www.AJOG.org Clinical Opinion

The syndrome: issues to consider in creating a classification system

Robert L. Goldenberg, MD; Michael G. Gravett, MD; Jay Iams, MD; Aris T. Papageorghiou, MBChB, MRCOG; Sarah A. Waller, MD; Michael Kramer, MD; Jennifer Culhane, PhD, MPH; Fernando Barros, PhD; Augustin Conde-Agudelo, MD, MPH; Zulfiqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD; Hannah E. Knight, MSc; Jose Villar, MD, MSc, MPH, FRCOG

n the first article of this series, the po- Itential benefits of a classification sys- A comprehensive classification system for preterm birth requires expanded gestational tem for preterm birth were articulated boundaries that recognize the early origins of preterm parturition and emphasize fetal and a brief history of attempts to classify maturity over fetal age. Exclusion of stillbirths, terminations, and multifetal preterm birth was presented.1 In this ar- gestations prevents comprehensive consideration of the potential causes and presenta- ticle, our goal is to raise many of the is- tions of preterm birth. Any step in parturition (cervical softening and ripening, decidual- sues that need to be addressed and the membrane activation, and/or myometrial contractions) may initiate preterm parturition, decisions that need to be made to create a and should be recorded for every preterm birth, as should the condition of the , preterm birth classification system. As in , newborn, and , before a phenotype is assigned. the other articles in this series, the au- Key words: classification, phenotype, preterm birth thors were brought together as a direct result of the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) In addition to discussing the issues the assumption that the clinical pre- meeting with instructions to determine that need to be resolved before a clas- sentation for delivery defines distinct the need for such a classification system, sification system can be created, we causes and acceptance of the arbitrary to define the issues related to creating a also intend to cause readers to consider gestational age boundaries that define preterm birth classification system, and conceptual issues that may have hin- prematurity. In writing this commen- to present a prototype classification sys- dered progress toward better under- tary, we began with many diverse opin- tem for general consideration. standing preterm birth. These include ions regarding the development of a classification system for preterm birth. We found that, by isolating each issue and posing a specific question regard- From the Department of and Gynecology (Dr Goldenberg), Drexel University, Philadelphia, PA; Department of Obstetrics and Gynecology (Drs Gravett and Waller), University ing the issue, we could better under- of Washington, Seattle, and Global Alliance to Prevent Prematurity and Stillbirth, Seattle stand the principles on which to base a Children’s, Seattle, WA; Division of Maternal Fetal , Department of Obstetrics and classification system and, eventually, Gynecology (Dr Iams), The Ohio State University Medical Center, Columbus OH; Nuffield came to a consensus on each of the is- Department of Obstetrics and (Drs Papageorghiou, Knight, and Villar), and Oxford sues. We have tried to identify and em- Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, phasize clearly superior options among UK; Departments of and of Epidemiology, Biostatistics, and Occupational Health (Dr the possible choices, although noting Kramer), McGill University Faculty of Medicine, Montreal, Canada; Department of Pediatrics other potential options and the ratio- (Dr Culhane), University of Pennsylvania, Philadelphia, PA; Post-Graduate Course in Health and nale for our choices. Behavior (Dr Barros), Catholic University of Pelotas, RS, Brazil; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National What is the reason for creating Institutes of Health/Department of Health and Human Services (Dr Conde-Agudelo), Bethesda, this classification system MD and Detroit, MI; and the Division of Women and Child Health (Dr Bhutta), The Aga Khan for preterm birth? University, Karachi, Pakistan. There are many reasons to classify preterm Received May 29, 2011; revised Aug. 27, 2011; accepted Oct.19, 2011. births and to consider various systems of This project was supported by the Bill and Melinda Gates Foundation and the Global Alliance to classification. In this article, we focus on Prevent Prematurity and Stillbirth, an initiative of Seattle Children’s, and by INTERGROWTH-21st the decisions involved in creating a classi- Grant ID 49038 from the Bill and Melinda Gates Foundation to the University of Oxford, for which we are very grateful. fication system for use in both popula- The authors report no conflict of interest. tion surveillance and research, so that Reprints not available from the authors. when specific types of preterm births are 0002-9378/$36.00 • © 2012 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2011.10.865 discussed, studied, or compared across populations or over time, categories See related editorial, page 99 have consistent definitions that are widely understood and accepted.

FEBRUARY 2012 American Journal of Obstetrics & Gynecology 113 Clinical Opinion Obstetrics www.AJOG.org

What should the gestational age gestational age groups may also be use- tem. Data about method of delivery boundaries in a classification ful.16-18 The exact thresholds matter less should be noted and collected separately. of preterm births be? than the common use of a universal sys- One question raised in relation to The lower and upper gestational age tem of gestational age groupings, so that those preterm births considered as boundaries for defining preterm birth differences in the gestational age distri- “spontaneous” in many prior studies is are variably defined. Although most geo- bution of preterm birth can be under- whether the findings at initial clinical graphic areas base their preterm birth stood. Finally, because menstrual dating of presentation (eg, contractions, preterm rates on live births (usually excluding gestational age is often inaccurate, we be- premature rupture of membranes [P- stillbirths), the boundaries at both ends lieve gestational age estimation should, PROM], , or advanced dilation), are arbitrary. For example, if a lower ges- whenever possible, be corroborated by an or the likely pathway leading to the final tational age boundary for defining a pre- early, high quality and the best presentation (eg, short or polyhy- term birth is used at all, the cutoffs range obstetric estimate be used for all gesta- dramnios), should be primary. In this mat- from 200/7 to 22 or even 28 weeks. How- tional age determinations in the classifica- ter, we were influenced by evidence sug- 19 ever, as demonstrated in the first paper tion system. gesting that a common “phenotype” of in this series, the risk factors, causes, and spontaneous preterm birth is primarily recurrence risks for spontaneous births What information will be characterized by progressive cervical ef- collected in this preterm at 16-19 weeks do not differ substantially facement, after which P-PROM, persistent birth classification system? from those births occurring at 20-24 mild contractions, prolapsed membranes, 2-11 Because the system we envision will be or bleeding could be the acute reason for weeks. Thus, if the objective is to ex- 20 plore the full range of preterm birth, used for research and population sur- seeking care. Based on this consider- there is no reason to exclude births at veillance, we propose to classify the pre- ation, we believe that the most useful clas- term birth at some time after delivery, sification system will not only capture in- 16-19 weeks from the classification sys- with as much information available as pos- formation about the clinical presentation tem. Regardless of the lower cutoff cho- sible. The clinical record should be the pri- on admission (contractions, P-PROM, sen, for comparison purposes across sites mary source of information. This record bleeding, advanced cervical dilation with- or over time, some clearly defined, scien- should include antepartum and intrapar- out P-PROM or significant contractions, tifically sound, lower gestational age cut- tum data, a record of all prior , or none of these for a provider initiated de- off that defines preterm birth should be medical history, a patient and physician in- livery), but will also be based on conditions used. terview when preterm birth has been and observations during pregnancy, in- Similarly, there is now abundant evi- scheduled and where the reason for deliv- cluding significant maternal infection, dence that many infants born at 37 or 38 ery is not completely clear, and finally, a short cervical length, increased or de- weeks of gestation experience increased gross and microscopic placental evalua- creased amniotic fluid volume, as well as neonatal mortality and even lifetime tion and, for stillbirths, an or pa- relevant clinical, laboratory, and placental morbidity related to immaturity of one thology report. Without examining each findings. or more organs as compared with infants of these sources, an important potential Ն 12-15 born at 39 weeks. The historical cause or phenotype might be missed. Should risk factors be part of choice of 37 weeks as the upper gesta- the classification system? tional age cutoff for defining a preterm Should a classification system be The next issue is whether risk factors birth was arbitrary and may no longer based on phenotype or cause? should be part of the classification sys- serve a useful purpose, because it does Because the cause of a specific case of tem. We believe that distal determinants not coincide with functional maturity. preterm birth is rarely known with any that have no clear causal pathway to pre- For this reason, we believe that defining a degree of certainty, the authors agreed term birth, such as low socioeconomic preterm birth as any occurring before 39 that the optimal classification system status, ethnicity, smoking, or illicit drug weeks would be more appropriate. For should primarily be based on the clinical use, should be collected in a systematic research and reporting purposes, ex- phenotype, defined in this study as one way, but should not be part of the classi- tending both the lower and upper or more characteristics of the mother, fe- fication system. Some classification sys- boundaries of preterm birth should be tus, placenta, and the presentation for tems include potential causes, like stress, considered. delivery. We also agree that more than 1 unspecified immune, or allergic path- Regardless of the final gestational age phenotype may be present in a single ways, with no clear means of defining cutoffs for defining preterm birth, there case of preterm delivery and that each how a specific case gets so classified.21 At was universal agreement (the authors phenotype present should be recorded this point, unless a condition can be agreed) that gestational age data should so that the choice of a single category is clearly defined and there is a reasonably be collected and recorded in narrow cat- not forced. Finally, the actual method of clear pathway from that condition to the egories (eg, no more than 1 week) to al- delivery (spontaneous or instrumental preterm birth, we believe it should be low flexibility in later categorization. Di- vaginal or cesarean birth) should not be considered a potential risk factor but viding the preterm births into several part of the phenotypic classification sys- should not constitute a phenotype in a

114 American Journal of Obstetrics & Gynecology FEBRUARY 2012 www.AJOG.org Obstetrics Clinical Opinion classification system. One such example ten similar to those for live born preterm neous vs indicated deliveries.28-33 How- is whether the method of conception (as- births (eg, or abrup- ever, review of papers using these catego- sisted reproductive technologies [ART] tion).25-27 In fact, many intrapartum still- ries reveals that these terms are neither vs spontaneous) should be considered a births occur during preterm labor after a well defined nor consistently used. An risk factor for preterm birth or merit a decision that a live fetus in distress is too indicated preterm birth is often defined separate phenotypic category? Because immature to salvage by cesarean delivery. as one that occurred because continua- there is no clear etiologic pathway link- Further confusion is added when a still- tion of the pregnancy risked the health of ing ART to increased risk of preterm birth that occurs in the antepartum period the mother and/or fetus, but the degree birth among singleton or even multifetal presents in preterm labor or with P-PROM. of risk is variably defined, affected by lo- gestations, we believe that the method of With these considerations in mind, the au- cal circumstances, and may arise from a conception should be considered as a thors agreed that the classification system of pregnancy that had a risk factor for preterm birth but should for preterm birth should include all pre- “spontaneous” onset (eg, infection after not constitute a phenotype. term stillbirths. ruptured membranes). Thus, these terms need further exposition for any classifi- Should pregnancy terminations How do we deal with multiple births? cation system to be acceptable to most and stillbirths be included? Should multiple births be combined users. We believe that coming to a clear The issue of whether to include preg- with singletons in the same classification consensus on this issue is one of the most nancy terminations (live born or still- system, or should they be considered important requirements to create a born), occurring at or above the lower separately? And if separately, should widely accepted classification system. gestational age limit in the classification, and higher-order multiples be is controversial. Various stillbirth classi- considered together? If multiples are How do we classify P-PROM, fication systems handle these cases dif- considered separately, should they be spontaneous dilation, and bleeding? ferently, with many systems excluding classified using the same system used for Classification of preterm (Ͻ37 weeks) pre- them.22 An important question in this singletons? If a single system were used mature (before the onset of labor) rupture study is whether the reason for the termi- for classifying both singleton and multi- of the fetal membranes (P-PROM) is a par- nation makes a difference. Terminations ple preterm births, multiplicity could be ticularly difficult issue.31,34 Most women occur electively but also for diverse rea- part of a preterm birth phenotype. Thus, with confirmed P-PROM enter spontane- sons, such as severe growth retardation, there are many questions related to the ous preterm labor within several hours or absence of amniotic fluid, P-PROM, ad- inclusion or exclusion of multiples in days, depending on the gestational age and vanced cervical dilatation, or a major this system. Perhaps the most important cause of rupture, but some remain unde- anomaly detected at a previable gestational influence on the group was the senti- livered for many days without infection or age above the lower threshold for defining ment that all preterm births should be other complications. In women who do preterm birth. Some of these are ei- included in this preterm birth classifica- not labor spontaneously, labor might be ther live born or die before delivery. tion system. Therefore, our recommen- induced or a cesarean delivery performed Should these deliveries be included in the dation is to create a single classification for many reasons, most commonly be- classification system at all, and if so, should system, with multiples included in the cause of clinical or laboratory evidence some be considered spontaneous, indi- system as 1 potential phenotype for pre- or fear of infection. Should births in the cated, or elective terminations? Our pref- term birth. The number of fetuses latter category be classified as “indi- erence is to include all births above the should, of course, be noted. In addition, cated” (because the were not in lower gestational age threshold for pre- there are issues related to multiples that spontaneous labor), or instead be classi- term birth, whether it was a termination or do not apply to singletons that could be fied as “spontaneous” (because the pro- not, and within the system, to classify ter- considered subcategories within the cess that led to the preterm delivery—the minations of pregnancy by the phenotypes multiples phenotype, including vanish- P-PROM—was spontaneous)? To un- used for all other preterm births. A system ing , twin/twin transfusion, fetal de- derstand preterm birth, it seems clear that includes some terminations but not mise of 1 of multiples, and the type of that the phenotypic classification system others would likely be confusing for all. placentation. These characteristics could should include information about the Stillbirth is also a difficult issue. In many be considered fetal and placental condi- presentation at delivery, and this would data sets used to study preterm birth, still- tions in association with the multiples include P-PROM, regardless of whether births are not combined with the live phenotype. it was followed by spontaneous labor or births. Preterm births are reported only for an induction. Forcing it into a spontane- live born infants. This is an important con- What should the definition of ous or indicated category will likely re- sideration because, in developed countries, indicated and spontaneous flect a physician management decision as many as 50% of stillbirths occur before births be and how do we draw and, thus would not help to define a pre- 28 weeks and 80% or more of stillbirths are a distinction between them? term birth phenotype. preterm.23,24 Also, the pathologic pro- The most common classifications divide A spontaneously dilating cervix with- cesses leading to preterm stillbirths are of- all live born preterm births into sponta- out contractions may lead to delivery

FEBRUARY 2012 American Journal of Obstetrics & Gynecology 115 Clinical Opinion Obstetrics www.AJOG.org with few or no contractions, usually at ditions, as well as having either signs of ical indication, regardless of the mode of early gestational ages. At later—but still spontaneous initiation of parturition delivery, is also an issue of recent con- preterm—gestational ages, the finding (contractions, cervical effacement, or P- cern.39 Should these still be considered of advanced cervical dilatation may be PROM) or a nonspontaneous initiation “indicated,” because the physician chose followed by a cesarean delivery because of parturition (induction or prelabor ce- to deliver and there was no spontaneous of fear of spontaneous membrane rup- sarean birth). This discussion empha- maternal process leading to labor or de- ture, followed by head entrapment in sized the need for the classification sys- livery? Should these be called “iatro- cases of breech presentation or a pro- tem to have several potential phenotypic genic” or designated as being performed lapsed cord. In both instances, parturi- components, including the maternal for “social reasons”? In any case, we tion is present without any indication of condition, the fetal condition, and the agreed that, for this classification system, active labor. Should these cases be classi- presentation at delivery. provider initiated deliveries be subdi- fied as spontaneous, because the dilation vided into 3 or 4 groups, with headings occurred spontaneously, or as indicated, How should we define and classify such as urgent, discretionary, iatrogenic, because active labor was not present? As indicated preterm births? and/or social. with P-PROM, for the purposes of phe- For this classification system, mainte- There were a number of remaining notypic classification, the important in- nance of the existing terminology related questions. For example, how do we clas- formation is that the patient presented to what are customarily called indicated sify preterm deliveries where the mother with a dilated cervix, not that she be preterm births, proved confusing.35-37 entered the hospital before term with forced into a specific spontaneous or in- Thus, we chose to define a category of contractions or slight cervical change but dicated category. These discussions sug- (indicated) preterm birth as one in without active labor? If her labor was gest that categorical assignment of all pre- which parturition was initiated by the “augmented” by amniotomy or oxytocin term births into one of the traditional caregivers. This designation would apply or a cesarean birth performed, is this to categories as spontaneous or indicated to a preterm birth in which there was no be categorized as a spontaneous preterm contributes to confusion rather than clar- evidence that any part of the parturi- birth or an indicated, discretionary, or ity in the creation of a useful classification tional process had begun (ie, little cervi- iatrogenic preterm birth? For the classi- system. cal shortening or effacement and no fication system, we must be able to dis- Similar issues arise when bleeding is fluid leakage, persistent contractions or tinguish between (1) essentially social the initial or dominant manifestation of bleeding, and specifically, little likeli- or convenience inductions of labor in parturition. Bleeding may be associated hood that birth would have occurred women with minimal signs of active la- with a , placenta pre- within the next several days, unless initi- bor and (2) appropriate augmentation of via, or no obvious pathology. Each con- ated by the obstetric care giver). spontaneous dysfunctional labor. Thus, dition may have different bleeding pat- However, even if this definition is ac- an important issue is whether the classi- terns in timing and volume over the cepted, other questions remain. For ex- fication system should attempt to deter- course of pregnancy. As with P-PROM, ample, should medically indicated pre- mine the reason and perhaps appropri- induction of labor, or cesarean birth for term births be defined as those following ateness for the physician’s decision to bleeding because of an ongoing abrup- a cesarean delivery or induction of labor initiate delivery? We agree that both the tion or a placenta previa might be classi- only for urgent maternal or fetal indica- type of indication, such as urgent, discre- fied as a spontaneous or indicated pre- tions (eg, clearly defined maternal or fe- tionary, and iatrogenic or social, and the term birth. Because there was no labor tal distress as evidenced by severe pre- medical or social conditions leading to and delivery was accomplished after a or a dangerously abnormal the decision to initiate a preterm delivery prelabor cesarean delivery or induction fetal heart rate pattern)? If so, how do we should be captured in this classification of labor, the preterm birth could be con- classify physician-initiated deliveries system. sidered medically indicated. Conversely, with “softer” indications, such as mild should it be considered spontaneous, be- preeclampsia or mild fetal growth re- Other important issues cause the precipitating event followed a striction, in which there is clearly some At times, signs of spontaneous parturi- spontaneously occurring maternal con- discretion in timing of the delivery? Are tion will occur in pregnancies compli- dition? The discussion surrounding this these preterm births as “indicated” as cated by preeclampsia, maternal illness, issue again led the authors to conclude those in the prior group, or should we fetal growth restriction, and fetal dis- that attempts to assign preterm births call these deliveries “discretionary”? tress, although these conditions might related to bleeding into spontaneous What are the threshold events that de- not be part of another obvious pheno- and indicated groups would be artifac- mark the boundary between indicated type that led to the preterm birth.40 If tual. Women who present for delivery and discretionary, and how are they af- preeclampsia is present in a preterm with bleeding, either with an abruption fected by the gestational age and avail- birth that follows spontaneous onset of or a previa or without a clearly defined ability of neonatal care?38 labor, should this birth be still be classi- cause, can be characterized phenotypi- Classification of scheduled births be- fied as a spontaneous preterm birth? We cally as having one of those clinical con- fore 39 weeks that lack any obvious med- agree that these births should still be clas-

116 American Journal of Obstetrics & Gynecology FEBRUARY 2012 www.AJOG.org Obstetrics Clinical Opinion sified as having signs of spontaneous livery was urgent, discretionary, or iatro- categorize the presentation for delivery parturition, but the type of information genic. A classification system with these have not been used in a consistent fashion discussed previously should be collected, characteristics would allow analysis of all and would be better replaced by less con- as it will allow an examination of the link cases of , for example, as fusing, more descriptive terms. Neverthe- between various maternal and fetal con- a single group, regardless of whether less, by carefully defining the presentation ditions and different preterm delivery the woman presented for delivery with for delivery, the concept of 2 broad catego- presentations. P-PROM, labor, a spontaneously dilated ries of preterm births—those following Another important issue is how to best cervix, or for one of many reasons was spontaneous signs of parturition and integrate placental pathologic and other induced, had a termination, or had a ce- those cases where there was none—should laboratory information into a classifica- sarean birth before the appearance of be retained, with cases where the birth pro- tion system based on phenotype. For the signs of spontaneous parturition. cess is of maternal/fetal origin, including placenta, if histologic chorioamnionitis, This discussion also led us to add a shortening cervix, P-PROM, contrac- signs of abruption, or of placental dys- fourth component to the classification sys- tions, and bleeding classified as spontane- function (as might be indicated by large tem, one dealing with the fetal condition. ous. All other births in which delivery areas of infarction or necrosis) are pres- Thus, the presence of a fetal demise, fetal would likely not have happened within ent, how should these findings affect distress, fetal growth restriction, a congen- several days without the intervention of a the classification? For laboratory tests, ital anomaly, multifetal pregnancy, and caregiver, should be placed in the sec- would an elevated white count or a pos- poly- or may influence ond, provider-initiated group. Several itive blood or amniotic fluid culture be when a delivery occurs and should be in- broad categories of maternal conditions included in an infection-related pheno- cluded in the fetal component of the clas- should be noted as part of the phenotypes, type? These questions must also be con- sification system. usually based on information available be- sidered before a classification system can fore presentation for delivery, including be developed. Discussion surrounding Definitions clinical categories, such as shortened cervix this issue led us to recommend that the For this classification system to achieve its and polyhydramnios. placental findings be included as part of goals, virtually all of the maternal and fetal the phenotype of preterm birth with 4 conditions, presentations at delivery, and Conclusions potential components: infection, hem- placental findings that may comprise a Preterm birth is a syndrome defined by orrhage, infarction, or no pathology. phenotype must be rigorously defined. For time and clearly is not a distinct clinical Important laboratory findings, such as example, how much hydramnios must oc- phenotype. Births at gestational ages less evidence of infection/inflammation on cur and when must it occur for polyhy- than 20 weeks and many of those at 37 amniocentesis, would become part of the dramnios to be considered a component of and 38 weeks share with births at 20-36 phenotype within the category on im- the phenotype of a preterm birth? weeks several etiologic and prognostic portant maternal pregnancy-related features that suggest these boundaries conditions. Moving toward a are artificial and therefore, should be re- In this study, we use polyhydramnios classification system considered.2-15,42,43 Because the cause of as an example of how the classification From the foregoing discussion, the issues many preterm births is unknown, we system might work. Women with appar- and components of a preterm birth phe- also believe that, at least for the near fu- ently similar degrees of polyhydramnios notypic classification system are coming ture, preterm birth classification systems may present with spontaneous contrac- more clearly into focus. After much discus- will need to focus on phenotype rather tions, develop P-PROM, or dilate their sion, we agree that a preterm phenotype than suspected cause. These phenotypes, cervix.41 Still others will be induced or could be defined as having the following 4 whenever possible, should be based, at undergo cesarean delivery performed for components: (1) the presence of impor- least in part, on maternal and/or fetal an- fear of prolapsed cord or a ruptured tant maternal pregnancy related condi- tecedent events, such as a shortening cer- . In discussing whether all such tions; (2) important fetal conditions; (3) vix or fetal death, with the understand- cases should be considered spontaneous clinical presentation for delivery, includ- ing that presentation at delivery, because the process started with a mater- ing evidence of spontaneous parturition; including P-PROM, bleeding, contrac- nal or fetal condition or whether the and (4) placental findings. Risk factors for tions, or cervical dilation, may all be spontaneous classification should be re- preterm birth, such as smoking, could be symptoms of the underlying process and served for only those cases that presented collected but would not be part of the phe- may not be primary in determining or with contractions or P-PROM, it be- notype. We recognize that the dividing line labeling the pathway leading to the pre- came clear that the classification sys- between significant maternal conditions term delivery. Finally, when the care- tem should capture the presence of poly- and maternal risk factors is not always clear giver initiates a preterm delivery, a dis- hydramnios, the presence or absence of a and that various characteristics might be tinction should be made between cases fetal anomaly, whether there was evi- put in one or the other category with some in whom such interventions are clearly dence of spontaneous parturition, and if degree of arbitrariness. The use of the indicated, those in whom the timing of not, whether the physician initiated de- words “spontaneous” and “indicated” to intervention is discretionary, and those

FEBRUARY 2012 American Journal of Obstetrics & Gynecology 117 Clinical Opinion Obstetrics www.AJOG.org without a clinical indication. Thus, cre- neonatal outcomes. N Engl J Med 2009;360: etiologic heterogeneity. Am J Obstet Gynecol ating a classification system for preterm 111-20. 1991;164:467-71. 13. Zhang X, Kramer MS. Variations in mortality birth involves making many choices, 29. Ananth CV, Joseph KS, Oyelese Y, Demis- and morbidity by gestational age among infants sie K, Vintzileos AM. Trends in preterm birth and some of which are clearly controversial. born at term. J Pediatr 2009;154:358-62. among singletons: United The issues described in this article are 14. McIntire DD, Leveno KJ. Neonatal mortality States, 1989 through 2000. Obstet Gynecol some that should be considered in creat- and morbidity rates in late preterm births com- 2005;105:1084-91. ing a classification system for preterm pared with births at term. Obstet Gynecol 30. Barros F, Velez Mdel P. Temporal trends of 2008;111:35-41. birth phenotypes. f preterm birth subtypes and neonatal outcomes. 15. Bastek JA, Sammel MD, Paré E, Srinivas Obstet Gynecol 2006;107:1035-41. SK, Posencheg MA, Elovitz MA. Adverse neo- 31. Pickett KE, Abrams B, Selvin S. Defining natal outcomes: examining the risks between REFERENCES preterm delivery–the epidemiology of clinical preterm, late preterm, and term infants. Am J presentation. Paediatr Perinat Epidemiol 2000; 1. Kramer MS, Papageorghiou A, Culhane JF, Obstet Gynecol 2008;199:367.e1-8. 14:305-8. et al. Challenges in defining and classifying the 16. Chen A, Feresu SA, Barsoom MJ. Hetero- 32. Savitz DA, Dole N, Herring AH, et al. Should preterm birth syndrome. Am J Obstet Gynecol geneity of preterm birth subtypes in relation to spontaneous and medically indicated preterm 2012;206:108-12. neonatal death. Obstet Gynecol 2009;114: births be separated for studying aetiology? 2. Goldenberg RL, Mayberry SK, Copper RL, 516-22. Paediatr Perinat Epidemiol 2005;19:97-105. DuBard MB, Hauth JC. Pregnancy outcomes 17. Moutquin JM. Classification and heteroge- following a second trimester loss. Obstet Gyne- neity of preterm birth. Br J Obstet Gynaecol 33. McElrath TF, Hecht JL, Dammon O, et al. col 1993;81:444-6. 2003;110(suppl 20):30-3. Pregnancy disorders that lead to delivery before 3. Rasmussen S, Irgens LM, Skjaerven R, 18. Ancel PY, Saurel-Cubizolles MJ, Di Renzo the 28th week of gestation: an epidemiologic Melve KK. Prior adverse pregnancy outcome GC, Papiernik E, Breart G. Very and moderate approach to classification. Am J Epidemiol and the risk of stillbirth. Obstet Gynecol preterm births: are the risk factors different? 2008;168:980-9. 2009;114:1259-70. Br J Obstet Gynaecol 1999;106:1162-70. 34. Furman B, Shoham-Vardi I, Bashiri A, Erez 4. Iams JD, Berghella V. Care for women with 19. Behrman RE, Butler AS, eds. Preterm birth: O, Mazor M. Clinical significance and outcome prior preterm birth. Am J Obstet Gynecol causes, consequences, and prevention. Com- of preterm prelabor rupture of the membranes: 2010;203:89-100. mittee on understanding premature birth and population-based study. Eur J Obstet Gynecol 5. Nuovo GJ, Cooper LD, Bartholomew D. His- assuring healthy outcomes. Institute of Medi- Repro Biol 2000;92:209-16. tologic, infectious, and molecular correlates of cine of the National Academies. Washington, 35. Ananth CV, Vintzileos AM. Medically in- idiopathic spontaneous and perinatal DC: The National Academies Press; 2006:79. duced preterm birth: recognizing the impor- mortality. Diagn Mol Pathol 2005;14:152-8. 20. Celik E, To M, Gajewska K, Smith GC, Ni- tance of the problem. Clin Perinatol 2008;35: 6. Srinivas S, Ma Y, Sammel MD, et al. Placental colaides KH. Cervical length and obstetric his- 53-67. inflammation and viral infection are implicated in tory predict spontaneous preterm birth: devel- 36. Ananth CV, Joseph KS, Kinzler WL. The in- second trimester pregnancy loss. Am J Obstet opment and validation of a model to provide fluence of obstetric interventions on trends in Gynecol 2006;195:797-802. individualized risk assessment. Ultrasound Ob- twin stillbirths, United States1989-1999. J Ma- 7. Ancel PY, Saurel-Cubizolles MJ, Di Renzo stet Gynecol 2008;31:549-54. tern Fetal Neonatal Med 2004;15:380-7. GC, Papiernik E, Breart G. Risk factors for 21. Klebanoff MA, Shiono PH. Top down, bot- 37. Klebanoff MA. Conceptualizing categories 14-21 week : a case-control study in tom up and inside out: reflections on preterm of preterm birth. Prenatal Neonatal Med 1998; Europe. The Europop Group. Hum Reprod birth. Paediatr Perinat Epidemiol 1995;9:125-9. 3:13-5. 2000;15:2426-32. 22. Flenady V, Froen JF, Pinar H, et al. An eval- 38. Kierse MJNC. Elective induction, selective 8. Leitich H, Bodner-Adler B, Brunbauer M, uation of classification systems for stillbirth. deduction and cesarean section. Birth 2010; Kaider A, Egarter C, Husslein P. Bacterial vagi- BMC Pregnancy 2009;9:24. 37:252-6. nosis as a risk factor for preterm delivery: a 23. Goldenberg RL, Koski JF, Boyd BW, Cutter 39. Clark SL, Miller DD, Belfort MA, Dildy GA, meta-analysis. Am J Obstet Gynecol 2003; GR, Nelson KG. Fetal deaths in Alabama 1974 Frye DK, Meyers JA. Neonatal and maternal 189:139-47. to 1983: a birth weight-specific analysis. Obstet outcomes associated with elective term deliv- 9. Llahi-Camp JM, Rai R, Ison C, Regan L, Tay- Gynecol 1987;70:831-5. ery. Am J Obstet Gynecol 2009;200:156.e1-4. lor-Robinson D. Association of bacterial vagino- 24. Flenady V, Middleton P, Smith G, et al. Still- 40. Ananth CV, Savitz D, Luther E, Bowes W. sis with a history of second trimester miscar- birth: the way forward in high income countries. riage. Hum Reprod 1996;11:1575-8. Lancet 2011;377:1703-17. Preeclampsia and preterm birth subtypes in 10. Nelson DB, Bellamy S, Nachamkin I, Ness 25. Korteweg FJ, Gordijn SJ, Timmer A, Holm Nova Scotia, 1986 to 1992. Am J Perinatol RB, Macones GA, Allen-Taylor L. First trimester JP, Ravise JM, Erwich JJ. A placental cause of 1997;14:17-23. bacterial vaginosis, individual microorganism intra-uterine fetal death depends on the perina- 41. Many A, Hill LM, Lazebnik N, Martin JG. The levels, and risk of second trimester pregnancy tal mortality classification system used. Pla- association between polyhydramnios and pre- loss among urban women. Fertil Steril 2007;88: centa 2008;29:71-80. term delivery. Obstet Gynecol 1995;86:389-91. 1396-403. 26. Khong TY. The placenta in stillbirth. Curr 42. Kirby RS, Wingate M. Late preterm birth 11. Edlow AG, Srinivas SK, Elovitz MA. Second Diag Pathol 2006;12:161-72. and neonatal outcome: is 37 weeks’ gestation a trimester loss and subsequent pregnancy out- 27. Pinar H, Carpenter M. Placenta and umbil- threshold level or a road marker on the highway comes: what is the real risk? Am J Obstet Gy- ical cord abnormalities seen with stillbirth. Clin of perinatal risk? Birth 2010;37:169-71. necol 2007;197:581.e1-6. Obstet Gynecol 2010;53:656-72. 43. Fleischman AR, Oinuma M, Clark SL. Re- 12. Tita ATN, Landon MB, Spong CY, et al. 28. Savitz DA, Blackmore CA, Thorp JM. Epi- thinking the definition of “term pregnancy.” Ob- Timing of elective cesarean delivery at term and demiologic characteristics of preterm delivery: stet Gynecol 2010;116:136-9.

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