Produção Nacional
Revisado por pares
Challenges in defining and classifying the preterm birth syndrome
2011; Elsevier BV; Volume: 206; Issue: 2 Linguagem: Inglês
10.1016/j.ajog.2011.10.864
ISSN1097-6868
AutoresMichael S. Kramer, Aris T. Papageorghiou, Jennifer F. Culhane, Zulfiqar A Bhutta, Robert L. Goldenberg, Michael G. Gravett, Jay D. Iams, Agustín Conde‐Agudelo, Sarah A. Waller, Fernando C. Barros, Hannah Knight, José Villar,
Tópico(s)Infant Development and Preterm Care
ResumoIn 2009, the Global Alliance to Prevent Prematurity and Stillbirth Conference charged the authors to propose a new comprehensive, consistent, and uniform classification system for preterm birth. This first article reviews issues related to measurement of gestational age, clinical vs etiologic phenotypes, inclusion vs exclusion of multifetal and stillborn infants, and separation vs combination of pathways to preterm birth. The second article proposes answers to the questions raised here, and the third demonstrates how the proposed system might work in practice. In 2009, the Global Alliance to Prevent Prematurity and Stillbirth Conference charged the authors to propose a new comprehensive, consistent, and uniform classification system for preterm birth. This first article reviews issues related to measurement of gestational age, clinical vs etiologic phenotypes, inclusion vs exclusion of multifetal and stillborn infants, and separation vs combination of pathways to preterm birth. The second article proposes answers to the questions raised here, and the third demonstrates how the proposed system might work in practice. Preterm birth, defined by the World Health Organization (WHO) as birth prior to 37 complete weeks (259 days) after the first day of the last menstrual period preceding the pregnancy,1World Health OrganizationManual of the international statistical classification of diseases, injuries, and causes of death. Vol. 1 (9th revision). World Health Organization, Geneva (Switzerland)1975Google Scholar is a major global public health problem.2Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (4734) Google Scholar, 3Lawn J.E. Gravett M.G. Nunes T.M. Rubens C.E. Stanton C. GAPPS Review GroupGlobal report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data.BMC Pregnan Childbirth. 2010; 10: S1Crossref PubMed Google Scholar Recent systematic reviews by WHO4Beck S. Wojdyla D. Say L. et al.The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.Bull World Health Organ. 2010; 88: 1-80Crossref Scopus (1383) Google Scholar and the March of Dimes5Howson C.P. Merialdi M. Lawn J.E. Requejo J.H. Say L. March of Dimes white paper on preterm birth: the global and regional toll. March of Dimes Foundation, White Plains, NY2009Google Scholar have estimated that in 2005, 13 million infants were born preterm worldwide. The majority of these preterm births (85%) occur in Africa and Asia: the former because of high rates, the latter because of the large number of births. For several decades, preterm birth has been the focus of research and public health intervention in many developed countries because of the associated high risks of infant mortality and long-term neurocognitive, visual, and pulmonary sequelae and because rates have been stable or increasing.2Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (4734) Google Scholar, 6Muglia L.J. Katz M. The enigma of spontaneous preterm birth.N Engl J Med. 2010; 362: 529-535Crossref PubMed Scopus (498) Google ScholarSee related editorial, page 99In low- and middle-income countries, attention to preterm birth has been more recent, largely because gestational age (GA) at birth is not routinely recorded in noninstitutional deliveries and is often unknown.3Lawn J.E. Gravett M.G. Nunes T.M. Rubens C.E. Stanton C. GAPPS Review GroupGlobal report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data.BMC Pregnan Childbirth. 2010; 10: S1Crossref PubMed Google Scholar, 4Beck S. Wojdyla D. Say L. et al.The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.Bull World Health Organ. 2010; 88: 1-80Crossref Scopus (1383) Google Scholar, 5Howson C.P. Merialdi M. Lawn J.E. Requejo J.H. Say L. March of Dimes white paper on preterm birth: the global and regional toll. March of Dimes Foundation, White Plains, NY2009Google Scholar The longstanding emphasis on low birthweight, rather than preterm birth, naturally led to a primary emphasis on maternal under nutrition, which does not appear to be a major contributor to preterm birth.7Kramer M. Determinants of low birth weight: methodological assessment and meta-analysis.Bull WHO. 1987; 65: 663-737PubMed Google ScholarIn 2009, more than 200 participants attended the International Conference on Prematurity and Stillbirth convened by the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), hosted by Seattle Children's Hospital with support from the Bill and Melinda Gates Foundation, March of Dimes, Save the Children, World Health Organization, United Nations Children's Fund, and Program for Appropriate Technology in Health. A Global Action Agenda was developed (an agenda) that, in part, highlighted the need for a comprehensive, consistent, and uniform classification system for preterm birth.3Lawn J.E. Gravett M.G. Nunes T.M. Rubens C.E. Stanton C. GAPPS Review GroupGlobal report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data.BMC Pregnan Childbirth. 2010; 10: S1Crossref PubMed Google ScholarThe authors of this paper and the following two in the series were brought together as a direct result of the GAPPS meeting, with instructions to determine the need for such a classification system, to define the issues related to creating a preterm birth classification system, and to present a prototype classification system for general consideration.Measurement issuesThe earlier international definition of prematurity (birthweight ≤2500 g) did not distinguish between infants born early from those born small for their GA.8American Academy of Pediatrics Committee on Fetus and NewbornNomenclature for duration of gestation, birth weight and intra-uterine growth.Pediatrics. 1967; 39: 935-939PubMed Google Scholar For that reason, WHO changed the term from prematurity to preterm birth and defines the latter (preterm birth) based on GA only: a birth before 37 completed weeks (259 days) after the first day of the last menstrual period (LMP).1World Health OrganizationManual of the international statistical classification of diseases, injuries, and causes of death. Vol. 1 (9th revision). World Health Organization, Geneva (Switzerland)1975Google Scholar That GA, a cutoff that was entirely arbitrary, however, is an issue that will be discussed later in this article.First, it is important to consider how GA is measured. In the past, the GA estimate on a population-wide scale was primarily based on the LMP, an estimate that assumes that conception occurs on the same day of ovulation and that ovulation and conception occur 14 days after the onset of the LMP. Differences in the duration of the menstrual cycle, however, and particularly on the day of the menstrual cycle on which ovulation occurs, account for considerable variability in the day of conception vis-à-vis the first day of the LMP.9Saito M. Yazawa K. Hashiguchi A. Kumasaka T. Nishi N. Kato K. Time of ovulation and prolonged pregnancy.Am J Obstet Gynecol. 1972; 112: 31-38PubMed Scopus (65) Google Scholar, 10Berg A.T. Menstrual cycle length and the calculation of gestational age.Am J Epidemiol. 1991; 133: 585-589PubMed Google Scholar In addition, LMP reporting is subject to error in recall and can be influenced by spotting or frank bleeding (which may reflect early miscarriages of clinically unrecognized pregnancies).11Gjessing H.K. Skjaerven R. Wilcox A.J. Errors in gestational age: evidence of bleeding early in pregnancy.Am J Pub Health. 1999; 89: 213-218Crossref PubMed Scopus (104) Google Scholar, 12Wier M.L. Pearl M. Kharrazi M. Gestational age estimation on United States live birth certificates: a historical overview.Paediatr Perinat Epidemiol. 2007; 21: 4-12Crossref PubMed Scopus (56) Google ScholarHistorically, obstetricians and other prenatal care providers often used uterine fundal height as a check to validate the estimated duration of gestation, but more recently, clinical GA estimates have been based on ultrasound fetal measurements in the first half of the pregnancy.12Wier M.L. Pearl M. Kharrazi M. Gestational age estimation on United States live birth certificates: a historical overview.Paediatr Perinat Epidemiol. 2007; 21: 4-12Crossref PubMed Scopus (56) Google Scholar These are usually calculated from the biparietal diameter in the second trimester (13-20 weeks) or crown-rump length before 14 weeks of gestation.Ultrasound-based estimates of GA have been shown to yield GA estimates that are 2-3 days earlier than LMP-based estimates (corresponding to ovulation on day 16-17 vs day 14), on average, and yield slightly higher rates of preterm birth.13Kramer M.S. McLean F.H. Boyd M.E. User R.H. The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations.JAMA. 1988; 260: 3306-3308Crossref PubMed Scopus (391) Google Scholar, 14Goldenberg R. Davis R. Cutter G. Hoffman H. Brumfield C. Foster J. Prematurity, postdates, and growth retardation: the influence of use of ultrasonography on reported gestational age.Am J Obstet Gynecol. 1989; 160: 462-470Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 15Gardosi J. Geirsson R.T. Routine ultrasound is the method of choice for dating pregnancy.Br J Obstet Gynaecol. 1998; 105: 933-936Crossref PubMed Scopus (77) Google Scholar, 16Yang H. Kramer M.S. Platt R.W. et al.How does early ultrasound estimation of gestational age lead to higher rates of preterm birth?.Am J Obstet Gynecol. 2002; 186: 433-437Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Ultrasound-based estimations may also have errors related to insufficient standardization and quality control of the operators, are based on equations derived from small samples (especially at early GAs) from different selected populations, do not provide variability around the GA estimates, and assume that all fetuses with the same measurement have the same GA (ie, they do not account for true differences in fetal growth in early gestation).17Smith G.C. Smith M.F. McNay M.B. Fleming J.E. First-trimester growth and the risk of low birth weight.N Engl J Med. 1998; 339: 1817-1822Crossref PubMed Scopus (263) Google Scholar, 18Morin I. Morin L. Zhang X. et al.Determinants and consequences of discrepancies in menstrual and ultrasonographic gestational age estimates.BJOG. 2005; 112: 145-152Crossref PubMed Scopus (71) Google Scholar Data entry errors can arise with either LMP or ultrasound GA estimates and can lead to an apparent bimodal or upwardly skewed distribution of birthweight at preterm GAs (especially at 27-32 weeks), owing to inclusion of term or near-term births.19Williams R.L. Creasy R.K. Cunningham G.C. Hawes W.E. Norris F.D. Tashiro M. Fetal growth and perinatal viability in California.Obstet Gynecol. 1982; 59: 624-632PubMed Google Scholar, 20David R. Did low birth weight among US blacks really increase?.Am J Public Health. 1986; 76: 380-384Crossref PubMed Scopus (10) Google Scholar, 21Platt R.W. Abrahamowicz M. Kramer M.S. et al.Detecting and eliminating erroneous gestational ages: a normal mixture model.Stat Med. 2001; 20: 3491-3503Crossref PubMed Scopus (50) Google Scholar, 22Ananth C.V. Menstrual versus clinical estimate of gestational age dating in the United States: temporal trends and variability in indices of perinatal outcomes.Paediatr Perinat Epidemiol. 2007; 21: 22-30Crossref PubMed Scopus (124) Google Scholar, 23Haglund B. Birthweight distributions by gestational age: comparison of LMP-based and ultrasound-based estimates of gestational age using data from the Swedish Birth Registry.Paediatr Perinat Epidemiol. 2007; 21: 72-78Crossref PubMed Scopus (36) Google ScholarIn the United States and the United Kingdom, official estimates of preterm birth rates are based on LMP GA estimates. Despite the evidence from clinical and hospital-based study samples that ultrasound-based estimates are slightly shorter than LMP-based estimates,13Kramer M.S. McLean F.H. Boyd M.E. User R.H. The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations.JAMA. 1988; 260: 3306-3308Crossref PubMed Scopus (391) Google Scholar, 14Goldenberg R. Davis R. Cutter G. Hoffman H. Brumfield C. Foster J. Prematurity, postdates, and growth retardation: the influence of use of ultrasonography on reported gestational age.Am J Obstet Gynecol. 1989; 160: 462-470Abstract Full Text PDF PubMed Scopus (100) Google Scholar preterm birth rates based on the menstrual estimates in the United States have been shown to be considerably higher than those based on the clinical estimate, which, as in other countries, is increasingly based on ultrasound-derived GA estimates.12Wier M.L. Pearl M. Kharrazi M. Gestational age estimation on United States live birth certificates: a historical overview.Paediatr Perinat Epidemiol. 2007; 21: 4-12Crossref PubMed Scopus (56) Google Scholar, 22Ananth C.V. Menstrual versus clinical estimate of gestational age dating in the United States: temporal trends and variability in indices of perinatal outcomes.Paediatr Perinat Epidemiol. 2007; 21: 22-30Crossref PubMed Scopus (124) Google Scholar, 24Martin J.A. United States vital statistics and the measurement of gestational age.Paediatr Perinat Epidemiol. 2007; 21: 13-21Crossref PubMed Scopus (45) Google Scholar US and Canadian preterm birth rates, for example, have been shown to be closer when the US rate is based on the clinical estimate.25Joseph K.S. Huang L. Liu S. et al.Reconciling the high rates of preterm and postterm birth in the United States.Obstet Gynecol. 2007; 109: 813-822Crossref PubMed Scopus (87) Google Scholar The higher US preterm birth rate based on the LMP GA estimate may reflect errors in recalling the date of the LMP, particularly among women with late onset of prenatal care.The neonatal mortality rates among preterm births are very similar in Canada and the United States when the US rate is based on the clinical estimate but considerably lower when based on the menstrual (LMP) estimate, suggesting the inclusion of some term births among those classified as preterm based on LMP.25Joseph K.S. Huang L. Liu S. et al.Reconciling the high rates of preterm and postterm birth in the United States.Obstet Gynecol. 2007; 109: 813-822Crossref PubMed Scopus (87) Google Scholar Similarly, relative risks (vs infants born ≥37 weeks) are also very similar in Canada and the United States when based on the US clinical GA estimate but are considerably lower in the United States when based on the LMP-based estimate. Postterm rates (GA ≥42 weeks) are virtually identical in the United States (including both US whites and blacks) and Canada when the US rates are based on the clinical estimate but much higher in the United States when based on the menstrual estimate.25Joseph K.S. Huang L. Liu S. et al.Reconciling the high rates of preterm and postterm birth in the United States.Obstet Gynecol. 2007; 109: 813-822Crossref PubMed Scopus (87) Google Scholar In summary, these measurement differences can lead to substantial disparities in the GA distribution, and specifically the preterm birth rate, for different populations.Finally, postnatal examination of the newborn infant has also been used to estimate GA, based on physical and neurological criteria. These estimates are far less satisfactory than early ultrasound-based prenatal estimates, however, because they are influenced by race, pregnancy complications, delivery complications, and birthweight for GA.26Alexander G.R. de Caunes F. Hulsey T.C. Tompkins M.E. Allen M. Validity of postnatal assessments of gestational age: a comparison of the method of Ballard et al. and early ultrasonography.Am J Obstet Gynecol. 1992; 166: 891-895Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 27Allen M.C. Assessment of gestational age and neuromaturation.Ment Retard Devel Disab Res Rev. 2005; 11: 21-33Crossref PubMed Scopus (27) Google ScholarPhenotypic heterogeneityPreterm birth is an unusual entity because it is defined by time, not by a distinctive clinical phenotype. Consider the hypothetical analogy of premature death. Premature death (ie, death occurring at an age earlier than expected; eg, <65 years) would consist largely of deaths from cancer, coronary heart disease, unintentional injury, and suicide.Imagine the etiological research based on such an entity. Risk factors differ vastly for cancer, coronary heart disease, unintentional injury, and suicide. A genome-wide association study, study of biomarkers, or investigation of physiological/biochemical mechanisms underlying premature death would be meaningless and uninterpretable. This is a similar situation to that currently faced by preterm birth and at least partly explains why we have not made much headway in understanding its etiology.2Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (4734) Google Scholar, 6Muglia L.J. Katz M. The enigma of spontaneous preterm birth.N Engl J Med. 2010; 362: 529-535Crossref PubMed Scopus (498) Google ScholarExisting phenotypic classifications or subdivisions include subdivisions by GA (early vs late); clinical presentation (spontaneous preterm labor, preterm prelabor rupture of membranes [PPROM], and iatrogenic [indicated] preterm birth); and pathology or presumed pathophysiological pathways (infectious/inflammatory, vasculopathic, and stress-induced).Subdivision by GA usually separates early preterm birth (variably defined but often <32 completed weeks) vs late preterm births, those between 32 and 36 (or 34-36) completed weeks.Subdivision by clinical presentation distinguishes cases of preterm birth presenting with spontaneous preterm labor, those with PPROM, and iatrogenic (indicated) preterm birth.28Savitz D.A. Blackmore C.A. Thorp J.M. Epidemiologic characteristics of preterm delivery: etiologic heterogeneity.Am J Obstet Gynecol. 1991; 164: 467-471Abstract Full Text PDF PubMed Scopus (313) Google ScholarFinally, placental pathology or postulated physiological mechanisms have also been used to subdivide preterm birth into infectious/inflammatory, vasculopathic, and stress-induced pathways to preterm birth.2Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (4734) Google Scholar, 6Muglia L.J. Katz M. The enigma of spontaneous preterm birth.N Engl J Med. 2010; 362: 529-535Crossref PubMed Scopus (498) Google Scholar, 29Romero R. Mazor M. Munoz H. Gomez R. Galasso M. Sherer D.M. The preterm labor syndrome.Ann N Y Acad Sci. 1994; 734: 414-429Crossref PubMed Scopus (324) Google Scholar, 30Lockwood C.J. Stress-related preterm delivery: the role of corticotropin-releasing hormone.Am J Obstet Gynecol. 1999; 180: S264-S266Abstract Full Text Full Text PDF PubMed Google Scholar, 31Klebanoff M.A. Shiono P.H. Top down, bottom up and inside out: reflections on preterm birth.Paediatr Perinat Epidemiol. 1995; 9: 125-129Crossref PubMed Scopus (64) Google ScholarStudies have been consistent in showing that early preterm births are more frequently associated with infection/inflammation, as revealed by leukocytosis or high levels of inflammatory cytokines in the amniotic fluid, histological chorioamnionitis, or even cultured organisms from the genital tract.32Goldenberg R.L. Hauth J.C. Andrews W.W. Intrauterine infection and preterm delivery.N Engl J Med. 2000; 342: 1500-1507Crossref PubMed Scopus (1958) Google Scholar Other features of the subdivision, however, have been less robust. For instance, distinguishing preterm labor from PPROM by history can be difficult. Women often present with preterm labor already underway and membranes already ruptured. It is often impossible to determine which occurred first, even on careful questioning. The criteria used to make this distinction also vary from study to study, as do the relative proportions between the 2 presentation categories.33Hartmann K. Thorp Jr, J.M. McDonald T.L. Savitz D.A. Granados J.L. Cervical dimensions and risk of preterm birth: a prospective cohort study.Obstet Gynecol. 1999; 93: 504-509Crossref PubMed Scopus (31) Google Scholar, 34Ananth C.V. Vintzileos A.M. Epidemiology of preterm birth and its clinical subtypes.J Matern Fetal Neonat Med. 2006; 19: 773-782Crossref PubMed Scopus (324) Google Scholar, 35Meis P.J. Ernest J.M. Moore M.L. Causes of low birth weight births in public and private patients.Am J Obstet Gynecol. 1987; 156: 1165-1168Abstract PubMed Google Scholar, 36Connon A.F. An assessment of key aetiological factors associated with preterm birth and perinatal mortality.Aust N Z J Obstet Gynaecol. 1992; 32: 200-203Crossref PubMed Scopus (10) Google Scholar, 37Schieve L.A. Handler A. Preterm delivery and perinatal death among black and white infants in a Chicago-area perinatal registry.Obstet Gynecol. 1996; 88: 356-363Crossref PubMed Scopus (46) Google ScholarSome studies have required a minimum duration of rupture of membranes prior to onset of regular contractions before classifying a case as PPROM,33Hartmann K. Thorp Jr, J.M. McDonald T.L. Savitz D.A. Granados J.L. Cervical dimensions and risk of preterm birth: a prospective cohort study.Obstet Gynecol. 1999; 93: 504-509Crossref PubMed Scopus (31) Google Scholar whereas others base the distinction on questioning the mother of which event occurred first. Although early publications proposing this subdivision suggested that African-American women had higher relative risks vs whites for PPROM than for spontaneous preterm labor38Zhang J. Savitz D.A. Preterm birth subtypes among blacks and whites.Epidemiology. 1992; 3: 428-433Crossref PubMed Scopus (62) Google Scholar and that PPROM was more often associated with an infectious etiology than was spontaneous preterm labor,39Furman B. Shoham-Vardi I. Bashiri A. Erez O. Mazor M. Clinical significance and outcome of preterm prelabor rupture of membranes: population-based study.Eur J Obstet Gynecol Reprod Biol. 2000; 92: 209-216Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar those findings have not been confirmed in more recent studies.34Ananth C.V. Vintzileos A.M. Epidemiology of preterm birth and its clinical subtypes.J Matern Fetal Neonat Med. 2006; 19: 773-782Crossref PubMed Scopus (324) Google Scholar, 40Berkowitz G.S. Blackmore-Prince C. Lapinski R.H. Savitz D.A. Risk factors for preterm birth subtypes.Epidemiology. 1998; 9: 279-285Crossref PubMed Scopus (174) Google Scholar The observed black-white differences could theoretically reflect racial or cultural differences in the interval between onset of clinical symptoms and seeking of medical care or even bias in the type of questioning by health care providers or their belief in the accuracy of reporting.The category of indicated preterm birth is etiologically and prognostically heterogeneous.34Ananth C.V. Vintzileos A.M. Epidemiology of preterm birth and its clinical subtypes.J Matern Fetal Neonat Med. 2006; 19: 773-782Crossref PubMed Scopus (324) Google Scholar The category includes both fetal and maternal indications (eg, fetal growth restriction and nonreassuring tests of fetal well-being and pregnancy-induced hypertension and antepartum hemorrhage). Within the overall category of indicated preterm birth, some etiological risk factors can have opposite effects, depending on the indication. For example, maternal smoking and low maternal prepregnancy body mass index are risk factors for fetal growth restriction but are protective against preeclampsia, whereas maternal obesity is protective against fetal growth restriction but a risk factor for preeclampsia. Moreover, indicated preterm births have increased over time largely because the indication threshold has fallen as obstetric care has become more aggressive and interventive.41Ananth C.V. Joseph K.S. Oyelese Y. Demissie K. Vintzileos A.M. Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000.Obstet Gynecol. 2005; 105: 1084-1091Crossref PubMed Scopus (285) Google Scholar In the United States, this increase has been more prominent among whites than among blacks,41Ananth C.V. Joseph K.S. Oyelese Y. Demissie K. Vintzileos A.M. Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000.Obstet Gynecol. 2005; 105: 1084-1091Crossref PubMed Scopus (285) Google Scholar which may be partly responsible for the recent modest attenuation in the racial disparity in that country.Phenotype vs etiologyExisting subdivisions of preterm birth often include presumed etiological or mechanistic pathways, as well as descriptive characteristics that might be preferable in definable a pure phenotype. Atherosclerotic coronary heart disease is a clinical, radiological, and/or pathological phenotypic entity that does not consider serum lipids, glucose tolerance, family history, blood pressure, smoking history, or genotype. Similarly, non–small-cell lung cancer is a combined clinical/pathological phenotype that is assigned based on clinical, radiological, and pathological characteristics present at the time of diagnosis, not on history of smoking, environmental exposure, or occupation.Deciding on what characteristics should be included or excluded from the phenotypic classification of preterm birth, however, is far more difficult. It seems reasonable to exclude such potential risk factors as socioeconomic status and smoking from the list of phenotypic criteria. But what about documented amniotic fluid infection or inflammation, placenta previa, cervical shortening, or prior history of preterm delivery? Should these be considered risk factors (potential etiological determinants) or phenotypic features? These issues will be discussed in greater depth in the second paper of this series.A further complication in defining phenotypic subtypes of preterm birth is the rapidly changing landscape. The falling threshold for obstetric intervention (labor induction or prelabor cesarean delivery) is a moving target.42Fuchs K. Wapner R. Elective cesarean section and induction and their impact on late preterm births.Clin Perinatol. 2006; 33: 793-801Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 43Bettegowda V.R. Dias T. Davidoff M.J. Damus K. Callaghan W.M. Petrini J.R. The relationship between cesarean delivery and gestational age among US singleton births.Clin Perinatol. 2008; 35: 309-323Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar We are not commenting here on the benefits or harms of these profound temporal changes for maternal, fetal, and neonatal health. But some of today's or tomorrow's preterm births would have been spontaneous term births or preterm stillbirths in the past. Clinical intervention makes it impossible to determine the natural phenotype (ie, the phenotype that would have been observed in the absence of the intervention, and prevents phenotypic stability over time, however desirable that might be for etiological or prognostic research). In other words, the entirety of the natural phenotype is unknowable because the visible phenotype is influenced by prenatal and peripartum care. This phenomenon will increasingly and unavoidably complicate etiological research on preterm birth.Other definitional problemsIt is often difficult or impossible to determine whether studies or population prevalence rates include or exclude stillbirths. Although stillbirths account for only around 5% of all preterm births, the majority of stillbirths occur prior to 37 completed weeks. Although few studies have examined whether the etiological risk factors, or their relative importance, differ in preterm stillbirths and preterm live births. Poor fetal growth is strongly associated with both.44Gardosi J. Mul T. Mongelli M. Fagan D. Analysis of birthweight and gestational age in antepartum stillbirths.Br J Obstet Gynaecol. 1998; 105: 524-530Crossref PubMed Scopus (171) Google Scholar, 45Zeitlin J. Ancel P.Y. Saurel-Cubizolles M.J. Papiernik E. The relationship between intrauterine growth restriction and preterm delivery: an empirical approach using data from a European case-control study.Br J Obstet Gynaecol. 2000; 107: 750-758Crossref Scopus (143) Google Scholar, 46Pedersen N.G. Figueras F. Wojdemann K.R. Tabor A. Gardosi J. Early fetal size and growth as predictors of adverse outcome.Obstet Gynecol. 2008; 112: 765-771Crossref PubMed Scopus (44) Google Scholar, 47Hutcheon J.A. Zhang X. Cnattingius S. Kramer M.S. Platt R.W. Customised birthweight percentiles: does adjusting for maternal characteristics matter?.BJOG. 2008; 115: 1397-1404Crossref PubMed Scopus (99) Google Scholar, 48Hemming K. Hutton J.L. Bonellie S. A comparison of customized and population-based birth-weight standards: the influence of gestational age.Eur J Obstet Gynecol Reprod Biol. 2009; 146: 41-45Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Moreover, risk factors have been shown to strongly overlap for live vs stillborn births as early as 14-21 weeks of gestation.49Ancel P.Y. Saurel-Cubizolles M.J. Di Renzo G.C. Papiernik E. Breart G. Risk factors for 14-21 week abortions: a case-control study in Europe The Europop Group.Hum Reprod. 2000; 15: 2426-2432Crossref PubMed Scopus (28) Google ScholarLate pregnancy terminations are a tiny fraction of all preterm births but a rising and important fraction of perinatal deaths. Studies from Canada indi
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