key: cord-0916609-nfpzcago
authors: Crispi, F.; Crovetto, F.; Larroya, M.; Camacho, M.; Sibila, O.; Badia, J. R.; Lopez, M.; Vellve, K.; Garcia, F.; Trilla, A.; Faner, R.; Blanco, I.; Borras, R.; Agusti, A.; Gratacos, E.
title: LOW BIRTH WEIGHT AS A RISK FACTOR FOR SEVERE COVID-19 IN ADULTS
date: 2020-09-15
journal: nan
DOI: 10.1101/2020.09.14.20193920
sha: 65a07985aa94ff370c40f3d844dc91274646d706
doc_id: 916609
cord_uid: nfpzcago

The identification of factors predisposing to severe COVID-19 in young adults remains partially characterized. Low birth weight (LBW) alters cardiovascular and lung development and predisposes to adult disease. We hypothesized that LBW is a risk factor for severe COVID-19 in non-elderly subjects. We analyzed a prospective cohort of 397 patients (18-70y) with laboratory-confirmed SARS-CoV-2 infection attended in a tertiary hospital, where 15% required admission to Intensive Care Unit (ICU). Perinatal and current potentially predictive variables were obtained from all patients and LBW was defined as birth weight [≤]2,500 g. Age (adjusted OR (aOR) 1.04 [1-1.07], P=0.012), male sex (aOR 3.39 [1.72-6.67], P<0.001), hypertension (aOR 3.37 [1.69-6.72], P=0.001), and LBW (aOR 3.61 [1.55-8.43], P=0.003) independently predicted admission to ICU. The area under the receiver-operating characteristics curve (AUC) of this model was 0.79 [95% CI, 0.74-0.85], with positive and negative predictive values of 29.1% and 97.6% respectively. Results were reproduced in an independent cohort, from a web-based survey in 1,822 subjects who self-reported laboratory-positive SARS-CoV-2 infection, where 46 patients (2.5%) needed ICU admission (AUC 0.74 [95% CI 0.68-0.81]). LBW seems to be an independent risk factor for severe COVID-19 in non-elderly adults and might improve the performance of risk stratification algorithms.

COVID-19 is a mild or asymptomatic condition in the majority of patients, but in up to 1-2% it may result in severe disease and death. 1, 2 Older age, male sex and coexisting conditions are the main risk factors described so far for severe COVID-19 disease. [3] [4] [5] [6] [7] [8] However, a small proportion of young and apparently healthy adults may eventually require critical care. There is a need for comprehensive models that identify factors associated to the risk of severe forms of COVID-19. 9 The association between low birth weight (LBW) and adult health has long been recognized. [10] [11] [12] LBW, defined as ≤ 2,500 g, [13] [14] can result from fetal growth restriction, prematurity or both. 13 Fetal growth restriction has been associated with increased cardiovascular mortality, 10, 15 lower lung functional capacity 16-18 and increased respiratory morbidity [18] [19] in adulthood. Likewise, prematurity has been described as a risk factor for suboptimal cardiovascular 20 and lung 21 development and a greater predisposition to heart failure 22 and lung disease 23 later in life. For studies in adults, birth weight is an accessible and robust surrogate for fetal growth restriction and preterm births, and a strong predictor of short and long-term morbidity. 24 From the above observations, we hypothesized that LBW could increase the risk of developing severe illness in non-elderly adults with COVID-19. To test this hypothesis, we designed a prospective study in confirmed COVID-19 patients (18-70 years) admitted to our institution, a public, tertiary, referral, university hospital in Spain (development dataset) and validated the model in an independent cohort of self-reported laboratory-confirmed COVID-19 subjects recruited through a web-based survey (validation dataset).

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The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.14.20193920 doi: medRxiv preprint Table 1 displays the characteristics of the 337 non-critically ill patients (home hospitalization (n=98) or in hospital (n=239)) with those treated in the ICU (n=60).

The latter were older, more frequently males, had a higher body mass index (BMI) and a higher prevalence of hypertension. Of note, they were also born with LBW (18.3 vs. 9.5%, p=0.041) and suffered fetal growth restriction (25 vs. 14.8%, p=0.043) more often. Individuals born with LBW had a higher probability for ICU admission as compared with those with normal birth weight ( Figure 2 ). P=0.003) remained independent predictors of ICU. As shown in Figure 3 (left), the area under the receiver-operating characteristics curve (AUC) for predicting ICU admission was 0.79 (95% CI, 0.74-0.85). The model had a sensitivity of 91.7%, specificity of 60.2%, . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.14.20193920 doi: medRxiv preprint positive predictive value (PPV) of 29.1% and negative predictive value (NPV) of 97.6% (Table 3) . Figure 1 (right panel) presents the CONSORT diagram of the validation dataset. We received 9,320 responses of subjects aged 18 to 70 years who referred symptoms suggestive of COVID-19. Among them, 1,822 self-reported COVID-19 confirmed by RT-PCR. A total of 1,215 of them (67%) reported mild symptoms and did not require hospital admission whereas 607 (33%) were hospitalized of whom 46 (8%) patients required ICU admission (30 of them (65% of ICU patients) were mechanically ventilated, and one male patient (2% of ICU patients) died at the age 68 years as reported later by her daughter. Table 4 shows the characteristics of the 1,776 non-critically ill patients (treated at home (n=1,215) or in hospital (n=561)) with those treated in the ICU (n=46). Like we observed in the developing cohort, ICU patients in the validation dataset were older, more frequently males, had a higher BMI and a higher prevalence of hypertension. Importantly, again, they were born with LBW (19.6 vs. 7.3%, p=0.006) and suffered fetal growth restriction (26.1 vs. 12.4%, p=0.010) more often. In this validation dataset, the prevalence of prematurity was also higher in ICU patients (23.9 vs. 10.9%, p=0.011).

The model obtained in development dataset was applied to the validation dataset, obtaining an AUC of 0.74 (95% CI 0.68-0.81) (Figure 2 , right panel), with a sensitivity of 73.9%, specificity of 67.3%, PPV of 5.5% and NPV of 99% (Table 3) .

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This study provides evidence that recording birth weight might improve the prognostic stratification of COVID-19 in non-elder patients. Most young patients present mild forms of COVID-19, but a small proportion might require admission to ICU for severe complications, [3] [4] [5] [6] [7] [8] which is clearly associated to non-obvious predisposing factors. Early interventions in COVID-19 have demonstrated to reduce mortality. 4, 6 Consequently, the identification of predisposing factors -particularly in a priori non high-risk subjects-might allow early therapeutic measures eventually preventing serious evolution to serious illness.

In this study we evaluated an innovative approach by studying early life risk factors not usually taken into account in current clinical practices. Birth weight is one of the most universally recorded information for any given individual and self-recalled birth weight has demonstrated to be a reliable information, particularly in subjects born after the 1960s. 41 If confirmed that LBW identifies high risk for complicated COVID-19, this should be included in initial assessment of non-elder infected subjects and would offer opportunities for early interventions to prevent complications.

Despite the large number of studies on prognostic factors for severe COVID-19, 3-8,25-36 to our knowledge no previous study has investigated the predictive role of early life events as a risk factor for severe COVID-19 in adulthood. Results confirmed our working hypothesis, which was aligned with a long-standing research line in this field. [11] [12] [18] [19] 37 Besides, results confirmed previous studies showing a strong predictive value for severe COVID-19 of older age, male sex and coexisting conditions such as hypertension. [3] [4] [5] [6] [7] [8] [25] [26] [27] [28] [29] [30] [31] The fact that we studied non-elderly adults (≤70 years) may have limited the identification of significant . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.14.20193920 doi: medRxiv preprint associations with other reported coexisting conditions such as chronic lung disease, 2,6-8,27 diabetes, [2] [3] [4] [5] 7, 8, [25] [26] 30 ,32 obesity 8,31,33 or cancer. 3, 34 Current or previous smoking status 35 and chronic treatment with ACE inhibitors 36 were not associated with COVID-19 severity in our dataset.

Our results show that LBW is an independent risk factor for severe COVID-19 in adulthood. This finding is consistent with previous epidemiological and experimental studies supporting the developmental origin of adult diseases. Adverse in utero environment induces permanent changes in the structure, function and metabolism of the developing fetal organs. Most developmental changes of early life persist in the long term which leads to a greater risk of disease in adulthood. 10, 11 It is suggested that fetal adaptation to perinatal events represents a 'first hit' leading to latent susceptibility, which combined with a 'second hit' later in life could increase the risk for adult diseases. 10, 11 This notion has been consistently demonstrated in experimental research, 40 but evidence in humans is limited. The COVID-19 pandemic represents a unique opportunity to study the response of a significant number of individuals born LBW to a specific and well-defined stressor.

LBW has been consistently associated with increased adult cardiovascular mortality, hypertension, metabolic syndrome, diabetes and lung morbidity. 10,11,12,15-21 LBW can be a result of being born too small -fetal growth restriction-and/or too early -prematurity-.

Fetal growth restriction is caused by placental insufficiency leading to a sustained reduction in fetal oxygen and nutrient supply. 11 This triggers an adaptive fetal response including cardiovascular remodeling, 12,36 increased blood pressure, 12 altered lipoprotein profile, lost of nephrons, and disturbed pulmonary alveolarization and vascular growth. 11 In . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.14.20193920 doi: medRxiv preprint prematurity, key developmental stages have to take place ex utero in non-physiological conditions 39 leading to cardiovascular hypertrophy and impaired lung development, insulin sensitivity and bone density. [20] [21] [22] 39 

This study has some strengths and limitations that merit comment. Among the strengths, we prospectively collected information spanning the full COVID-19 clinical spectrum, from mild to hospitalized and ICU patients. Likewise, we validated our observations in an independent dataset. Finally, we included only non-elderly subjects (<70 years) to avoid the potential confounding effect of age-related comorbidities. The study sample size was too small to assess the predictive value of LBW across age ranges. We acknowledge that the evidence here presented should be validated in another prospective hospital cohort. We opted for an online survey to shorten validation time. We acknowledge also a potential selection bias since there were virtually no deaths in our study population. Firstly, mortality rate for COVID-19 was very low in our hospital (8%, 194/2,425) with most cases occurring in subjects >70 years-old. Secondly, we tried to contact all COVID-19 patients identified in the EMRs, but a few very severe cases were directly intubated and died preventing the interview for the study. Finally, we acknowledge the potential inaccuracy of the perinatal data obtained by interview or online survey. However, self-reported birth weight has demonstrated to be a good surrogate of adverse in utero environment, particularly in nonelderly subjects. 41

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The copyright holder for this this version posted September 15, 2020. .

Low birth weight increases the risk of severe COVID-19 in non-elderly adults. This new information further supports the importance of early life events in adult diseases and should be considered in future risk stratification algorithms.

Prospective observational cohort that included non-elderly adults (aged 18 to 70 years) pneumonia) and therapeutic management while in hospital followed the in-house protocols.

The primary outcome of the study was admission to the ICU, which was determined by the attending physician on a patient by patient basis following standard clinical assessment criteria. 42 Follow-up time was censored on May 25, 2020 so that each patient had at least 30 days of observation. The study was approved by the Ethical Committee of our institution (HCB/2020/0353) and informed consent was obtained from all patients.

Cases were identified by daily review of hospital attendance logs in electronic medical records. Likewise, demographics, smoking exposure, coexisting conditions, treatment received during the last two weeks before hospitalization, need for ICU admission, complications or death during the clinical course, and therapeutic management . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

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interventions were obtained by reviewing electronic medical records. On the other hand, perinatal (birth weight and gestational age at delivery) and childhood ("asthma" or other respiratory disease in childhood) data were obtained by a face-to-face or telephone interview. Birth weight centiles were calculated adjusted by gender and gestational age at birth according to local standards. 43 LBW was defined as birth weight equal or below 2,500g. 14 Fetal growth restriction was defined as a birth weight below the 10 th centile for gestational age 44 and preterm delivery as born before 37 weeks of gestation. 45

To validate externally the performance of the prognostic algorithm created by the development cohort, we collected independent data from self-selected volunteers who 

Results are presented as counts (percentage) or mean (SD) as appropriate. Variables with p<0.05 on univariate analyses were entered in the multivariate logistic regression analysis . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.14.20193920 doi: medRxiv preprint to determine independent risk factors for ICU admission. A forward stepwise selection algorithm was applied to select the final model in the development dataset. Odds ratio and 95% confidence interval [95%CI] were calculated. Hosmer and Lemeshow test were used to assess the goodness of fit of the final model. 46 Analysis of the Receiver Operating Curve (ROC) was used to evaluate the predictive performance of the model in the development datasets and the optimal cut-off was computed using Youden criteria. 47 The model determined in the development dataset was used to predict ICU admission in the validation dataset and we report the statistical parameters for development and validation. All pvalues are 2-sided and considered statistically significant if <0.05. Data were analysed with SPSS v26 and R software version 3.6.2 (R project for statistical computing, Vienna, Austria).

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Authors thank all participants in the study for their willingness to contribute to medical research as well as all the health workers who fought the COVID-19 pandemia.

This research was partially supported by "La Caixa" Foundation. The funding source had no involvement in study design, in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication.

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The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.14.20193920 doi: medRxiv preprint §According to the logistic regression model, criteria positive is defined as a probability greater than 10.554%

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