Abstract

Preterm birth (PB) is a syndrome resulting from a complex relationship between multiple factors which do not have fully understood relationships and causality. This article discusses a hierarchical theoretical model of PB determinants, considering maternal characteristics such as sociodemographic, psychosocial, nutritional, behavioral and biological aspects, traditionally associated with increased risk of PB. The variables were distributed in six dimensions within three hierarchical levels (distal, intermediate and proximal). In this model, the socioeconomic determinants of the mother, family, household and neighborhood play indirect effects on PB through variables at the intermediate level, which in turn affect biological risk factors at the proximal level that have a direct effect on PB. The study presents a hierarchical theoretical model of the factors involved in the PB determination chain and their interrelationships. Understanding these interrelationships is an important step in trying to break the causal chain that makes some women vulnerable to preterm birth.

Key words:
Preterm birth; Risk factors; Theoretical models

Introduction

Preterm birth (PB) is defined as every birth which takes place before 37 full weeks of pregnancy, or in less than 259 days since the first day of the last menstrual period (LMP)¹1 World Health Organization (WHO). WHO: recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. Modifications recommended by FIGO as amended October 14, 1976. Acta Obstet Gynecol Scand 1977; 56(3): 247-253.. Global estimates show an increase in the preterm birth rate over the years, varying between 9.8% in 2000 and 10.6% in 2014. This increase is equivalent to an estimated number of 14.6 million preterm births around the world²2 Chawanpaiboon S, Vogel JP, Moller AB, Lumbiganon P, Petzold M, Hogan D, Landoulsi S, Jampathong N, Kongwattanakul K, Laopaiboon M, Lewis C, Rattanakanokchai S, Teng DN, Thinkhamrop J, Watananirun K, Zhang J, Zhou W, Gülmezoglu AM. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health 2019; 7(1):e37-e46.. In 2016, the complications of PB were considered the main cause of death among children under the age of five, corresponding to approximately 16% of all deaths, and 35% of deaths among newborns³3 United Nations Children's Fund (UNICEF), World Bank Group, United Nations (UN). Levels & Trends in Child Mortality. New York: Unicef; 2017. p. 36.. In addition to its contribution to mortality, PB has effects throughout the lives of the survivors, with consequences related to neurological and cognitive deficits, visual/auditory deficiency, and an increased risk of chronic diseases in their adult lives⁴4 Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet 2012; 379(9814):445-52.^,55 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2..

PB can be subdivided into categories, based on the newborn’s gestational age: extremely (< 28 weeks); very (≥ 28 and < 32 weeks), and moderate-to-late preterm (≥ 32 and < 37 complete weeks of pregnancy)⁶6 Bick D. Born too soon: the global issue of preterm birth. Midwifery 2012; 28(4):341-342.. These subdivisions are important, since the reduction in gestational age is associated with the newborn’s survival and neonatal complications⁷7 Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379(9832):2162-2172.. PB may also be classified into two large subtypes: (i) spontaneous preterm birth, defined as the spontaneous start of labour, or following the premature rupture of membranes (PRM); and (ii) premature labour started by health professionals (previously called “iatrogenic”), defined as induction of labour, or elective caesarean, before 37 full weeks of pregnancy, due to maternal or fetal indications, or other non-medical reasons⁸8 Goldenberg RL, Gravett MG, Iams J, Papageorghiou AT, Waller SA, Kramer M, Culhane J, Barros F, Conde-Agudelo A, Bhutta ZA, Knight HE, Villar J. The preterm birth syndrome: issues to consider in creating a classification system. Am J Obstet Gynecol 2012; 206(2):113-118..

PB is a syndrome which results from a complex relationship between sociodemographic, psychosocial, nutritional, behavioural and biological maternal factors. However, although these risk factors are well-known in literature, the cause and relationship between them are not fully understood⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.. Therefore, theoretical models have been proposed, in the attempt to explain potential interrelationships between the various risk factors when determining results in health¹⁰10 Lima Sd, Carvalho MLd, Vasconcelos AGG. Proposta de modelo hierarquizado aplicado à investigação de fatores de risco de óbito infantil neonatal. Cad Saude Publica 2008; 24(8):1910-1916.^,1111 Rodrigues MCC, Mello RR, Silva KS, Carvalho ML. Desenvolvimento cognitivo de prematuros à idade escolar: proposta de modelo hierarquizado para investigação dos fatores de risco. Cad Saude Publica 2011; 27:1154-1164.. However, the use of a hierarchical theoretical model to construct reviews on the determinants of PB is a differential and innovative approach. Thus, this article involving the review of literature, presents a hierarchical theoretical model of the determinants of preterm birth, providing subsidies to further discussion on the interrelationship of these different determinants.

Determinants of preterm birth

The complexity of a health outcome may be observed both through the influence that each of the factors exerts on its occurrence, and the interrelationships and interdependences of these different factors¹²12 Belfort GP, Santos MMAS, Pessoa LS, Dias JR, Heidelmann SP, Saunders C. Determinantes do baixo peso ao nascer em filhos de adolescentes: uma análise hierarquizada. Cien Saude Colet 2018; 23(8):2609-2620.. A preterm birth prediction at a closer level can be determined by biological factors, such as a previous preterm labour, multiple pregnancy, maternal comorbidities, such as hypertension and diabetes, and other conditions related to the newborn, such as intrauterine growth restriction (IUGR) and fetal distress⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.^,1313 Phillips C, Velji Z, Hanly C, Metcalfe A. Risk of recurrent spontaneous preterm birth: a systematic review and meta-analysis. BMJ Open 2017; 7(6):e015402.. Factors which represent the mother’s lifestyle, psychological health, and healthcare, may possibly be observed at the intermediate levels of determination. Lastly, in general, the more distal factors refer to the mother’s socio-economic and demographic conditions.

Based on an extensive review of literature, a hierarchical theoretical model of the determinants of preterm birth was proposed, which describes the interrelations between the variables that form each level of its determination (Figure 1). In the model presented, the variables were distributed into six dimensions, within three hierarchical levels (distal, intermediate, and proximal). The variables of a same dimension are connected by continuous lines. The direct effects between the different levels of determination, or different dimensions at the same level, are represented by arrows. The double arrows indicate the dimensions which establish bidirectional relationships between themselves. The indirect effects between the dimensions of different levels on the outcome are represented by dashed arrows. Lastly, the direct effects on the outcome, exercised by determinants located at the proximal level, are represented by arrows.

Distal determinants

Socio-economic determinants have been consistently identified as distal risk factors associated with preterm birth. Socio-economic status (SES) is an important predictor of health disparities, since socio-economically underprivileged groups tend to have worse health outcomes¹⁴14 Campbell EE, Gilliland J, Dworatzek PDN, De Vrijer B, Penava D, Seabrook JA. Socioeconomic status and adverse birth outcomes: a population-based Canadian sample. J Biosoc Sci 2018; 50(1):102-113.. The economic dimension, represented in particular by family income, education and occupation, plays an important role in the determination, and adverse results of pregnancy¹⁵15 Kramer MS, Goulet L, Lydon J, Séguin L, McNamara H, Dassa C, Platt RW, Chen MF, Gauthier H, Genest J, Kahn S, Libman M, Rozen R, Masse A, Miner L, Asselin G, Benjamin A, Klein J, Koren G. Socio-economic disparities in preterm birth: causal pathways and mechanisms. Paediatr Perinat Epidemiol 2001; 15(Suppl. 2):104-123..

Income is highlighted as one of the most important socio-economic factors related to social inequality and, consequently, health inequalities¹⁶16 Kramer MS, Seguin L, Lydon J, Goulet L. Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly? Paediatr Perinat Epidemiol 2000; 14(3):194-210.. Differences in income determine the nature of people’s working and housing conditions, access to food, and health services, which are explanatory factors on the paths in which income is associated with preterm birth¹⁷17 Meng G, Thompson ME, Hall GB. Pathways of neighbourhood-level socio-economic determinants of adverse birth outcomes. Int J Health Geogr 2013; 12:32.. Family income is equally important as individual socio-economic factors, to explain the relation between SES and health. Family income represents a standard of living, and life opportunities which family members experience by sharing goods and services¹⁸18 Daly MC, Duncan GJ, McDonough P, Williams DR. Optimal indicators of socioeconomic status for health research. Am J Public Health 2002; 92(7):1151-1155..

The educational level is a SES proxy which predicts health conditions with more strength and consistency, particularly for women and their children¹⁵15 Kramer MS, Goulet L, Lydon J, Séguin L, McNamara H, Dassa C, Platt RW, Chen MF, Gauthier H, Genest J, Kahn S, Libman M, Rozen R, Masse A, Miner L, Asselin G, Benjamin A, Klein J, Koren G. Socio-economic disparities in preterm birth: causal pathways and mechanisms. Paediatr Perinat Epidemiol 2001; 15(Suppl. 2):104-123.. Women with a higher level of education have greater access to better jobs and income which, in turn, leads to access to essential goods, such as higher quality food. The level of education is also an important marker of access to health services, above all in relation to aspects such as the decision on the number and timing of the pregnancy, increased access and use of medical information, as well as the reduction of risk behaviour, such as the use of alcohol and tobacco¹⁹19 Dolatian M, Mirabzadeh A, Forouzan AS, et al. Relationship between structural and intermediary determinants of health and preterm delivery. J Reprod Infertil 2014; 15(2):78-86..

The impact of socio-economic inequalities also determines the nature of people’s working conditions. The strenuous work carried out by women at a lower socio-economic level, often with a less education, is also associated with adverse birth results, including preterm birth²⁰20 Cai C, Vandermeer B, Khurana R, Nerenberg K, Featherstone R, Sebastianski M, Davenport MH. The impact of occupational shift work and working hours during pregnancy on health outcomes: a systematic review and meta-analysis. Am J Obstet Gynecol 2019; 221(6):563-576.. Occupations characterised as heavy manual labour, under stressful conditions, with exposure to chemical agents, or a long period of time in the workplace, are factors which justify this relation²¹21 Norlén F, Gustavsson P, Wiebert P, Rylander L, Albin M, Westgren M, Plato N, Selander J. Occupational exposure to inorganic particles during pregnancy and birth outcomes: a nationwide cohort study in Sweden. BMJ Open 2019; 9(2) e023879.^,2222 von Ehrenstein OS, Wilhelm M, Ritz B. Maternal occupation and term low birth weight in a predominantly latina population in los angeles, california. Int J Occup Environ Med 2013; 55(9):1046-1051..

In addition to income-related aspects, studies suggest an association between the maternal marital situation and results of the pregnancy²³23 Merklinger-Gruchala A, Kapiszewska M. The effect of prenatal stress, proxied by marital and paternity status, on the risk of preterm birth. Int J Environ Res Public Health 2019; 16(2):273.^,2424 Bloch JR, Webb DA, Mathews L, Dennis EF, Bennett IM, Culhane JF. Beyond marital status: The quality of the mother-father relationship and its influence on reproductive health behaviors and outcomes among unmarried low income pregnant women. Matern Child Health J 2010; 14(5):726-734.. Single mothers suffer more from increased maternal stress related to uncertainty about the future, insecurity in the relationship, less emotional/social support, and economic disadvantage, when compared to mothers with partners²³23 Merklinger-Gruchala A, Kapiszewska M. The effect of prenatal stress, proxied by marital and paternity status, on the risk of preterm birth. Int J Environ Res Public Health 2019; 16(2):273.^,2525 Zeitlin J, Saurel-Cubizolles MJ, De Mouzon J, Rivera L, Ancel PY, Blondel B, Kaminski M. Fetal sex and preterm birth: are males at greater risk? Hum Reprod 2002; 17(10):2762-2768..

The role of race/ethnicity in preterm birth has been reported in many studies which demonstrate variations in the length of the pregnancy among various ethnic groups²⁶26 Sadovsky ADI, Mascarello KC, Miranda AE, Silveira MF. The associations that income, education, and ethnicity have with birthweight and prematurity: how close are they? Rev Panam Salud Publica 2018; 42:e92-e.^,2727 Oliveira KA, Araújo EM, Oliveira KA, Casotti CA, Silva CAL, Santos DBD. Association between race/skin color and premature birth: a systematic review with meta-analysis. Rev Saude Publica 2018; 52:26.. For black women, exposure to stressful psychosocial factors (poverty, lack of housing, living in dangerous neighbourhoods, domestic violence, and experience of discrimination, or racism), and risk behaviours associated with stress may favour the increased risk of preterm birth²⁸28 Kramer MR, Hogue CJ, Dunlop AL, Menon R. Preconceptional stress and racial disparities in preterm birth: an overview. Acta Obstet Gynecol Scand 2011; 90(12):1307-1316..

Residential segregation, defined as the extension to which social groups characterised by income or race/ethnicity are spatially separated from each other, may also contribute to preterm birth disparities²⁹29 Kim D, Saada A. The social determinants of infant mortality and birth outcomes in Western developed nations: a cross-country systematic review. Int J Environ Res Public Health 2013; 10(6):2296-2335.. Residential segregation is a display of structural racism which affects opportunities in many dimensions, including economic well-being, education, and health³⁰30 Kramer MR, Cooper HL, Drews-Botsch CD, Waller LA, Hogue CR. Metropolitan isolation segregation and Black-White disparities in very preterm birth: a test of mediating pathways and variance explained. Soc Sci Med (1982) 2010; 71(12):2108-2116.. Women who reside in racially-isolated neighbourhoods accumulate disadvantages, such as less access to quality basic education, and higher economic and residential instability, which limits the opportunities associated with health improvements and increases stress, which may lead to negative birth outcomes³¹31 Debbink MP, Bader MD. Racial residential segregation and low birth weight in Michigan's metropolitan areas. Am J Public Health 2011; 101(9):1714-1720..

Housing is another social determinant associated with birth outcomes³²32 Harville EW, Rabito FA. Housing conditions and birth outcomes: The National Child Development Study. Environ Res 2018; 161:153-157.^,3333 Miranda ML, Messer LC, Kroeger GL. Associations between the quality of the residential built environment and pregnancy outcomes among women in North Carolina. Environ Health Perspect 2012; 120(3):471-477.. Inadequate housing conditions (floor and wall coverings, exposure to mould, or humidity and basic sanitation) and household crowding are associated with a greater risk to health, mainly for the occurrence of infectious and respiratory diseases, which constitute important risk factors for preterm birth³²32 Harville EW, Rabito FA. Housing conditions and birth outcomes: The National Child Development Study. Environ Res 2018; 161:153-157.^,3434 Vettore MV, Gama SGNd, Lamarca GdA, Schilithz AOC, Leal MdC. Housing conditions as a social determinant of low birthweight and preterm low birthweight. Rev Saude Publica 2010; 44:1021-1031.. Household crowding is also a marker of poverty and social deprivation³⁵35 Patrick Breysse NF, Warren Galke, Bruce Lanphear, Rebecca Morley, Linda Bergofsky. The relationship between housing and health: children at risk. Environ Health Perspect 2004; 112(15):1583-1588., which may be associated with preterm birth, considering that the number of people in a family may influence access to food and other essential services. Crowding may also trigger stress factors in the pregnant woman’s health and well-being, exposure to risk factors associated with injuries in the home, social tension, and exposure to passive smoking³⁶36 Ormandy D. Housing and child health. Paediatr Int Child Health 2014; 24(3):115-117.. In addition, home ownership may attribute feelings of security and/or prestige to the individual, especially when compared to situations of instability such as rent (social or private) and makeshift homes, which are susceptible to eviction. This instability directly affects psychosocial commitment, which produces impacts during the pregnancy³³33 Miranda ML, Messer LC, Kroeger GL. Associations between the quality of the residential built environment and pregnancy outcomes among women in North Carolina. Environ Health Perspect 2012; 120(3):471-477..

The socio-economic characteristics at the neighbourhood level are considered important determinants for adverse birth outcomes¹⁷17 Meng G, Thompson ME, Hall GB. Pathways of neighbourhood-level socio-economic determinants of adverse birth outcomes. Int J Health Geogr 2013; 12:32.^,2929 Kim D, Saada A. The social determinants of infant mortality and birth outcomes in Western developed nations: a cross-country systematic review. Int J Environ Res Public Health 2013; 10(6):2296-2335., independent of socio-economic measures at the individual level¹⁷17 Meng G, Thompson ME, Hall GB. Pathways of neighbourhood-level socio-economic determinants of adverse birth outcomes. Int J Health Geogr 2013; 12:32.. Characteristics of the area of residence may influence preterm birth through difference in access to health care and other essential goods, maternal psychosocial stress, and health behaviours¹⁷17 Meng G, Thompson ME, Hall GB. Pathways of neighbourhood-level socio-economic determinants of adverse birth outcomes. Int J Health Geogr 2013; 12:32..

Studies suggest that violence in the neighbourhood of residence may also lead to an indirect effect on increased risk of preterm birth and other birth outcomes³⁷37 Foureaux Koppensteiner M, Manacorda M. Violence and birth outcomes: evidence from homicides in Brazil. J Dev Econ 2016; 119:16-33.^,3838 Matoba N, Reina M, Prachand N, Davis MM, Collins JW. Neighborhood Gun Violence and Birth Outcomes in Chicago. Matern Child Health J 2019; 23(9):1251-1259.. Exposure to contextual violence may lead to fear and psychological stress, mainly in the first trimester of pregnancy, which could lead to prematurity. In addition, violence may also lead to additional indirect effects on results of the delivery, such as interrupted access to health services, particularly prenatal services, and risk behaviours such as an increase in smoking and the consumption of alcohol during pregnancy, in response to stress³⁷37 Foureaux Koppensteiner M, Manacorda M. Violence and birth outcomes: evidence from homicides in Brazil. J Dev Econ 2016; 119:16-33..

Intermediate determinants

At the intermediate level of determination, maternal psychological health, risk behaviours and access and use of health services are associated with premature delivery⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2..

High levels of maternal stress, anxiety and depression during pregnancy may have a negative impact on the development of the fetus, and be associated with premature labour³⁹39 Staneva A, Bogossian F, Pritchard M, Wittkowski A. The effects of maternal depression, anxiety, and perceived stress during pregnancy on preterm birth: a systematic review. Women and Birth 2015; 28(3):179-193.. The vulnerability of pregnant women to stress, anxiety, and depression may be increased by factors such as a lack of emotional stability, uncertainty about the future, unstable housing, insecurity in a relationship, little support from a partner, a violent partner, financial difficulties, an unplanned or unwanted pregnancy, and lack of an adequate social support system⁴⁰40 Merklinger-Gruchala A, Kapiszewska M. The effect of prenatal stress, proxied by marital and paternity status, on the risk of preterm birth. Int J Environ Res Public Health 2019; 16(2):273.^,4141 Lancaster CA, Gold KJ, Flynn HA, Yoo H, Marcus SM, Davis MM. Risk factors for depressive symptoms during pregnancy: a systematic review. Am J Obstet Gynecol 2010; 202(1):5-14.. In certain circumstances, pregnancy in itself may become a stressful and difficult life experience²³23 Merklinger-Gruchala A, Kapiszewska M. The effect of prenatal stress, proxied by marital and paternity status, on the risk of preterm birth. Int J Environ Res Public Health 2019; 16(2):273.. These maternal psychosocial factors can be significant determinants of birth outcomes, acting through behavioural or physiological channels⁴²42 Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 2010; 67(10):1012-1024..

In addition, women exposed to anxiety and stressful conditions during pregnancy have increased serum concentrations of the corticotropin-releasing hormone (CRH) and pro-inflammatory cytokines. These findings suggest systemic inflammation as a pathophysiological path through which anxiety and stress could increase the risk of preterm delivery⁴³43 Coussons-Read ME, Okun ML, Nettles CD. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav Immun Health 2007; 21(3):343-350.^,4444 Mancuso RA, Schetter CD, Rini CM, Roesch SC, Hobel CJ. Maternal prenatal anxiety and corticotropin-releasing hormone associated with timing of delivery. Psychosom Med 2004; 66(5):762-769.. Maternal depression during pregnancy may be the result of disruption of the hypothalamic-pituitary-adrenocortical axis, which encourages the release of cortisol and catecholamines. These biological alterations may result in placental hypoperfusion, and the consequent restriction of oxygen and nutrients to the fetus, which leads to restricted fetal growth and/or precipitating a preterm birth⁴⁵45 Federenko IS, Wadhwa PD. Women's mental health during pregnancy influences fetal and infant developmental and health outcomes. CNS Spectr 2004; 9(3):198-206.^,4646 Borders AEB, Grobman WA, Amsden LB, Holl JL. Chronic stress and low birth weight neonates in a low-income population of women. Obstet Gynecol 2007; 109(2):331-338.. Prenatal depression may be another factor which affects the functioning of the immunological system which, in turn, may lead to infection of the reproductive tract and preterm birth⁴⁵45 Federenko IS, Wadhwa PD. Women's mental health during pregnancy influences fetal and infant developmental and health outcomes. CNS Spectr 2004; 9(3):198-206.. An increase in smoking, the use of drugs and alcohol, poor diet, and less frequent use of the health service among women with depression may also contribute to worse maternal psychological health³⁹39 Staneva A, Bogossian F, Pritchard M, Wittkowski A. The effects of maternal depression, anxiety, and perceived stress during pregnancy on preterm birth: a systematic review. Women and Birth 2015; 28(3):179-193..

Although the biological effects of the majority of chemical products present in smoking cigarettes are unknown⁴⁷47 Benowitz NL, Dempsey DA, Goldenberg RL, Hughes JR, Dolan-Mullen P, Ogburn PL, Oncken C, Orleans CT, Slotkin TA, Whiteside HP Jr, Yaffe S. The use of pharmacotherapies for smoking cessation during pregnancy. Tob Control 2000; 9(Suppl. 3):III91-III4., it is known that nicotine and carbon monoxide are potent vasoconstrictors associated with placental damage, and a decrease in uteroplacental blood flow. This may lead to restricted fetal growth, which is one of the risk factors for preterm birth⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.^,4848 Meghea CI, Rus IA, Chereches RM, Costin N, Caracostea G, Brinzaniuc A. Maternal smoking during pregnancy and birth outcomes in a sample of Romanian women. Cent Eur J Public Health 2014; 22(3):153-158.. Smoking is also associated with a systemic inflammatory response, which may increase spontaneous preterm birth in this way⁴⁹49 Tracy RP, Psaty BM, Macy E, Bovill EG, Cushman M, Cornell ES, Kuller LH. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 1997; 17(10):2167-2176.^,5050 Bermudez EA, Rifai N, Buring JE, Manson JE, Ridker PM. Relation between markers of systemic vascular inflammation and smoking in women. Am J Cardiol 2002; 89(9):1117-1119..

High alcohol consumption is also a behavioural factor associated with the risk of preterm birth⁵¹51 Nykjaer C, Alwan NA, Greenwood DC, Simpson NA, Hay AW, White KL, Cade JE. Maternal alcohol intake prior to and during pregnancy and risk of adverse birth outcomes: evidence from a British cohort. J Epidemiol Community Health 2014; 68(6): 542-549.^,5252 Ikehara S, Kimura T, Kakigano A, Sato T, Iso H, Japan Environment Children's Study G. Association between maternal alcohol consumption during pregnancy and risk of preterm delivery: the Japan Environment and Children's Study. BJOG 2019; 126(12):1448-1454., which may be related to an increase in the secretion of prostaglandins and uterine contractions⁵²52 Ikehara S, Kimura T, Kakigano A, Sato T, Iso H, Japan Environment Children's Study G. Association between maternal alcohol consumption during pregnancy and risk of preterm delivery: the Japan Environment and Children's Study. BJOG 2019; 126(12):1448-1454.^,5353 Anton RF, Becker HC, Randall CL. Ethanol increases PGE and thromboxane production in mouse pregnant uterine tissue. Life Sci 1990; 46(16):1145-1153.. In addition, alcohol may increase the risk of hypertensive disorders during pregnancy, which is one of the risk factors for preterm birth⁵⁴54 Iwama N, Metoki H, Nishigori H, Mizuno S, Takahashi F, Tanaka K, Watanabe Z, Saito M, Sakurai K, Ishikuro M, Obara T, Tatsuta N, Nishijima I, Sugiyama T, Fujiwara I, Kuriyama S, Arima T, Nakai K, Yaegashi N, Japan Environment & Children's Study Group. Association between alcohol consumption during pregnancy and hypertensive disorders of pregnancy in Japan: the Japan Environment and Children's Study. Hypertens Res 2019; 42(1):85-94.. The use of chemical substances and heroin have also been associated with adverse results of pregnancy, due to recurrent intrauterine hypoxic stress⁵⁵55 Maghsoudlou S, Cnattingius S, Montgomery S, Aarabi M, Semnani S, Wikström AK, Bahmanyar S. Opium use during pregnancy and risk of preterm delivery: A population-based cohort study. PloS One 2017; 12(4):e0176588.. Maternal exposure to narcotics may induce fluctuating cycles of intoxication and abstinence to the fetus, which may not have its oxygen needs met during abstinence⁵⁶56 Huestis MA, Choo RE. Drug abuse's smallest victims: in utero drug exposure. Forensic Sci Int 2002; 128(1-2):20-30.. Simultaneously, other health problems associated with high risk behaviour among users of these substances, including insufficient prenatal appointments, restricted food intake, and an increase in maternal infections, may also increase the risk of preterm birth⁵⁷57 Vucinovic M, Roje D, Vucnovic Z, Capkun V, Bucat M, Banovic I. Maternal and neonatal effects of substance abuse during pregnancy: our ten-year experience. Yonsei Med J 2008; 49(5):705-713.^,5858 Bandstra ES, Morrow CE, Mansoor E, Accornero VH. Prenatal drug exposure: infant and toddler outcomes. J Addict Dis 2010; 29(2):245-258..

Maternal diet and eating habits may also favour a preterm birth⁵⁹59 Englund-Ögge L, Brantsæter AL, Sengpiel V, Haugen M, Birgisdottir BE, Myhre R, Meltzer HM, Jacobsson B. Maternal dietary patterns and preterm delivery: results from large prospective cohort study. BMJ 2014; 348:g1446.^,6060 Myhre R, Brantsæter AL, Myking S, et al. Intakes of garlic and dried fruits are associated with lower risk of spontaneous preterm delivery. J Nutr 2013; 143(7): 1100-8.. The experience of food insecurity, when there is no guarantee of regular and permanent access to quality food and in sufficient quantities⁶¹61 Brasil. Lei nº 11.346, de 15 de setembro de 2006. Cria o Sistema Nacional de Segurança Alimentar e Nutricional-SISAN com vistas em assegurar o direito humano à alimentação adequada e dá outras providências. Diário Oficial da União 2006; 18 set., is a prevalent condition among women with a low-income¹⁷17 Meng G, Thompson ME, Hall GB. Pathways of neighbourhood-level socio-economic determinants of adverse birth outcomes. Int J Health Geogr 2013; 12:32.. In addition, food insecurity precedes stages of nutritional shortcomings which may have a negative effect on fetal growth and birth results⁶²62 Keats EC, Haider BA, Tam E, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev 2019; 3(3):Cd004905..

Similarly, access and use of health services are associated with preterm birth⁶³63 Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet 2008; 371(9607):164-175.. Studies indicate that the number of prenatal appointments, late start of prenatal appointments, and prenatal quality, have a strong influence on the occurrence, or otherwise, of a preterm birth⁶⁴64 Yamey G, Horvath H, Schmidt L, Myers J, Brindis CD. Reducing the global burden of Preterm Birth through knowledge transfer and exchange: a research agenda for engaging effectively with policymakers. Reprod health 2016; 13:26.^,6565 Gonzaga ICA, Santos SLD, Silva ARV, Campelo V. Atenção pré-natal e fatores de risco associados à prematuridade e baixo peso ao nascer em capital do Nordeste brasileiro. Cien Saude Colet 2016; 21(6):1965-1974.. Despite the expansion of prenatal assistance coverage in Brazil in recent decades, regional and social inequalities in access to adequate prenatal assistance remain⁶⁶66 Domingues RMSM, Viellas EF, Dias MAB, Torres JA, Theme-Filha MM, Gama SGN, Leal MC. Adequação da assistência pré-natal segundo as características maternas no Brasil. Rev Panam Salud Publica 2015; 37(3):140-147.. Therefore, women with a lower probability of having access, and regularly attending prenatal appointments during pregnancy, are more prone to attaining adverse results during pregnancy or delivery⁶³63 Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet 2008; 371(9607):164-175.. In addition, prenatal assistance may also be considered a mediator of maternal socio-economic conditions⁶⁷67 Oliveira AA, Almeida MF, Silva ZP, Assunção PL, Silva AMR, Santos HG, Alencar GP. Fatores associados ao nascimento pré-termo: da regressão logística à modelagem com equações estruturais. Cad Saude Publica 2019; 35:e00211917..

Proximal determinants

Among the proximal determinants of preterm birth, maternal factors, and those associated with the fetus can be highlighted⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.^,99 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.. Young and advanced maternal ages have been associated with an increased risk of prematurity⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.. The high risk of a preterm birth in adolescence occurs due to biological immaturity, blood supply of the uterus or cervix⁶⁸68 Amorim MMR, Lima LA, Lopes CV, Araújo DKL, Silva JGG, César LC, Melo Aso. Fatores de risco para a gravidez na adolescência em uma maternidade-escola da Paraíba: estudo caso-controle. Rev Bras Ginecol Obstet 2009; 31(8):404-410., and competition for nutrients between the fetus and pregnant adolescent⁶⁹69 Restrepo-Méndez MC, Lawlor DA, Horta BL, Matijasevich A, Santos IS, Menezes AM, Barros FC, Victora CG. The association of maternal age with birthweight and gestational age: a cross-cohort comparison. Paediatr Perinat Epidemiol 2015; 29(1):31-40.. This association may also be related to the psychological and socio-economic consequences that a teenage pregnancy may cause⁶⁸68 Amorim MMR, Lima LA, Lopes CV, Araújo DKL, Silva JGG, César LC, Melo Aso. Fatores de risco para a gravidez na adolescência em uma maternidade-escola da Paraíba: estudo caso-controle. Rev Bras Ginecol Obstet 2009; 31(8):404-410.. At advanced ages, in other words, mothers aged ≥ 35 at the time of birth, a preterm birth may be associated with pre-existing maternal conditions, such as high blood pressure, and other obstetric complications⁷⁰70 Ludford I, Scheil W, Tucker G, Grivell R. Pregnancy outcomes for nulliparous women of advanced maternal age in South Australia, 1998-2008. Aust N Z J Obstet Gynaecol 2012; 52(3):235-241. which are more frequent in this age group.

Maternal nutritional status during pregnancy, specifically low weight or pre-gestational obesity, may increase the risk of preterm birth through different potential mechanisms⁷¹71 Hannaford KE, Tuuli MG, Odibo L, Macones GA, Odibo AO. Gestational weight gain: association with adverse pregnancy outcomes. Am J Perinatol 2017; 34(02):147-154.^,7272 Pigatti Silva F, Souza RT, Cecatti JG, Passini R Jr, Tedesco RP, Lajos GJ, Nomura ML, Rehder PM, Dias TZ, Oliveira PF, Silva CM, Brazilian Multicenter Study on Preterm Birth (EMIP) study group. Role of Body Mass Index and gestational weight gain on preterm birth and adverse perinatal outcomes. Sci Rep 2019; 9(1):13093.. For malnourished women, a preterm birth may be related to vulnerability to infection, associated with low concentrations of vitamins and minerals, which leads to a decrease in blood flow⁷³73 Requejo J, Merialdi M, Althabe F, Keller M, Katz J, Menon R. Born too soon: care during pregnancy and childbirth to reduce preterm deliveries and improve health outcomes of the preterm baby. Reprod health 2013; 10(Suppl. 1):S4.^,7474 Goldenberg RL. The plausibility of micronutrient deficiency in relationship to perinatal infection. J Nutr 2003; 133(5):1645S-1648S.. On the other hand, excess maternal weight may also be related to a higher risk of complications during pregnancy, responsible for a medically-induced preterm birth, such as pre-eclampsia and diabetes⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.^,7575 Poalelungi CV, Ples L, Hudita D, Ceausu I. Risk factors and clinical follow-up of patients with preterm births in a tertiary referral maternity unit in Bucharest, Romania. J Pak Med Assoc 2018; 68(4):559-564..

A short interval between pregnancies (for example, less than 18 months) has also frequently been associated with an increased risk of preterm birth⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.^,7676 Koullali B, Kamphuis EI, Hof MH, Robertson SA, Pajkrt E, de Groot CJ, Mol BW, Ravelli AC. The effect of interpregnancy interval on the recurrence rate of spontaneous preterm birth: a retrospective cohort study. Am J Perinatol 2017; 34(2):174-182.. Short intervals between pregnancies increases the risk of a preterm birth, due to the time that the uterus takes to return to its normal state, including resolution of the inflammatory status associated with a previous pregnancy⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.^,7777 Conde-Agudelo A, Rosas-Bermudez A, Castano F, Norton MH. Effects of birth spacing on maternal, perinatal, infant, and child health: a systematic review of causal mechanisms. Stud Fam Plann 2012; 43(2):93-114.. A further association is related to maternal nutritional and folate depletion, since maternal stocks of essential vitamins, minerals, and amino-acids may be scarce in a short interval between pregnancies⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.^,7777 Conde-Agudelo A, Rosas-Bermudez A, Castano F, Norton MH. Effects of birth spacing on maternal, perinatal, infant, and child health: a systematic review of causal mechanisms. Stud Fam Plann 2012; 43(2):93-114.. It is important to highlight that in low- and middle-income countries, a mother’s socio-economic status, lower level of education, and younger age, are frequently associated with short intervals between births⁷⁸78 Pimentel J, Ansari U, Omer K, Gidado Y, Baba MC, Andersson N, Cockcroft A. Factors associated with short birth interval in low- and middle-income countries: a systematic review. BMC Pregnancy Childbirth 2020; 20(1):156.. Similarly, long intervals (for example, more than 60 months) between pregnancies are associated with an increased risk of preterm birth⁷⁷77 Conde-Agudelo A, Rosas-Bermudez A, Castano F, Norton MH. Effects of birth spacing on maternal, perinatal, infant, and child health: a systematic review of causal mechanisms. Stud Fam Plann 2012; 43(2):93-114.. It is possible that, physiologically, the mother returns to the physical state of a woman who has not yet been pregnant, which makes her less physically prepared for becoming pregnant⁷⁸78 Pimentel J, Ansari U, Omer K, Gidado Y, Baba MC, Andersson N, Cockcroft A. Factors associated with short birth interval in low- and middle-income countries: a systematic review. BMC Pregnancy Childbirth 2020; 20(1):156..

Multiple pregnancies also represent a substantial risk of a preterm birth⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.^,99 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84., since uterine hyperdistention may cause contractions and premature rupture of the membrane (PRM), this being a mechanism which triggers an increased rate of spontaneous preterm births⁷⁹79 Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, Chaiworapongsa T, Mazor M. The preterm parturition syndrome. BJOG 2006; 113(Suppl. 3):17-42.. Additionally, the occurrence of pre-eclampsia, or other maternal or fetal disorders, may result in the preterm births indicated⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.. The growing availability of assisted reproduction in high-income countries has been put forward as a contributing factor for the high incidence of multiple births⁸⁰80 Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Warner L, Barfield WD. Assisted reproductive technology surveillance - United States, 2014. MMWR Surveillance Summaries 2017; 66(6):1..

Infection is a frequent condition during pregnancy, which plays an important role in prematurity⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.^,99 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.^,8181 Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014; 345(6198):760-765.. The mechanisms through which intrauterine infections lead to premature labour are related to activation of the immune system and myometrial contractility, which may induce rupture of the membrane⁸¹81 Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014; 345(6198):760-765.^,8282 Gravett MG, Rubens CE, Nunes TM, Group GR. Global report on preterm birth and stillbirth (2 of 7): discovery science. BMC Pregnancy Childbirth 2010; 10(Suppl. 1):S2. Among these, we highlight intrauterine, genital tract, and systemic infections⁸¹81 Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014; 345(6198):760-765.^,8282 Gravett MG, Rubens CE, Nunes TM, Group GR. Global report on preterm birth and stillbirth (2 of 7): discovery science. BMC Pregnancy Childbirth 2010; 10(Suppl. 1):S2.. However, it is not clear if infection is a cause, or consequence, of PRM. Intrauterine infection is recognised as one of the most important, and potentially avoidable, causes of preterm birth⁸²82 Gravett MG, Rubens CE, Nunes TM, Group GR. Global report on preterm birth and stillbirth (2 of 7): discovery science. BMC Pregnancy Childbirth 2010; 10(Suppl. 1):S2..

Chronic maternal diseases, such as diabetes, hypertension, anaemia, asthma and thyroid disease, are associated with the increase in premature birth rates which, in many cases, are indicated due to maternal complications⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.^,99 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.. Bidirectional relationships between preterm birth, low birth weight, and chronic non-communicable diseases (CNCDs), such as diabetes and hypertension, result in a vicious cycle of intergenerational risk⁸³83 Hovi P, Andersson S, Eriksson JG, Järvenpää AL, Strang-Karlsson S, Mäkitie O, Kajantie E. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007; 356(20):2053-2063.. Women with CNCDs have a high risk of having a premature child. In turn, premature babies run a greater risk of developing CNCDs in adult life and, if they are female, of having a premature baby⁸³83 Hovi P, Andersson S, Eriksson JG, Järvenpää AL, Strang-Karlsson S, Mäkitie O, Kajantie E. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007; 356(20):2053-2063.^,8484 Bertagnolli M, Luu TM, Lewandowski AJ, Leeson P, Nuyt AM. Preterm birth and hypertension: is there a link? Curr Hypertens Rep 2016; 18(4):28.. Thus, women with chronic conditions during pregnancy require greater health and maternal care, including prenatal diagnosis and managing their CNCDs⁷³73 Requejo J, Merialdi M, Althabe F, Keller M, Katz J, Menon R. Born too soon: care during pregnancy and childbirth to reduce preterm deliveries and improve health outcomes of the preterm baby. Reprod health 2013; 10(Suppl. 1):S4..

A history of premature birth is also a risk factor for a subsequent preterm birth¹³13 Phillips C, Velji Z, Hanly C, Metcalfe A. Risk of recurrent spontaneous preterm birth: a systematic review and meta-analysis. BMJ Open 2017; 7(6):e015402.. However, although preterm birth tends to be repeated, the mechanism for its recurrence is not always clear. It is believed that persistent or recurrent intrauterine infections probably account for many spontaneous, repetitive preterm births, and the continuity of underlying disorders for pregnancies which cause preterm births, such as diabetes, hypertension, or obesity⁹9 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606):75-84.. Similarly, the risk factors shared by pregnancies (smoking during pregnancy, for example) may also contribute to the recurrence of premature birth⁸⁵85 Ananth CV. Epidemiologic approaches for studying recurrent pregnancy outcomes: challenges and implications for research. Semin Perinatol 2007; 31(3):196-201.^,8686 McManemy J, Cooke E, Amon E, Leet T. Recurrence risk for preterm delivery. Am J Obstet Gynecol 2007; 196(6):576.e1-6..

Other adverse events in a previous pregnancy have also been described in literature, such as the risk of a preterm birth in a subsequent pregnancy, for example miscarriage, stillbirth, small baby for the gestational age, placental abruption, and pre-eclampsia⁸⁷87 Van Oppenraaij R, Jauniaux E, Christiansen O, Horcajadas J, Farquharson R, Exalto N. Predicting adverse obstetric outcome after early pregnancy events and complications: a review. Hum Reprod Update 2009; 15(4):409-421.^,8888 Malacova E, Regan A, Nassar N, Raynes-Greenow C, Leonard H, Srinivasjois R, W Shand A, Lavin T, Pereira G. Risk of stillbirth, preterm delivery, and fetal growth restriction following exposure in a previous birth: systematic review and meta-analysis. BJOG 2018; 125(2):183-192.. Weakening of the cervix, due to damage resulting from the surgical handling of a miscarriage, is a possible condition for these associations⁸⁹89 McCarthy FP, Khashan AS, North RA, Rahma MB, Walker JJ, Baker PN, Dekker G, Poston L, McCowan LM, O'Donoghue K, Kenny LC, SCOPE Consortium. Pregnancy loss managed by cervical dilatation and curettage increases the risk of spontaneous preterm birth. Hum Reprod 2013; 28(12):3197-3206., as well as other common or shared conditions among the outcomes, such as abnormality in the placenta, with reduced placental perfusion⁹⁰90 Getahun D, Lawrence JM, Fassett MJ, Strickland D, Koebnick C, Chen W, Jacobsen SJ. The association between stillbirth in the first pregnancy and subsequent adverse perinatal outcomes. Am J Obstet Gynecol 2009; 201(4):378.e1-6.^,9191 Salihu HM, August EM, De La Cruz C, Weldeselasse H, Sanchez E, Alio AP, Marty PJ. All-cause infant mortality and the risk for subsequent preterm birth. Minerva Ginecol 2013; 65(5):557-566..

Data in literature also demonstrates a genetic or epigenetic predisposition for preterm birth⁹²92 Menon R. Spontaneous preterm birth, a clinical dilemma: etiologic, pathophysiologic and genetic heterogeneities and racial disparity. Acta Obstet Gynecol Scand 2008; 87(6):590-600.^,9393 Pennell CE, Jacobsson B, Williams SM, Buus RM, Muglia LJ, Dolan SM, Morken NH, Ozcelik H, Lye SJ; PREBIC Genetics Working Group, Relton C. Genetic epidemiologic studies of preterm birth: guidelines for research. Am J Obstet Gynecol 2007; 196(2):107-118.. Some of the evidence of genetic contribution in preterm birth is genetic heritability shown in studies conducted with twins; increased risk of the recurrence of premature birth in women with a previous prematurity; women who were born premature presenting an increased risk of having a premature birth; increased risk of premature birth among sisters and daughters of women who had a premature birth; and racial disparities in preterm birth which are independent of socio-economic factors⁸²82 Gravett MG, Rubens CE, Nunes TM, Group GR. Global report on preterm birth and stillbirth (2 of 7): discovery science. BMC Pregnancy Childbirth 2010; 10(Suppl. 1):S2.. Studies with candidate genes identified more than 30 single nucleotide polymorphisms (SNPs) predominant in inflammatory pathways and tissue remodelling, associated with increased or decreased risks of preterm birth, or PRM⁹⁴94 Buhimschi CS, Rosenberg VA, Dulay AT, Thung S, Sfakianaki AK, Bahtiyar MO, Buhimschi IA. Multidimensional system biology: genetic markers and proteomic biomarkers of adverse pregnancy outcome in preterm birth. Am J Perinatol 2008; 25(3):175-187..

In addition to maternal factors, risk factors related to the fetus are also associated with preterm birth⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.. A pregnancy with a male fetus has been associated with an increased risk of complications in pregnancy and adverse obstetric outcomes, for example, due to a higher incidence of premature labour for this sex⁹⁵95 Al-Qaraghouli M, Fang YMV. Effect of fetal sex on maternal and obstetric outcomes. Front Pediatr 2017; 5:144.. Possible mechanisms have been proposed to explain this association, such as the relatively higher weight of male, compared to female fetuses, and greater susceptibility to complications in pregnancy (hypertension or infection) in women carrying a male fetus⁹⁶96 McGregor JA, Leff M, Orleans M, Baron A. Fetal gender differences in preterm birth: findings in a North American cohort. Am J Perinatol 1992; 9(1):43-48..

A preterm birth started by health professionals or, in other words, induced labour or elective caesarean, is associated with maternal and fetal indications, or other non-medical reasons⁸8 Goldenberg RL, Gravett MG, Iams J, Papageorghiou AT, Waller SA, Kramer M, Culhane J, Barros F, Conde-Agudelo A, Bhutta ZA, Knight HE, Villar J. The preterm birth syndrome: issues to consider in creating a classification system. Am J Obstet Gynecol 2012; 206(2):113-118.. The most important direct causes, recognised as maternal and fetal complications, are pre-eclampsia, placental abruption, intrauterine growth restriction (IUGR), and fetal distress. However, these conditions may also predispose the spontaneous start of labour in premature gestational ages⁹⁷97 Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006; 19(12):773-782..

Pre-eclampsia is the most serious form of hypertensive disorder in pregnancy, and is associated with the preterm birth indicated⁹⁸98 Aseidu EK, Bandoh DA, Ameme DK, Nortey P, Akweongo P, Sackey SO, Afari E, Nyarko KM, Kenu E. Obstetric determinants of preterm delivery in a regional hospital, Accra, Ghana 2016. BMC Pregnancy Childbirth 2019; 19(1):248.^,9999 Bakker R, Steegers EAP, Hofman A, Jaddoe VWV. Blood pressure in different gestational trimesters, fetal growth, and the risk of adverse birth outcomes: the generation R study. Am J Epidemiol 2011; 174(7):797-806.. Higher blood pressure levels are associated with IUGR and, consequently, preterm birth⁹⁹99 Bakker R, Steegers EAP, Hofman A, Jaddoe VWV. Blood pressure in different gestational trimesters, fetal growth, and the risk of adverse birth outcomes: the generation R study. Am J Epidemiol 2011; 174(7):797-806.. Obstetric intervention before term may also explain the association between pre-eclampsia and premature birth, considering that when blood pressure becomes uncontrollable and/or eclampsia occurs, an early intervention to empty the uterus becomes the option to deal with women with hypertensive complications in pregnancy⁹⁸98 Aseidu EK, Bandoh DA, Ameme DK, Nortey P, Akweongo P, Sackey SO, Afari E, Nyarko KM, Kenu E. Obstetric determinants of preterm delivery in a regional hospital, Accra, Ghana 2016. BMC Pregnancy Childbirth 2019; 19(1):248..

Placental abruption is characterised by chronic placental dysfunction and separation from the uterine wall, the progression of which may lead to a corresponding reduction in the placental surface area available to exchange oxygen and supply nutrients to the fetus¹⁰⁰100 Ananth CV, Oyelese Y, Prasad V, Getahun D, Smulian JC. Evidence of placental abruption as a chronic process: associations with vaginal bleeding early in pregnancy and placental lesions. Eur J Obstet Gynecol Reprod Biol biology 2006; 128(1-2):15-21.. In addition, placental abruption may progress to a significant loss of maternal blood, hypoxia and fetal death, as well as requiring an emergency cesarean¹⁰¹101 Downes KL, Grantz KL, Shenassa ED. Maternal, labor, delivery, and perinatal outcomes associated with placental abruption: a systematic review. Am J Perinatol 2017; 34(10):935-957.^,102102 Tikkanen M. Placental abruption: epidemiology, risk factors and consequences. Acta Obstet Gynecol Scand 2011; 90(2):140-149.. These processes may increase the risk of preterm birth.

IUGR is a common complication of pregnancy, and is associated with fetal (congenital anomalies and infections), placental insufficiency, or maternal factors (poor nutrition, smoking, and gestational hypertension)¹⁰³103 Mayer C, Joseph KS. Fetal growth: a review of terms, concepts and issues relevant to obstetrics. Ultrasound Obstet Gynecol 2013; 41(2):136-145.^,104104 Sato Y, Benirschke K, Marutsuka K, Yano Y, Hatakeyama K, Iwakiri T, Yamada N, Kodama Y, Sameshima H, Ikenoue T, Asada Y. Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases. Histol Histopathol 2013; 28(1):127-132.. Restricted blood flow to the fetus is a common element in the majority of pregnancies with IUGR, which results in a lack of oxygen and supply of nutrients to the fetus¹⁰³103 Mayer C, Joseph KS. Fetal growth: a review of terms, concepts and issues relevant to obstetrics. Ultrasound Obstet Gynecol 2013; 41(2):136-145..

Fetal distress is the term used to describe fetal asphyxia or, in other words, a fetus with compromised gas exchange during the pre-labour or intrapartum phase. Fetal hypoxia resulting from this compromise, if it is not reversed, or delivery is unnecessarily delayed, may lead to permanent damage, or death of the fetus¹⁰⁵105 Parer JT, Livingston EG. What is fetal distress? Am J Obstet Gynecol 1990; 162(6):1421-1425.. Fetal distress requires immediate intervention, being in the urgent category for a caesarean and, consequently, premature birth started by health professionals¹⁰⁶106 Afolayan JM, Olajumoke TO, Esangbedo SE, Edomwonyi NP. Spinal anaesthesia for caesarean section in pregnant women with fetal distress: time for reappraisal. Int J Biomed Sci 2014; 10(2):103-110..

The rise in prematurity rates worldwide is frequently associated with the increase in obstetric interventions, such as induced labour and caesarean delivery¹⁰⁷107 Morisaki N, Togoobaatar G, Vogel JP, Souza JP, Rowland Hogue CJ, Jayaratne K, Ota E, Mori R, WHO Multicountry Survey on Maternal and Newborn Health Research Network. Risk factors for spontaneous and provider-initiated preterm delivery in high and low Human Development Index countries: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG 2014; 121(1):101-109.. Caesarean rates have risen in recent decades¹⁰⁸108 Boerma T, Ronsmans C, Melesse DY, Barros AJD, Barros FC, Juan L, Moller AB, Say L, Hosseinpoor AR, Yi M, Rabello Neto DL, Temmerman M. Global epidemiology of use of and disparities in caesarean sections. Lancet 2018; 392(10155):1341-1348., with the majority boosted by an increase in the use of caesareans without medical indication¹⁰⁹109 Vogel JP, Betrán AP, Vindevoghel N, Souza JP, Torloni MR, Zhang J, Tunçalp Ö, Mori R, Morisaki N, Ortiz-Panozo E, Hernandez B, Pérez-Cuevas R, Qureshi Z, Gülmezoglu AM, Temmerman M, WHO Multi-Country Survey on Maternal and Newborn Health Research Network. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. Lancet Glob Health 2015; 3(5):e260-e270.. A number of authors highlight that elective caesareans are more frequent among women who receive private health care during delivery, with higher levels of education, and a more favourable economic situation¹¹⁰110 Nakamura-Pereira M, do Carmo Leal M, Esteves-Pereira AP, Domingues RM, Torres JA, Dias MA, Moreira ME. Use of Robson classification to assess cesarean section rate in Brazil: the role of source of payment for childbirth. Reprod health 2016; 13(Suppl. 3):128.. In addition, changes in maternal characteristics and professional practice, as well as economic, organisational, social and cultural factors, have been described as some of the factors related to the rise in preterm birth rates¹¹¹111 Leal M, Pereira A, Domingues R, Theme Filha MM, Dias MA, Nakamura-Pereira M, Bastos MH, Gama SG. Obstetric interventions during labor and childbirth in Brazilian low-risk women. Cad Saude Publica 2014; 30(1):S1-S16..

In addition, newborns with congenital anomalies, including neural tube defects, are more prone to premature births⁵5 Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J, Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10(Suppl. 1):S2.. The mechanism for this association has not been fully clarified, considering that premature birth and congenital malformations are conditions which have common risk factors¹¹²112 Grandi C, Luchtenberg G, Rittler M. The contribution of birth defects to spontaneous preterm birth. Am J Perinatol 2007; 24(8):487-492.. The prenatal diagnosis of a fetal malformation may also lead to induced labour or a caesarean delivery, independent of gestational age¹¹³113 Kelkay B, Omer A, Teferi Y, Moges Y. Factors associated with singleton preterm birth in Shire Suhul general hospital, Northern Ethiopia, 2018. J pregnancy 2019; 2019:4629101..

Lastly, environmental exposure has also been associated with adverse results of pregnancy in different studies¹¹⁴114 Xiao Q, Chen H, Strickland MJ, Kan H, Chang HH, Klein M, Yang C, Meng X, Liu Y. Associations between birth outcomes and maternal PM2.5 exposure in Shanghai: a comparison of three exposure assessment approaches. Environ Int 2018; 117:226-236.

115 Balakrishnan K, Ghosh S, Thangavel G, Sambandam S, Mukhopadhyay K, Puttaswamy N, Sadasivam A, Ramaswamy P, Johnson P, Kuppuswamy R, Natesan D, Maheshwari U, Natarajan A, Rajendran G, Ramasami R, Madhav S, Manivannan S, Nargunanadan S, Natarajan S, Saidam S, Chakraborty M, Balakrishnan L, Thanasekaraan V. Exposures to fine particulate matter (PM2.5) and birthweight in a rural-urban, mother-child cohort in Tamil Nadu, India. Environ Res 2018; 161:524-531.^-116116 Chen G, Guo Y, Abramson MJ, Williams G, Li S. Exposure to low concentrations of air pollutants and adverse birth outcomes in Brisbane, Australia, 2003-2013. Sci Total Environ 2018; 622-623:721-726.. Air pollution [particulate matter; ozone (O3); sulphur dioxide (SO2); nitrogen dioxide (NO2); airborne particles (PM_{2.5 and} PM₁₀); carbon monoxide (CO) and lead] may be directly associated with preterm birth through different biological mechanisms¹¹⁴114 Xiao Q, Chen H, Strickland MJ, Kan H, Chang HH, Klein M, Yang C, Meng X, Liu Y. Associations between birth outcomes and maternal PM2.5 exposure in Shanghai: a comparison of three exposure assessment approaches. Environ Int 2018; 117:226-236.

115 Balakrishnan K, Ghosh S, Thangavel G, Sambandam S, Mukhopadhyay K, Puttaswamy N, Sadasivam A, Ramaswamy P, Johnson P, Kuppuswamy R, Natesan D, Maheshwari U, Natarajan A, Rajendran G, Ramasami R, Madhav S, Manivannan S, Nargunanadan S, Natarajan S, Saidam S, Chakraborty M, Balakrishnan L, Thanasekaraan V. Exposures to fine particulate matter (PM2.5) and birthweight in a rural-urban, mother-child cohort in Tamil Nadu, India. Environ Res 2018; 161:524-531.^-116116 Chen G, Guo Y, Abramson MJ, Williams G, Li S. Exposure to low concentrations of air pollutants and adverse birth outcomes in Brisbane, Australia, 2003-2013. Sci Total Environ 2018; 622-623:721-726.. PM_2.5 may induce rupture of the membrane and placental abruption,¹¹⁷117 Bell ML, Ebisu K, Belanger K. Ambient air pollution and low birth weight in Connecticut and Massachusetts. Environ Health Perspect 2007; 115(7):1118-1124. and increase intrauterine inflammation¹¹⁸118 Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills-Karp M, Wang X. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: The Boston Birth Cohort. Environ Health Perspect 2016; 124(10):1608-1615.. Similarly, ozone exposure may cause the release of proinflammatory mediators, which contribute to preterm birth¹¹⁹119 Lin Y-T, Jung C-R, Lee YL, Hwang B-F. Associations between ozone and preterm birth in women who develop gestational diabetes. Am J Epidemiol 2015; 181(4):280-287..

Final considerations

Preterm birth is a complex, multifactorial phenomenon involving a network of causal mechanisms which cannot all be covered in a single model, as proposed in this review. However, the use of a hierarchical model in an analysis of the determinant factors of preterm birth is a possible and always applicable approach, anchored in a review of pertinent literature on the topic. Combined with this, considering the complexity of preterm birth, it is only one of the possible hierarchical approaches, and new models could be proposed in this segment.

In the model presented, the factors in the distinct levels of determination interrelate, influencing the occurrence of preterm birth. The socio-economic determinants were classified as distal risk factors which indirectly act on preterm birth through intermediate variables, for example, healthcare, psychosocial and behavioural factors, which are expressed in food, tobacco and alcohol consumption patterns, among others. These variables may be influenced by the mother’s socio-economic condition, family, housing, and neighbourhood. These intermediate factors determine the proximal level, which are those related to the mother, pregnancy, delivery, and fetus. At the proximal level, biological risk factors have a direct effect on preterm birth, with these being influenced by factors situated at higher (distal variables) and lower levels (intermediate variables).

We hope that this model can serve as a theoretical base for statistical modelling in studies that evaluate the interrelationships and effects of mediating the determinants of preterm birth. The proposal is to test this in a large cohort of births. We hope that the application of this hierarchical model may contribute to understanding the risk factors of preterm birth and its interrelationships. In addition, that it may contribute towards the development of specific strategies to prevent preterm births, in an attempt to interrupt the chain of determination of this outcome.

Acknowledgements

We would like to thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the grant awarded to ASR.

References

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