The preterm birth syndrome: issues to consider in creating a classification system

doi:10.1016/j.ajog.2011.10.865

American Journal of Obstetrics and Gynecology

Volume 206, Issue 2, February 2012, Pages 113-118

https://doi.org/10.1016/j.ajog.2011.10.865 Get rights and content

A comprehensive classification system for preterm birth requires expanded gestational boundaries that recognize the early origins of preterm parturition and emphasize fetal maturity over fetal age. Exclusion of stillbirths, pregnancy terminations, and multifetal gestations prevents comprehensive consideration of the potential causes and presentations of preterm birth. Any step in parturition (cervical softening and ripening, decidual-membrane activation, and/or myometrial contractions) may initiate preterm parturition, and should be recorded for every preterm birth, as should the condition of the mother, fetus, newborn, and placenta, before a phenotype is assigned.

Section snippets

What is the reason for creating this classification system for preterm birth?

There are many reasons to classify preterm births and to consider various systems of classification. In this article, we focus on the decisions involved in creating a classification system for use in both population surveillance and research, so that when specific types of preterm births are discussed, studied, or compared across populations or over time, categories have consistent definitions that are widely understood and accepted.

What should the gestational age boundaries in a classification of preterm births be?

The lower and upper gestational age boundaries for defining preterm birth are variably defined. Although most geographic areas base their preterm birth rates on live births (usually excluding stillbirths), the boundaries at both ends are arbitrary. For example, if a lower gestational age boundary for defining a preterm birth is used at all, the cutoffs range from 20^0/7 to 22 or even 28 weeks. However, as demonstrated in the first paper in this series, the risk factors, causes, and recurrence

What information will be collected in this preterm birth classification system?

Because the system we envision will be used for research and population surveillance, we propose to classify the preterm birth at some time after delivery, with as much information available as possible. The clinical record should be the primary source of information. This record should include antepartum and intrapartum data, a record of all prior pregnancies, medical history, a patient and physician interview when preterm birth has been scheduled and where the reason for delivery is not

Should a classification system be based on phenotype or cause?

Because the cause of a specific case of preterm birth is rarely known with any degree of certainty, the authors agreed that the optimal classification system should primarily be based on the clinical phenotype, defined in this study as one or more characteristics of the mother, fetus, placenta, and the presentation for delivery. We also agree that more than 1 phenotype may be present in a single case of preterm delivery and that each phenotype present should be recorded so that the choice of a

Should risk factors be part of the classification system?

The next issue is whether risk factors should be part of the classification system. We believe that distal determinants that have no clear causal pathway to preterm birth, such as low socioeconomic status, ethnicity, smoking, or illicit drug use, should be collected in a systematic way, but should not be part of the classification system. Some classification systems include potential causes, like stress, unspecified immune, or allergic pathways, with no clear means of defining how a specific

Should pregnancy terminations and stillbirths be included?

The issue of whether to include pregnancy terminations (live born or stillborn), occurring at or above the lower gestational age limit in the classification, is controversial. Various stillbirth classification systems handle these cases differently, with many systems excluding them.²² An important question in this study is whether the reason for the termination makes a difference. Terminations occur electively but also for diverse reasons, such as severe growth retardation, absence of amniotic

How do we deal with multiple births?

Should multiple births be combined with singletons in the same classification system, or should they be considered separately? And if separately, should twins and higher-order multiples be considered together? If multiples are considered separately, should they be classified using the same system used for singletons? If a single system were used for classifying both singleton and multiple preterm births, multiplicity could be part of a preterm birth phenotype. Thus, there are many questions

What should the definition of indicated and spontaneous births be and how do we draw a distinction between them?

The most common classifications divide all live born preterm births into spontaneous vs indicated deliveries.28, 29, 30, 31, 32, 33 However, review of papers using these categories reveals that these terms are neither well defined nor consistently used. An indicated preterm birth is often defined as one that occurred because continuation of the pregnancy risked the health of the mother and/or fetus, but the degree of risk is variably defined, affected by local circumstances, and may arise from

How do we classify P-PROM, spontaneous dilation, and bleeding?

Classification of preterm (<37 weeks) premature (before the onset of labor) rupture of the fetal membranes (P-PROM) is a particularly difficult issue.31, 34 Most women with confirmed P-PROM enter spontaneous preterm labor within several hours or days, depending on the gestational age and cause of rupture, but some remain undelivered for many days without infection or other complications. In women who do not labor spontaneously, labor might be induced or a cesarean delivery performed for many

How should we define and classify indicated preterm births?

For this classification system, maintenance of the existing terminology related to what are customarily called indicated preterm births, proved confusing.35, 36, 37 Thus, we chose to define a category of (indicated) preterm birth as one in which parturition was initiated by the caregivers. This designation would apply to a preterm birth in which there was no evidence that any part of the parturitional process had begun (ie, little cervical shortening or effacement and no fluid leakage,

Other important issues

At times, signs of spontaneous parturition will occur in pregnancies complicated by preeclampsia, maternal illness, fetal growth restriction, and fetal distress, although these conditions might not be part of another obvious phenotype that led to the preterm birth.⁴⁰ If preeclampsia is present in a preterm birth that follows spontaneous onset of labor, should this birth be still be classified as a spontaneous preterm birth? We agree that these births should still be classified as having signs

Definitions

For this classification system to achieve its goals, virtually all of the maternal and fetal conditions, presentations at delivery, and placental findings that may comprise a phenotype must be rigorously defined. For example, how much hydramnios must occur and when must it occur for polyhydramnios to be considered a component of the phenotype of a preterm birth?

Moving toward a classification system

From the foregoing discussion, the issues and components of a preterm birth phenotypic classification system are coming more clearly into focus. After much discussion, we agree that a preterm phenotype could be defined as having the following 4 components: (1) the presence of important maternal pregnancy related conditions; (2) important fetal conditions; (3) clinical presentation for delivery, including evidence of spontaneous parturition; and (4) placental findings. Risk factors for preterm

Conclusions

Preterm birth is a syndrome defined by time and clearly is not a distinct clinical phenotype. Births at gestational ages less than 20 weeks and many of those at 37 and 38 weeks share with births at 20-36 weeks several etiologic and prognostic features that suggest these boundaries are artificial and therefore, should be reconsidered.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 42, 43 Because the cause of many preterm births is unknown, we also believe that, at least for the near future,

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The maternal-fetal neurodevelopmental groundings of preterm birth risk
2024, Heliyon
Altered neurodevelopment is a major clinical sequela of Preterm Birth (PTB) being currently unexplored in-utero.
To study the link between fetal brain functional (FbF) connectivity and preterm birth, using resting-state functional magnetic resonance imaging (rs-fMRI).
Prospective single-centre cohort study.
A sample of 31 singleton pregnancies at 28–34 weeks assigned to a low PTB risk (LR) (n = 19) or high PTB risk (HR) (n = 12) group based on a) the Maternal Frailty Inventory (MaFra) for PTB risk; b) a case-specific PTB risk gradient.
Fetal brain rs-fMRI was performed on 1.5T MRI scanner. First, directed causal relations representing fetal brain functional connectivity measurements were estimated using the Greedy Equivalence Search (GES) algorithm. HR vs. LR group differences were then tested with a novel ad-hoc developed Monte Carlo permutation test. Second, a MaFra-only random forest (RF) was compared against a MaFra-Neuro RF, trained by including also the most important fetal brain functional connections. Third, correlation and regression analyses were performed between MaFra-Neuro class probabilities and i) the GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks.
First, fewer fetal brain functional connections were evident in the HR group. Second, the MaFra-Neuro RF improved PTB risk prediction. Third, MaFra-Neuro class probabilities showed a significant association with: i) GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks.
Fetal brain functional connectivity is a novel promising predictor of PTB, linked to maternal risk profiles, ahead of birth, and clinical markers of neurodevelopmental risk, at birth, thus potentially “connecting” different PTB phenotypes.
Etiologically Based Functional Taxonomy of the Preterm Birth Syndrome
2024, Clinics in Perinatology
Small vulnerable newborns—big potential for impact
2023, The Lancet
Despite major achievements in child survival, the burden of neonatal mortality has remained high and even increased in some countries since 1990. Currently, most neonatal deaths are attributable to being born preterm, small for gestational age (SGA), or with low birthweight (LBW). Besides neonatal mortality, these conditions are associated with stillbirth and multiple morbidities, with short-term and long-term adverse consequences for the newborn, their families, and society, resulting in a major loss of human capital. Prevention of preterm birth, SGA, and LBW is thus critical for global child health and broader societal development. Progress has, however, been slow, largely because of the global community's failure to agree on the definition and magnitude of newborn vulnerability and best ways to address it, to frame the problem attractively, and to build a broad coalition of actors and a suitable governance structure to implement a change. We propose a new definition and a conceptual framework, bringing preterm birth, SGA, and LBW together under a broader umbrella term of the small vulnerable newborn (SVN). Adoption of the framework and the unified definition can facilitate improved problem definition and improved programming for SVN prevention. Interventions aiming at SVN prevention would result in a healthier start for live-born infants, while also reducing the number of stillbirths, improving maternal health, and contributing to a positive economic and social development in the society.
Placental transcriptomic signatures of spontaneous preterm birth
2023, American Journal of Obstetrics and Gynecology
Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth.
This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth).
The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate–adjusted P value of <.05.
In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function.
This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.
Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis
2022, American Journal of Obstetrics and Gynecology
Citation Excerpt :
There are several reasons why meta-analyses evaluating the efficacy of any proposed intervention to prevent preterm birth in high-risk populations should not group women with different risk factors into a single category. They are as follows: (1) preterm birth is a complex syndrome caused by multiple etiological factors with different mechanisms of disease and significant individual heterogeneity.15–22 This is the rationale for assessing separately the proposed interventions to prevent preterm birth in multiple gestations; (2) the groups of patients with a sonographic short cervix and those with a history of spontaneous preterm birth do not overlap in clinical practice.
To assess the efficacy and safety of vaginal progesterone to prevent recurrent preterm birth and adverse perinatal outcomes in singleton gestations with a history of spontaneous preterm birth.
MEDLINE, Embase, LILACS, and CINAHL (from their inception to February 28, 2022), Cochrane databases, Google Scholar, bibliographies, and conference proceedings.
Randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a singleton gestation and a history of spontaneous preterm birth.
The primary outcomes were preterm birth <37 and <34 weeks of gestation. The secondary outcomes included adverse maternal and perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. We assessed the risk of bias in the included studies, heterogeneity (I² test), small-study effects, publication bias, and quality of evidence; performed subgroup and sensitivity analyses; and calculated 95% prediction intervals and adjusted relative risks.
Ten studies (2958 women) met the inclusion criteria: 7 with a sample size <150 (small studies) and 3 with a sample size >600 (large studies). Among the 7 small studies, 4 were at high risk of bias, 2 were at some concerns of bias, and only 1 was at low risk of bias. All the large studies were at low risk of bias. Vaginal progesterone significantly decreased the risk of preterm birth <37 weeks (relative risk, 0.64; 95% confidence interval, 0.50–0.81; I²=75%; 95% prediction interval, 0.31–1.32; very low-quality evidence) and <34 weeks (relative risk, 0.62; 95% confidence interval, 0.42–0.92; I²=66%; 95% prediction interval, 0.23–1.68; very low-quality evidence), and the risk of admission to the neonatal intensive care unit (relative risk, 0.53; 95% confidence interval, 0.33–0.85; I²=67%; 95% prediction interval, 0.16–1.79; low-quality evidence). There were no significant differences between the vaginal progesterone and the placebo or no treatment groups in other adverse perinatal and maternal outcomes. Subgroup analyses revealed that vaginal progesterone decreased the risk of preterm birth <37 weeks (relative risk, 0.43; 95% confidence interval, 0.33–0.55; I²=0%) and <34 weeks (relative risk, 0.27; 95% confidence interval, 0.15–0.49; I²=0%) in the small but not in the large studies (relative risk, 0.98; 95% confidence interval, 0.88–1.09; I²=0% for preterm birth <37 weeks; and relative risk, 0.94; 95% confidence interval, 0.78–1.13; I²=0% for preterm birth <34 weeks). Sensitivity analyses restricted to studies at low risk of bias indicated that vaginal progesterone did not reduce the risk of preterm birth <37 weeks (relative risk, 0.96; 95% confidence interval, 0.84–1.09) and <34 weeks (relative risk, 0.90; 95% confidence interval, 0.71–1.15). There was clear evidence of substantial small-study effects in the meta-analyses of preterm birth <37 and <34 weeks of gestation because of funnel plot asymmetry and the marked differences in the pooled relative risks obtained from fixed-effect and random-effects models. The adjustment for small-study effects resulted in a markedly reduced and nonsignificant effect of vaginal progesterone on preterm birth <37 weeks (relative risk, 0.86; 95% confidence interval, 0.68–1.10) and <34 weeks (relative risk, 0.92; 95% confidence interval, 0.60–1.42).
There is no convincing evidence supporting the use of vaginal progesterone to prevent recurrent preterm birth or to improve perinatal outcomes in singleton gestations with a history of spontaneous preterm birth.
A cybernetic framework for predicting preterm and enhancing care strategies: A review
2021, Biomedical Engineering Advances
Preterm is viewed as the birth of a human foetus prior to 37 complete weeks of gestation. It has effects on the health of both the foetus and the mother, has financial consequences to the clinic and society as a whole, and due to its widespread occurrence is viewed as a global pandemic. Preterm can be viewed as a heterogeneous condition which is influenced by a variety of factors, the majority of which have been discussed separately in the medical literature, thus making it challenging for a comprehensive view and understanding to be formed of the topic. Using a semisystematic review methodology, this paper is structured in two parts where the first part gives a comprehensive review to what preterm is alongside a review of the topic under a number of pivotal discussion headings. Following this, in the second part of the paper, a review is conducted on the need and relevance of Artificial Intelligence (AI) models in clinical medicine, after which a cybernetic framework is proposed which utilises a combination of AI and a clinical expert within the loop (human intelligence) to yield a ‘superintelligence’ platform aimed at producing a more reliable means of preterm prediction, and also allowing for enhanced and optimised care strategies to be delivered to the pregnant patient. The paper concludes with a number of key future areas that need to be addressed in order for the overall enhancement of the proposed cybernetic framework, which includes the need for ethical sharing of patient physiological data, the further consideration of ethnicity in preterm prediction due to disparity in gestational length amongst various ethnic groups, and also the prospect of mobile pregnancy monitoring using wearables and telemedicine.

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: This project was supported by the Bill and Melinda Gates Foundation and the Global Alliance to Prevent Prematurity and Stillbirth, an initiative of Seattle Children's, and by INTERGROWTH-21st Grant ID 49038 from the Bill and Melinda Gates Foundation to the University of Oxford, for which we are very grateful.

: The authors report no conflict of interest.

: Reprints not available from the authors.

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Clinical opinionObstetricsThe preterm birth syndrome: issues to consider in creating a classification system

Section snippets

What is the reason for creating this classification system for preterm birth?

What should the gestational age boundaries in a classification of preterm births be?

What information will be collected in this preterm birth classification system?

Should a classification system be based on phenotype or cause?

Should risk factors be part of the classification system?

Should pregnancy terminations and stillbirths be included?

How do we deal with multiple births?

What should the definition of indicated and spontaneous births be and how do we draw a distinction between them?

How do we classify P-PROM, spontaneous dilation, and bleeding?

How should we define and classify indicated preterm births?

Other important issues

Definitions

Moving toward a classification system

Conclusions

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Fertil Steril

Am J Obstet Gynecol

Am J Obstet Gynecol

Br J Obstet Gynaecol

Lancet

Placenta

Curr Diag Pathol

Am J Obstet Gynecol

Eur J Obstet Gynecol Repro Biol

Clin Perinatol

Am J Obstet Gynecol

Obstet Gynecol

Pregnancy outcomes following a second trimester loss

Obstet Gynecol

Prior adverse pregnancy outcome and the risk of stillbirth

Obstet Gynecol

Histologic, infectious, and molecular correlates of idiopathic spontaneous abortion and perinatal mortality

Diagn Mol Pathol

Risk factors for 14-21 week abortions: a case-control study in EuropeThe Europop Group

Hum Reprod

Association of bacterial vaginosis with a history of second trimester miscarriage

Hum Reprod

Clinical opinion
Obstetrics
The preterm birth syndrome: issues to consider in creating a classification system