliper width of 0.2. Propensity scores were calculated using the following five matching variables according to their p-values on a univariate analysis: hypertensive disorders of pregnancy, maternal ritodrine administration, antenatal steroid use, gestational age, and infant birth weight.
      Statistical analysis was performed using JMP version 15 (SAS Institute Inc., Cary, NC, USA). A p-value of <0.05 was considered statistically significant.

      3. Results

      Our patient selection flowchart is presented in Fig. 1. A total of 421 infants (MgSO4 group, 124; and control group, 297) were evaluated. In this study, MgSO4 was used to treat threatened premature labor or pregnancy-induced hypertension. The median duration of MgSO4 treatment was 6.0 (IQR, 1.3–15) days. Table 1 presents the baseline maternal characteristics of each group. We performed a 1:1 propensity score-matching analysis to eliminate baseline variations using the abovementioned five variables because the different backgrounds of the MgSO4 and control groups as observed on the univariate analysis may have affected outcomes. Finally, 95 neonates in Model 1 and 86 in Model 2 were selected to match each group (Table 2a and 2b). As expected, serum Mg levels were significantly higher in the MgSO4 group than in the control group (p < 0.0001). In the matching cohort, hyperkalemia was significantly more prevalent in the MgSO4 group than in the hyperkalemia group (42.1% vs. 7.4% in Model 1, 44.2% vs. 5.8% in Model 2, respectively; p < 0.0001). There were no significant differences in gestational age, birth weight, blood pressure, fractional sodium excretion (FENa), urine K+/creatinine (Cr), 5 min Apgar score, gender, respiratory distress, and urine output between groups.
      Table 1Baseline characteristics of the unmatched cohort.
      Unmatched cohort
      MgSO4 group (n = 124)%Control group (n = 297)%p Value
      Maternal age (years, median [IQR])33 [28–37]33 [30–36]0.52
      Multiparous5645.514950.50.35
      Multiple pregnancies3830.710535.70.35
      Gestational diabetes21.6155.10.10
      Hypertensive disorders of pregnancy3125.0227.4<0.0001
      Antenatal ritodrine use9475.819465.30.035
      Antenatal steroid use9576.610836.4<0.0001
      Caesarean delivery10080.722575.80.28
      Gestational age (weeks, median [IQR])33 [30–34]35 [34–36]<0.0001
      Birth weight (gram, median [IQR])1736 [1292–2135]2164 [1856–2403]<0.0001
      Duration of magnesium sulfate use (days, median [IQR])6 [1.25–15]
      Results are presented as numbers unless indicated otherwise. IQR, interquartile range.
      Table 2Neonatal clinical features of the matched cohort. (a) Model 1 (b) Model 2.
      (a)
      MgSO4 group (n = 95)%missing dataControl group (n = 95)%missing datap value
      Umbilical artery pH (mean ± SD)7.33 ± 0.0647.29 ± 0.12110.02
      Gestational age (weeks, mean ± SD)33 ± 3.1032 ± 3.200.71
      Birth weight (grams, mean ± SD)1836 ± 52101824 ± 62500.88
      Lowest systolic blood pressure within 24 h (mmHg, mean ± SD)54 ± 8.4451 ± 7.800.09
      Serum calcium (mg/dL, mean ± SD)9.0 ± 0.7419.3 ± 0.7300.0012
      Serum inorganic phosphorous (mg/dL, mean ± SD)6.2 ± 0.9885.4 ± 1.136<0.0001
      Serum alkaline phosphatase (U/L, mean ± SD)805 ± 3222651 ± 21230.0002
      Serum magnesium (mg/dL, mean ± SD)4.1 ± 1.2112.2 ± 0.917<0.0001
      Serum sodium (mmol/dL, mean ± SD)135.0 ± 4.74136.9 ± 3.410.002
      FENa (%, mean ± SD)1.83 ± 1.7541.10 ± 0.6850.18
      urine K/Cr (mmol/L/g・Cr, mean ± SD)1.34 ± 0.94551.60 ± 0.39850.40
      Caffeine administration within 24 h of birth2021.1099.600.04
      5 min Apgar <71717.801010.500.21
      Male gender5355.806164.200.30
      Respiratory distress6265.307275.800.15
      Urine output <1.0 (g/kg/hr)1718.111718.111.00
      Hyperkalemia (serum potassium >6.0 mmol/dL)4042.1077.40<0.0001
      (b)
      MgSO4 group (n = 86)%missing dataControl group (n = 86)%missing datap value
      Umbilical artery pH (mean ± SD)7.33 ± 0.0717.30 ± 0.0100.05
      Gestational age (weeks, mean ± SD)32.4 ± 3.0032.9 ± 2.900.34
      Birth weight (grams, mean ± SD)1804 ± 54701855 ± 56200.55
      Lowest systolic blood pressure within 24 h (mmHg, mean ± SD)53 ± 8.5052 ± 7.000.43
      Serum calcium (mg/dL, mean ± SD)9.0 ± 0.7509.4 ± 0.7130.005
      Serum inorganic phosphorous (mg/dL, mean ± SD)6.1 ± 1.0265.3 ± 1.0140.0001
      Serum alkaline phosphatase (U/L, mean ± SD)811 ± 3061652 ± 21030.0001
      Serum magnesium (mg/dL, mean ± SD)4.1 ± 1.292.2 ± 0.819<0.0001
      Serum sodium (mmol/dL, mean ± SD)134.6 ± 4.74136.8 ± 3.220.0006
      FENa (%, mean ± SD)1.8 ± 1.6501.1 ± 0.6750.20
      urine K/Cr (mmol/L/g・Cr, mean ± SD)1.3 ± 0.9551.5 ± 0.4850.47
      Caffeine administration within 24 h s of birth1517.401011.800.29
      5 min Apgar <71719.80121400.30
      Male gender4855.805665.100.21
      Respiratory distress5767.106575.600.22
      Urine output <1.0 (g/kg/hr)1821.211113.120.16
      Hyperkalemia (serum potassium >6.0 mmol/dL)3844.2055.80<0.0001
      Results are presented as numbers unless indicated otherwise.
      Considering the effects of cumulative Mg doses caused by long-term maternal use, hyperkalemia incidence was compared between infants born to mothers administered MgSO4 for >48 h and those born to mothers administered MgSO4 for <48 h. The incidence was similar between groups (Table 3).
      Table 3Relationship between the duration of intrauterine exposure to MgSO4 and early-onset neonatal hyperkalemia incidence.
      Infant serum K+ > 6.0Infant serum K+ < 6.0
      Maternal MgSO4 treatment duration <48 h14 (43.8)18 (56.3)32
      Maternal MgSO4 treatment duration >48 h36 (39.1)56 (60.9)92
      5074124
      p = 0.68.

      4. Discussion

      In this study, we demonstrated an association between maternal MgSO4 and early-onset neonatal hyperkalemia in preterm infants. The doses and injection methods of MgSO4, and the serum Mg levels of infants in this study were similar to those reported in previous studies.
      • Mittendorf R.
      • Dammann O.
      • Lee K.S.
      Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor.
      ,
      • Fenton T.R.
      • Lyon A.W.
      • Rose M.S.
      Cord blood calcium, phosphate, magnesium, and alkaline phosphatase gestational age-specific reference intervals for preterm infants.
      We collected all sample data within 24 h of birth because hyperkalemia in infants born to mothers receiving MgSO4 has been unexceptionally recognized within this time in our preliminary study.
      • Omori S.
      • Tominaga T.
      • Ikeda K.
      Early-onset hyperkalemia of the newborn exposed to antenatal magnesium sulfate.
      A propensity score-matching analysis revealed that maternal MgSO4 increased hyperkalemia risk (Table 2). To our knowledge, only three studies in the literature in English, including one case report,
      • Yada Y.
      • Ohkuchi A.
      • Otsuki K.
      • Goishi K
      • Takahashi M
      • Yonemoto N
      • et al.
      Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: a Japanese nationwide retrospective cohort study.
      • Tanaka K.
      • Mori H.
      • Sakamoto R.
      • Matsumoto S
      • Mitsubuchi H
      • Nakamura K
      • et al.
      Early-onset neonatal hyperkalemia associated with maternal hypermagnesemia: a case report.
      • Aoki K.
      • Akaba K.
      Characteristics of nonoliguric hyperkalemia in preterm infants: a case-control study in a single center.
      have studied this topic. Moreover, several published papers and abstracts of case series on this topic in the literature in Japanese have indicated a correlation between antenatal MgSO4 and neonatal hyperkalemia since Hosoda et al. reported the first case of antenatal MgSO4-induced neonatal hyperkalemia in 2008.
      • Hosoda N.
      • Uchida T.
      • Kyoba S.
      • Watanabe M.
      Twins with hyperkalemia and hypotonia born from mother with administration of magnesium sulfate during pregnancy.
      Furthermore, the case–control study by Aoki et al. comparing premature infants born before 32 weeks of gestation with non-oliguric hyperkalemia (NOHK) and those without NOHK confirmed that intrauterine MgSO4 exposure, but not maternal ritodrine, was an independent risk factor for NOHK.
      • Aoki K.
      • Akaba K.
      Characteristics of nonoliguric hyperkalemia in preterm infants: a case-control study in a single center.
      Recently, Yada et al. have reported in a retrospective cohort study using a nationwide obstetrical database that maternal MgSO4 together with ritodrine has a synergic effect associated with neonatal hyperkalemia after birth in mid-to late-preterm infants born at 32–36 weeks of gestation, concluding that hyperkalemia incidence in women receiving MgSO4 only was not different from those receiving ritodrine only.
      • Yada Y.
      • Ohkuchi A.
      • Otsuki K.
      • Goishi K
      • Takahashi M
      • Yonemoto N
      • et al.
      Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: a Japanese nationwide retrospective cohort study.
      Our study initially targeted all infants born at 24–36 weeks of gestation (Model 1). Additionally, we performed an analysis that focused on infants with birth weights of 1000 g or more as Model 2. This was done because a wide range of variations, from extremely premature infants to near-term infants existed in the complete selected infant population, and generally, NOHK is not uncommon in extremely low birth weight infants. However, both models demonstrated that maternal MgSO4 increased the risk of neonatal hyperkalemia after birth.
      Our report also provides valuable data to hypothesize about the mechanisms of maternal MgSO4 underlying newborn hyperkalemia incidence. To the best of our knowledge, this is the first report to analyze serum and urine samples. Currently, the mechanisms of maternal MgSO4 underlying hyperkalemia incidence occurrence have not yet been fully elucidated. However, three hypotheses that for this mechanism have been proposed.
      • Tanaka K.
      • Mori H.
      • Sakamoto R.
      • Matsumoto S
      • Mitsubuchi H
      • Nakamura K
      • et al.
      Early-onset neonatal hyperkalemia associated with maternal hypermagnesemia: a case report.
      ,
      • Aoki K.
      • Akaba K.
      Characteristics of nonoliguric hyperkalemia in preterm infants: a case-control study in a single center.
      ,
      • Gulczynska E.
      • Gadzinowski J.
      • Wilczynski J.
      • Zylinska L.
      Prenatal MgSO4 treatment modifies the erythrocyte band 3 in preterm neonates.
      First, renal K excretion decreases when the glomerular filtration rate (GFR) decreases. Second, distal tubular K excretion is compromised, and renal K+ clearance is low in newborns, even when corrected for low GFR. The third hypothesis is immature activity of Na/K-ATPase in cell membranes, which causes K to shift from the intracellular to the extracellular space. Furthermore, maternal serum Mg easily passes through the placenta, followed by fetal hypermagnesemia, possibly inhibiting the influx of K into cells by inhibiting Na/K-ATPase. Moreover, in a rabbit study, the mean activity of Na/K-ATPase of the proximal convoluted tubules during the first week of life has been reported to be one-third of the mean adult value.
      • Schwartz G.J.
      • Evan A.P.
      Development of solute transport in rabbit proximal tubule. III. Na-K-ATPase activity.
      Bara et al. have shown that Mg is a modulator of the Na and K ion transportation systems in numerous tissues, thereby revealing that extracellular Mg inhibits Na/K-ATPase at high concentration.
      • Bara M.
      • Guiet-Bara A.
      • Durlach J.
      Regulation of sodium and potassium pathways by magnesium in cell membranes.
      However, we did not observe any significant differences in urine output and urine K/Cr between the MgSO4 and control groups in this study. This result may exclude the possibility of the first and second aforementioned mechanisms.
      The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support the short-term use of MgSO4 (usually ≤48 h).
      • Yada Y.
      • Ohkuchi A.
      • Otsuki K.
      • Goishi K
      • Takahashi M
      • Yonemoto N
      • et al.
      Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: a Japanese nationwide retrospective cohort study.
      ,
      • Elliott J.P.
      • Morrison J.C.
      • Bofill J.A.
      Risks and benefits of magnesium sulfate tocolysis in preterm labor (PTL).
      The median duration of maternal MgSO4 treatment was 6 days, since the leading societies for obstetrics in Japan have allowed long-term tocolysis unlike other countries. Aoki et al. suggested a dose-dependent relationship between maternal MgSO4 administration and newborn hyperkalemia.
      • Aoki K.
      • Matsuuchi S.
      • Akaba K.
      Effects of antenatal magnesium sulfate on early neonatal hyperkalemia in preterm infants.
      In this study, we analyzed data by dividing the patients into two groups, MgSO4 treatment for <48 h and MgSO4 treatment for >48 h groups (Table 3). Contradicting the study of Aoki et al., we did not observe any relationship between the duration of intrauterine exposure to MgSO4 and the early neonatal hyperkalemia incidence, even though the treatment time in our study was similar to theirs. Although the reasons behind this difference are currently unclear, it should be noted that neonatal hyperkalemia was caused even by short-term MgSO4 treatment. This may be clinically important since the short-term use of maternal MgSO4 is widely administered for fetal neuroprotection, prevention or treatment of seizures, preeclampsia or eclampsia.
      • Sentilhes L.
      • Sénat M.V.
      • Ancel P.Y.
      • Azria E
      • Benoist G
      • Blanc J
      • et al.
      Prevention of spontaneous preterm birth: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF).
      This study has several limitations. First, it was a single-center, retrospective, case–control study design, meaning that there is a possibility of selection bias; nevertheless, we adjusted for several confounders using the propensity score-matching. Furthermore, due to the retrospective nature of this study, the time to obtain clinical samples varied from patient to patient, and at least two blood samples were required. Second, we were unable to collect the urine laboratory data of all infants, which resulted in missing urine outputs, FENa, and urine K/Cr values, which had not been analyzed in previous reports.
      Maternal administration of MgSO4 is a risk factor for early neonatal hyperkalemia. This study showed that this phenomenon occurred following both the short- and long-term administration of maternal MgSO4. Therefore, medical professionals should pay attention to the serum K of infants born to mothers receiving MgSO4, especially within 24 h of birth.

      Statement of ethics

      This study protocol was approved by the ethics committee of the Saitama City Hospital, approval number A2811.

      Funding sources

      This study received no specific grant from any funding agency.

      Author contributions

      S.O-S. and K.I. designed the study. S.O-S. performed statistical analyses, and K.I. and T.T. checked the statistical results. K.I. supervised the study. All authors reviewed the manuscript and played an important role in the critical revision of the manuscript.

      Data availability statement

      The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

      Declaration of competing interest

      The authors have no conflicts of interest to declare.

      Acknowledgements

      We express our deep gratitude to Dr. Yasunori Sato, Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, for his advice on statistical processing.

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