Abstract
Introduction
Methods
Findings
Keywords
Introduction
Methods
The Lives Saved Tool. Available at: https://www.livessavedtool.org/. Accessed September 17, 2021.
WHO, UNICEF. Global breastfeeding scorecard | Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-scorecard. Accessed July 19, 2021.
Findings and Discussion
Health Benefits of Breastfeeding

Overall Mortality
Health Benefits During Infancy and early childhood
Age | Outcome | Source | Breastfeeding Intervention | Intervention Timing (Age of Infant) | Reference | Standardized Effect Size (95% CI | Population | No. of Studies | |
---|---|---|---|---|---|---|---|---|---|
Mortality | |||||||||
0-6 mo | Mortality, all cause | Sankar et al, 9 2015 | Exclusive | <6 mo | None | RR = 0.07 (0.03 to 0.17) | LMIC | 2 | |
Partial | RR = 0.36 (0.21 to 0.62) | LMIC | 3 | ||||||
Predominant | RR = 0.68 (0.53 to 0.88) | LMIC | 3 | ||||||
Mortality, infection related | Sankar et al, 9 2015 | Exclusive | <6 mo | None | RR = 0.12 (0.05 to 0.32) | LMIC | 2 | ||
Partial | RR = 0.22 (0.15 to 0.35) | LMIC | 3 | ||||||
Predominant | RR = 0.59 (0.41 to 0.85) | LMIC | 3 | ||||||
6-23 mo | Mortality, all cause | Sankar et al, 9 2015 | Continued | 12-<24 mo | None | RR = 0.51 (0.38 to 0.69) | LMIC | 9 | |
Mortality, infection related | Sankar et al, 9 2015 | Continued | 12-<24 mo | None | RR = 0.48 (0.39 to 0.60) | LMIC | 9 | ||
<5 y | Mortality, all cause | Pretorius et al, 10 2020 | Exclusive | <6 mo | Nonexclusive | RR = 0.18 (0.07 to 0.47) | SSA | 6 | |
<5 y | Mortality, all cause | Pretorius et al, 10 2020 | Early | <1 h | Delayed | RR = 0.31 (0.23 to 0.41) | SSA | 5 | |
Diarrhea | |||||||||
0-6 mo | Diarrhea, incidence | Horta et al, 14 2013 | Exclusive | <6 mo | None | RR = 0.20 (0.13 to 0.29) | HIC/LMIC | 11 | |
Partial | RR = 0.51 (0.37 to 0.70) | HIC/LMIC | 11 | ||||||
Predominant | RR = 0.44 (0.38 to 0.50) | HIC/LMIC | 11 | ||||||
Diarrhea, hospitalization | Horta et al, 14 2013 | Exclusive | <6 mo | None | RR = 0.09 (0.02 to 0.44) | HIC/LMIC | 9 | ||
Partial | RR = 0.20 (0.10 to 0.41) | HIC/LMIC | 9 | ||||||
Predominant | RR = 0.67 (0.23 to 1.98) | HIC/LMIC | 9 | ||||||
0-5 mo | Diarrhea, mortality | Lamberti et al, 11 2011 | Exclusive | <6 mo | None | RR = 0.10 (0.03 to 0.36) | LMIC | 3 | |
Partial | RR = 0.22 (0.09 to 0.56) | LMIC | 3 | ||||||
Predominant | RR = 0.44 (0.17 to 1.18) | LMIC | 3 | ||||||
6-23 mo | Diarrhea, mortality | Lamberti et al, 11 2011 | Continued | 12-23 mo | None | RR = 0.24 (0.13 to 0.45) | LMIC | 3 | |
Respiratory infection | |||||||||
<6 mo | Pneumonia, hospitalization | Horta et al, 14 2013 | Any | <6 mo | None | RR = 0.41 (0.25 to 0.69) | HIC/LMIC | 4 | |
<5 y | Pneumonia, incidence | Horta et al, 14 2013 | Any | Varied | None | RR = 0.68 (0.60 to 0.77) | HIC/LMIC | 18 | |
<5 y | Pneumonia, incidence | Alamneh, 76 2020
Magnitude and Predictors of Pneumonia among Under-Five Children in Ethiopia: A Systematic Review and Meta-Analysis. J Environ Public Health. 2020; https://doi.org/10.1155/2020/1606783 | Exclusive | <6 mo | None | OR = 0.41 (0.21 to 0.55) | Ethiopia | 8 | |
<5 y | Pneumonia, hospitalization | Horta et al, 14 2013 | Any | Varied | None | RR = 0.33 (0.24 to 0.46) | HIC/LMIC | 18 | |
<5 y | Pneumonia, mortality | Horta et al, 14 2013 | Any | Varied | None | RR = 0.30 (0.16 to 0.56) | HIC/LMIC | 4 | |
Intelligence | |||||||||
1-15 y | Intelligence scores | Horta et al, 17 ,18 2015 | Any | Varied | None to <6 mo | MD = 3.44 (2.30 to 4.58) | HIC/LMIC | 18 | |
Any | Varied | MD = 1.88 (−0.07 to 3.83) | LMIC | 2 | |||||
Noncommunicable disease | |||||||||
Varied | Systolic blood pressure | Horta et al, 17 ,18 2015 | More | Varied | Less or none | MD = −0.30 mm Hg (−1.02 to 0.43) | LMIC | 9 | |
Varied | Diastolic blood pressure | Horta et al, 17 ,18 2015 | More | Varied | Less or none | MD = 0.17 mm Hg (−0.12 to 0.45) | LMIC | 8 | |
Varied | Total cholesterol | Horta et al, 17 ,18 2015 | More | Varied | Less or none | MD = −0.09 mmol/L (-0.25-0.08) | LMIC | 7 | |
Varied | Overweight or obesity | Horta et al, 17 ,18 2015 | More | Varied | Less or none | OR = 0.76 (0.67 to 0.85) | LMIC | 34 | |
Varied | Type 2 diabetes mellitus | Horta et al, 17 ,18 2015 | Any or continued | Varied | None to <6 mo | OR = 0.65 (0.49 to 0.86) | HIC/LMIC | 11 | |
Maternal illness | |||||||||
Breast cancer | Unar-Munguía et al, 22 2018 | Any | Varied | None | SRR = 0.69 (0.40 to 1.18) | HIC/LMIC | 11 | ||
Exclusive | <6 mo | None | SRR = 0.72 (0.58 to 0.90) | HIC/LMIC | 6 | ||||
Chowdhury, 77 2015 | Any | Varied | None | OR = 0.78 (0.87 to 0.96) | HIC/LMIC | 98 | |||
Any | Varied | None | OR = 0.66 (0.56 to 0.77) | LMIC | 26 | ||||
Continued | >12 mo | None | OR = 0.74 (0.69 to 0.79) | HIC/LMIC | 50 | ||||
Ovarian cancer | Chowdhury, 77 2015 | Any | Varied | None | OR = 0.70 (0.64 to 0.77) | HIC/LMIC | 41 | ||
Any | Varied | None | OR = 0.48 (0.29 to 0.77) | LMIC | 6 | ||||
Continued | >12 mo | None | OR = 0.63 (0.56 to 0.71) | HIC/LMIC | 29 | ||||
Type 2 diabetes mellitus | Rameez, 78 2019 | Continued | >12 mo | Truncated | OR = 0.70 (0.62 to 0.78) | HIC | 4 | ||
Hypertension | Rameez, 78 2019 | Continued | >12 mo | Truncated | OR = 0.87 (0.78 to 0.97) | HIC | 4 |
Health Benefits During Childhood and Adulthood
Maternal Health Benefits
Global Breastfeeding Epidemiology: Indicators, Trends, and Targets

WHO, UNICEF. Global breastfeeding scorecard | Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-scorecard. Accessed July 19, 2021.
Global Indicator 1: Early Initiation of Breastfeeding Within 1 Hour of Birth
Global Indicator 2: Exclusive Breastfeeding Up to 6 Months of Age
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.

WHO, UNICEF. Global breastfeeding scorecard | Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-scorecard. Accessed July 19, 2021.
https://www.cdc.gov/breastfeeding/data/reportcard.htm, 2021. [Acessed 01 September 2021].
Global Indicator 3: Continued Breastfeeding Up to 2 Years of Age
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.

Global Indicator 4: Ever Breastfed
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
Global Indicator 5: Exclusively Breastfed for the First 2 Days After Birth
Global Indicator 6: Mixed Feeding Up to 6 Months of Age
Special Considerations for Breastfeeding
HIV
- Flynn PM
- Taha TE
- Cababasay M
- et al.
Small Infants
Breastfeeding in Difficult Circumstances
Breastfeeding and COVID-19
Breastfeeding Interventions
Health System, Hospital, and Health Worker Support
Fore H, Adhanom Ghebreyesus T. WHO/UNICEF statement on the 40th anniversary of the international code of marketing breastmilk substitutes. 2021. Available at: https://www.who.int/news/item/21-05-2021-WHO-UNICEF-statement-on-the-40th-anniversary-of-the-international-code-of-marketing-breastmilk-substitutes. Accessed August 10, 2021.
Peer and Community Support
Workplace Support
International Labor Organization. Convention C183 - Maternity Protection Convention, 2000 (No. 183). 2000. Available at: https://www.ilo.org/dyn/normlex/en/f?p=NORMLEXPUB:12100:0::NO::P12100_ILO_CODE:C183. Accessed August 9, 2021.
Maternity protection: Compliance with international labour standards. Available at: https://www.who.int/data/nutrition/nlis/info/maternity-protection-compliance-with-international-labour-standards. Accessed August 10, 2021.
International Labor Organization. Convention C183 - Maternity Protection Convention, 2000 (No. 183). 2000. Available at: https://www.ilo.org/dyn/normlex/en/f?p=NORMLEXPUB:12100:0::NO::P12100_ILO_CODE:C183. Accessed August 9, 2021.
Advocacy: Global Breastfeeding Collective
WHO, UNICEF. A global breastfeeding call to action | UNICEF Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-call-action. Accessed April 19, 2021.
WHO, UNICEF. Global breastfeeding scorecard | Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-scorecard. Accessed July 19, 2021.
WHO, UNICEF. Global breastfeeding scorecard | Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-scorecard. Accessed July 19, 2021.
Global Impact: Millions of Lives Could Be Saved If Goals Are Met
The World Bank Group. GDP (current US$) | Data. 2021. Available at: https://data.worldbank.org/indicator/NY.GDP.MKTP.CD. Accessed August 16, 2021.
Conclusions
CASE STUDIES
Yemen
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
Rwanda
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
Disclosure
Acknowledgments
References
- Infant and young child feeding.PINSA. 2016; 82: 1507-1517
- The United Nations Inter-agency Group for Child Mortality Estimation.Levels And Trends In Child Mortality: Report 2020. UN IGME. 2020: 50
- Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect.Lancet. 2016; 387: 475-490
The Lives Saved Tool. Available at: https://www.livessavedtool.org/. Accessed September 17, 2021.
- Saving newborn lives in Asia and Africa: cost and impact of phased scale-up of interventions within the continuum of care.Health Policy Plan. 2008; 23: 101-117
- CHERG Review Groups on Intervention Effects. Standards for CHERG reviews of intervention effects on child survival.Int. J. Epidemiol. 2010; 39: i21-i31
- Indicators for Assessing Infant and Young Child Feeding Practices: Definitions and Measurement Methods.WHO and UNICEF, Geneva2021
WHO, UNICEF. Global breastfeeding scorecard | Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-scorecard. Accessed July 19, 2021.
- Optimal breastfeeding practices and infant and child mortality: a systematic review and meta-analysis.Acta Paediatr. 2015; 104: 3-13
- Impact of breastfeeding on mortality in sub-Saharan Africa: a systematic review, meta-analysis, and cost-evaluation.Eur. J. Pediatr. 2020; 179: 1213-1225
- Breastfeeding and the risk for diarrhea morbidity and mortality.BMC Public Health. 2011; 11: S15
- The role of maternal breast milk in preventing infantile diarrhea in the developing world.Curr. Trop. Med. Rep. 2014; 1: 97-105
- Diarrhoeal disease.Clin. Med. 2011; 11: 488-491
- A systematic review on the benefits of breastfeeding on diarrhoea and pneumonia mortality.WHO Library Cataloguing-in-Publication Data. 2013;
- Implementation of Steps 1-9 to Successful Breastfeeding Reduces the Frequency of Mild and Severe Episodes of Diarrhea and Respiratory Tract Infection Among 0-6 Month Infants in Democratic Republic of Congo. Matern.Child Health J. 2018; 22: 762-771
- Comparison of incidence of acute respiratory infection in exclusively breastfed infants and not exclusively breastfed infants from 61 to 180 days of age: A prospective cohort study.J Family Med Prim Care. 2020; 9: 2823-2829
- Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil.Lancet Glob. Health. 2015; 3: e199-e205
- Long-term consequences of breastfeeding on cholesterol, obesity, systolic blood pressure and type 2 diabetes: a systematic review and meta-analysis.Acta Paediatr. 2015; 104: 30-37
- Breastfeeding and child cognitive development: new evidence from a large randomized trial.Arch. Gen. Psychiatry. 2008; 65: 578-584
- The protective effects of breastfeeding on chronic non-communicable diseases in adulthood: A review of evidence.Adv. Biomed. Res. 2014; 3: 3
- Association of exclusive breastfeeding with risk of obesity in childhood and early adulthood.Breastfeed Med. 2018 Nov 9; ([Epub ahead of print])
- Breastfeeding Mode and Risk of Breast Cancer: A Dose-Response Meta-Analysis.J Hum Lact. 2017; 33: 422-434
- Lactation and incidence of premenopausal breast cancer: a longitudinal study.Arch. Intern. Med. 2009; 169: 1364-1371
- Association between breastfeeding and ovarian cancer risk.JAMA Oncol. 2020; 6e200421
- The Extension of the 2025 Maternal, Infant and Young Child Nutrition Targets to 2030 - UNICEF DATA.WHO/UNICEF, 2021
- Delayed breastfeeding initiation and infant survival: A systematic review and meta-analysis.PLoS One. 2017; 12e0180722
- Early breastfeeding practices: Descriptive analysis of recent Demographic and Health Surveys.Matern Child Nutr. 2018; 14: e12535
- 2020 Global Nutrition Report - Global Nutrition Report.Development Initiatives, Bristol, UK2020
UNICEF. Infant and young child feeding - UNICEF DATA. 2020. Available at: https://data.unicef.org/topic/nutrition/infant-and-young-child-feeding/. Accessed May 11, 2021.
- State of the World's Children 2005: Childhood Under Threat.United Nations, 2004
- The State of the World's Children, 2011: Adolescence, an Age of Opportunity.United Nations, 2011
- The State of the World's Children 2019. Children, Food and Nutrition: Growing Well in a Changing World.UNICEF, New York2019 (Available at) (Accessed May 11, 2021)
- Maternal education and equity in breastfeeding: trends and patterns in 81 low- and middle-income countries between 2000 and 2019.Int J Equity Health. 2021; 20: 20
- When do newborns die? A systematic review of timing of overall and cause-specific neonatal deaths in developing countries.J Perinatol. 2016; 36: S1-S11
- Rates and time trends in the consumption of breastmilk, formula, and animal milk by children younger than 2 years from 2000 to 2019: analysis of 113 countries.Lancet Child Adolesc Health. 2021; 5: 619-630
- From the First Hour of Life: Making the Case for Improved Infant and Young Child Feeding Everywhere.UNICEF, New York2016
- Guideline: Updates on HIV and Infant Feeding: The Duration of Breastfeeding, and Support from Health Services to Improve Feeding Practices Among Mothers Living with HIV.World Health Organization, Geneva2016
- Infant feeding and transmission of human immunodeficiency virus in the United States.Pediatrics. 2013; 131: 391-396
- Optimal antiretroviral prophylaxis in infants at high risk of acquiring HIV: A systematic review.Pediatr. Infect. Dis. J. 2018; 37: 169-175
- Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach.2nd ed. World Health Organization, Geneva2016
- Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women With High CD4 Cell Count (IMPAACT PROMISE): A Randomized, Open-Label, Clinical Trial.J. Acquir. Immune Defic. Syndr. 2018; 77: 383-392
- Guidelines on Optimal Feeding of Low Birth-Weight Infants in Low- and Middle-Income Countries.World Health Organization, Geneva2011
- Strengthening Human Milk Banking: A Global Implementation Framework. Version 1.1.PATH, Seattle2013
- Global Strategy for Infant and Young Children Feeding.World Health Organization, 2003: 36
- Pregnancy and Breastfeeding During COVID-19 Pandemic: A Systematic Review of Published Pregnancy Cases.Front Public Health. 2020; 8558144
- COVID-19 guidelines for pregnant women and new mothers: A systematic evidence review.Int J Gynaecol Obstet. 2021; 153: 373-382
- Protecting breastfeeding during the COVID-19 pandemic.Am J Perinatol. 2020 Jul 21; ([Epub ahead of print])
- Characterization of SARS-CoV-2 RNA, antibodies, and neutralizing capacity in milk produced by women with COVID-19.MBio. 2021; 12 (-20): e03192
- SARS-CoV-2-specific antibodies in breast milk after COVID-19 vaccination of breastfeeding women.JAMA. 2021; 325: 2013-2014
- Old tricks, new opportunities: how companies violate the International Code of Marketing of Breast-Milk Substitutes and undermine maternal and child health during the COVID-19 Pandemic.Int J Environ Res Public Health. 2021; 18: 2381
- Breastfeeding media coverage and beliefs during the COVID-19 pandemic in Mexico: implications for breastfeeding equity.Res Sq. 2021; (rs.3.rs-528093)
- Why invest, and what it will take to improve breastfeeding practices?.Lancet. 2016; 387: 491-504
- Counselling interventions to enable women to initiate and continue breastfeeding: a systematic review and meta-analysis.Int Breastfeed J. 2019; 14: 42
- Implementation Guidance: Protecting, Promoting and Supporting Breastfeeding in Facilities Providing Maternity and Newborn Services – the Revised Baby-Friendly Hospital Initiative.World Health Organization, Geneva2018
- National Implementation of the Baby-Friendly Hospital Initiative, 2017.World Health Organization, Geneva2017
- Exploring the impact of the Baby-Friendly Hospital Initiative on trends in exclusive breastfeeding.Int Breastfeed J. 2009; 4: 11
- International Code of Marketing of Breast-Milk Substitutes.World Health Organization, Geneva1981: 36
Fore H, Adhanom Ghebreyesus T. WHO/UNICEF statement on the 40th anniversary of the international code of marketing breastmilk substitutes. 2021. Available at: https://www.who.int/news/item/21-05-2021-WHO-UNICEF-statement-on-the-40th-anniversary-of-the-international-code-of-marketing-breastmilk-substitutes. Accessed August 10, 2021.
- Improving breastfeeding practices at scale.Lancet Glob. Health. 2019; 7: e292-e293
- Effectiveness of community-based peer support for mothers to improve their breastfeeding practices: A systematic review and meta-analysis.PLoS One. 2017; 12e0177434
- Exclusive breastfeeding continuation and associated factors among employed women in North Ethiopia: A cross-sectional study.PLoS One. 2021; 16e0252445
International Labor Organization. Convention C183 - Maternity Protection Convention, 2000 (No. 183). 2000. Available at: https://www.ilo.org/dyn/normlex/en/f?p=NORMLEXPUB:12100:0::NO::P12100_ILO_CODE:C183. Accessed August 9, 2021.
Maternity protection: Compliance with international labour standards. Available at: https://www.who.int/data/nutrition/nlis/info/maternity-protection-compliance-with-international-labour-standards. Accessed August 10, 2021.
Addati L, Cassirer N, Gilchrist K, International Labour Office. Maternity and Paternity at Work: Law and Practice across the World. Geneva: International Labour Office
- Breastfeeding policy: a globally comparative analysis.Bull. World Health Organ. 2013; 91: 398-406
WHO, UNICEF. A global breastfeeding call to action | UNICEF Global Breastfeeding Collective. Available at: https://www.globalbreastfeedingcollective.org/global-breastfeeding-call-action. Accessed April 19, 2021.
- Cost analysis of maternal disease associated with suboptimal breastfeeding.Obstet. Gynecol. 2013; 122: 111-119
The World Bank Group. GDP (current US$) | Data. 2021. Available at: https://data.worldbank.org/indicator/NY.GDP.MKTP.CD. Accessed August 16, 2021.
- An Investment Framework for Nutrition: Reaching the Global Targets for Stunting, Anemia, Breastfeeding, and Wasting.The World Bank, 2017
- What is the economic value of improved labor market outcomes from infant nutrition? the case of breastfeeding in the United States.SSRN J. 2016; : 16-29
- Yemen's breastfeeding challenge.Al Jazeera Health News. 2014; (Available at) (Accessed September 9, 2021)
- Yeman National Strategy for Social and Behavior Change in Nutrition 2018-2021.Technical Rapid Response Team, Yemen Nutrition Cluster, 2018
- 2020 Global Nutrition Report: Action on Equity to End Malnutrition.Development Initiatives, Bristol, UK2020
- Rwanda's Success In Improving Maternal Health | PRB.Population Reference Bureau. 2015; (Accessed September 9, 2021)
https://www.cdc.gov/breastfeeding/data/reportcard.htm, 2021. [Acessed 01 September 2021].
- Magnitude and Predictors of Pneumonia among Under-Five Children in Ethiopia: A Systematic Review and Meta-Analysis.J Environ Public Health. 2020; https://doi.org/10.1155/2020/1606783
- Breastfeeding and maternal health outcomes: a systematic review and meta-analysis.Acta Paediatr. 2015; 104: 96-113https://doi.org/10.1111/apa.13102
- Association of Maternal Lactation With Diabetes and Hypertension: A Systematic Review and Meta-analysis.JAMA Netw Open. 2019; 2: e1913401https://doi.org/10.1001/jamanetworkopen.2019.13401