This chapter should be cited as follows:
Nambiar S, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419053

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 19

Pregnancy shortening: etiology, prediction and prevention

Volume Editors: Professor Arri Coomarasamy, University of Birmingham, UK
Professor Gian Carlo Di Renzo, University of Perugia, Perugia, Italy
Professor Eduardo Fonseca, Federal University of Paraiba, Brazil

Chapter

Preterm Birth: a Syndrome with Unsolved Issues

First published: February 2024

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INTRODUCTION

Preterm birth (PTB) is a significant health concern affecting neonates and their families worldwide. While advancements in medical care have improved survival rates for preterm neonates, the syndrome itself remains a complex and challenging condition. Despite ongoing research efforts, there are still many unsolved issues surrounding PTB. This chapter highlights some of the key unsolved issues in PTB and emphasizes the need for continued research and innovation to address these challenges.

DEFINITION AND PREVALENCE

Preterm birth (PTB) is defined as birth before 37 completed weeks of gestation. These are further divided into extreme preterm (before 28 weeks), very preterm (between 28 and 32 weeks) and moderate to late preterm (between 32 and 37 weeks).

It was estimated to occur in between 4 and 16% of births worldwide in 2020¹ and an estimated 13.4 million babies were born preterm in that year.² PTB is the leading cause of mortality under the age of 5 with 900,000 deaths in 2019.^1,2 Survivors are at an increased risk of short-term complications attributed to immaturity of multiple organ systems, as well as neurodevelopmental disorders such as cerebral palsy, intellectual disabilities and visual and hearing impairment.³

There has been little change in prevalence rates in 30 years despite significant research into the prediction and prevention of preterm birth.⁴ This may be because the underlying flaw is the assumption that preterm birth is a single condition and not a syndrome with multiple different etiologies leading to a common outcome of delivery before 37 weeks.⁵

THE ENIGMA OF ETIOLOGY

The initiation of labor at term, a physiological phenomenon, is in itself poorly understood. The factors that initiate PTB are even more of an enigma.

Two-thirds of PTB are spontaneous while the remainder are iatrogenic, when there is evidence of either maternal or fetal compromise in pre-eclampsia or intrauterine growth restriction.⁶ Spontaneous PTB may or may not be preceded by rupture of membranes. Regardless of the clinical presentation, it is thought that it is a syndrome with multiple etiologies and management strategies must take this into consideration.

The various proposed triggers for PTB are as follows:⁵

• Uterine overdistension;
• Ischemia;
• Infection;
• Cervical disease;
• Abnormal allograft reaction;
• Allergic phenomena;
• Endocrine disorder.

These factors may occur on their own or in combination. Since a precise mechanism cannot be established, various risk factors have been investigated to identify women at risk of PTB. It is important to establish that these risk factors may not explain the cause but have been found in epidemiological studies to be strongly associated with PTB.

RISK FACTORS FOR PRETERM BIRTH

Risk factor identification is important as it allows clinicians to target populations that might benefit from antenatal interventions.

Risk factors include:

• Social and demographic factors – Poverty, limited maternal education and unmarried status are associated with preterm labor and may be due to poor nutritional status and inadequate antenatal care.^7,8 Extremes of maternal age, smoking, alcohol and drug use are also strongly correlated. Body mass index (BMI) also plays a role. Women with a BMI less than 18.5 have an odds ratio of 3 (95% CI 1.2–1.3),⁸ while those with a BMI above 30 have an up to 3 fold higher risk the more obese they are.^7,8
• Ethnicity and genetics – In the USA and UK, women of African descent have consistently higher rates of PTB compared to those who are Caucasian.⁶ This may be due to access to care, but may also be genetically determined. Women who have a family history of PTB in either parent or siblings are also more likely to have a preterm delivery.
• Obstetric factors – Previous PTB appears to be the strongest risk factor with a 4–6 times higher risk in a current pregnancy.⁸ Multiple pregnancies are more likely to deliver preterm compared to singletons. History of cervical surgery like cone biopsy and repair of cervical lacerations appear to increase risk. A sonographically short cervix in midtrimester also increases the risk of spontaneous PTB.⁹ A cervical length of 15 mm increases the risk by 34%¹⁰ and so screening by transvaginal ultrasound is recommended as these women may benefit from vaginal progesterones. Women with uterine malformations like uterus didelphy, bicornuate, unicornuate and those with a septum have an overall 40% increased chance.
• Infection and inflammation – Microbiological studies suggest that intrauterine infection accounts for between 25 and 40% of PTB.⁶ These may be ascending infection or from hematogenous transmission.^5,6 Occasionally it may be a complication from invasive procedures such as amniocentesis. Systemic infection, such as malaria and other extrauterine sources like pyelonephritis, has also been found to trigger PTB.
• The vaginal microbiome and dysbiosis – There has been new interest in evaluating the vaginal microbiome which in healthy women is populated by Lactobacillus sp. There is an inverse correlation between the percentage of Lactobacillus colonization and development of bacterial vaginosis which increases PTB risk.¹¹ Current evidence does not support universal screening in asymptomatic women, but screening in high-risk women and treatment with clindamycin appear beneficial in some systemic reviews in reducing PTB.
• Antepartum hemorrhage – Bleeding in pregnancy increases the risk of PTB threefold. Bleeding in pregnancy also increases the risk of premature rupture of membranes which then leads to PTB both spontaneous and iatrogenic.

BIOLOGICAL PATHWAYS FOR PRETERM BIRTH

Uterine Overdistension

Uterine overdistension plays an important role in the onset of preterm labor in multiple pregnancies, polyhydramnios and macrosomia. Although the precise mechanism is not understood, stretching of the uterus has been shown to induce expression of gap junction proteins like CX-43 and CX-26 which are associated with contractions.¹² Stretching of the muscles in the lower segment also increases levels of interleukin (IL)-8 and collagenase which in turn facilitate cervical ripening. Prostaglandins like PGE and PHHS-2 are also increased when there is mechanical stretch of the myometrium in in vitro and animal studies.¹³ These effects can be blocked by progesterone administration in animal models.¹³ There are limited human studies to confirm these findings, but it would seem plausible to extrapolate that this mechanism might also be responsible for PTB in women with these risk factors.

Uteroplacental Thrombosis and Decidual Hemorrhage (Ischemia)

Ischemia of the placenta from vascular lesions is commonly associated with PTB and preterm premature rupture of membranes (PPROM).¹² Vascular insult, both thrombosis and hemorrhage, have been reported in 34% of women with PTB, 35% of women with PPROM and 12% of uncomplicated deliveries at term.¹⁴

The proposed mechanism linking vascular insult to PTB is related to uteroplacental ischemia and the role of thrombin in initiating the cascade of events leading to PTB.¹²

Thrombin is a multifunctional protease that elicits contractile activity of vascular, intestinal and myometrial smooth muscle.¹² Thrombin activates transmembrane receptors such as protease-activated receptor 1, 3 and 4 which in turn cause conformational changes that cause release of intracellular calcium from the endoplasmic reticulum. Activation of calmodulin, MLCK, actin and myosin cause phasic uterine contractions.¹⁵

In vitro and in vivo observations have confirmed the role of thrombin in increasing myometrial contractility. Furthermore, the addition of heparin, a known thrombin inhibitor, significantly reduced myometrial contractility.¹⁵

Infection and Inflammation

When infection is responsible for PTB, the rates of neonatal morbidity and mortality are high, particularly when it occurs before 28 weeks. The sources of infection include the genital tract, systemic maternal infections, asymptomatic bacteriuria and periodontal disease. Approximately 50% of PTB and 70% of PPROM are associated with intraamniotic infection.¹⁶ Evidence suggests that the proinflammatory cytokine-prostaglandin cascade is responsible for infection associated PTB.¹² These markers are produced by macrophages, decidual cells and fetal membranes in response to bacteria and bacterial products. Proinflammatory cytokines like IL-1B, IL-6, IL-8 and tumor necrosis factor (TNF)-α, prostaglandins and matrix metalloproteinases (MMPs) in amniotic fluid are increased between 24 and 48 hours before the onset of uterine contractility.¹²

Bacterial vaginosis represents an important and potentially preventable cause of PTB. However, antibiotic treatment of this condition did not show consistent reduction in rates of PTB in studies and meta-analyses.

Maternal periodontal disease has also been associated with PTB and other adverse pregnancy outcomes like pre-eclampsia and fetal loss. The mechanism suggested has been hematogenous spread to the placental membranes and amniotic fluid but has not been conclusively demonstrated and is poorly understood. However, three clinical trials of periodontal treatment have suggested an up to 50% reduction in PTB risk.¹²

Neuroendocrine Processes

The neuroendocrine process linking stress to prematurity is mediated by placental corticotropin releasing hormone (CRH).¹⁷ In vitro studies of human placental cells have shown a dose response increase in CRH to all biological effectors of stress including cortisol, catecholamines, oxytocin, angiotensin II and IL-1. In vivo studies show correlations between maternal psychological stress and levels of plasma CRH, ACTH and cortisol. Several studies have confirmed increases in maternal plasma CRH levels in relation to timing of birth at term. Placental CRH promotes fetal cortisol and dehydroepiandrosterone (DHEA)-s production and this positive feedback loop is amplified and drives the process of parturition from the fetal hypothalamic-pituitary-adrenal (HPA) axis. In women who deliver preterm, the levels of CRH in midgestation are significantly higher than those who deliver at term. It is thought that maternal stress could activate the placental CRH gene expression causing PTB.¹²

Role of Progesterone

Throughout most of a normal pregnancy, the uterus remains quiescent through the inhibition of myometrial activity by progesterone, prostacyclin (PGI2), nitric oxide, relaxin and parathyroid hormone-related peptide. In general, they increase intracellular cyclic nucleotides (cAMP and cGMP) and in turn inhibit intracellular calcium release and reduce myosin light-chain kinase (MLCK) activity. These two substances are central to uterine contractility.

Progesterone also blocks gap junction formation within the myometrium and inhibits placental CRH. Data suggest that a functional withdrawal of progesterone may occur in women by alterations in progesterone receptor isoforms at the onset of labor. Progesterone receptor (PR)-A expression increases which then suppresses the action of progesterone and this enables labor to start.

By these proposed mechanisms, recent evidence supports the use of progesterone to reduce the risks of both miscarriage and preterm labor.

Fetal Gender and Hormonal Influences

Gender differences in adverse pregnancy outcomes have been described. In low-risk populations, the male fetus is at significantly higher risk of spontaneous preterm birth with an odds ratio between 1.09 and 1.24 described in 24 large population datasets.¹⁸

Several mechanisms have been proposed to explain why pregnancies carrying male fetuses have a higher PTB risk:

• Heavier body weight which increases uterine distension.
• Greater susceptibility to certain medical complications such as pregnancy induced hypertension.
• Sex-linked biochemical interactions including labor induced by estrogen production from androgen precursors and IL-1.

Despite various hypotheses to explain the apparent increase in PTB risk among women carrying male fetuses, there is insufficient research to shed light on this issue and future analysis should explore the gender differences by etiology and possibly guide obstetric decision making in attempting to prevent PTB.¹⁸

SCREENING FOR PRETERM BIRTH

Cervical Length

A short midtrimester cervical length is associated with a higher risk of spontaneous preterm birth.¹⁹ A cervical length of <25 mm is associated with relative risk of 9.49.¹⁹ Several studies have been undertaken to assess the predictive value of cervical length measurements, but systemic reviews have concluded that a single cervical length measurement between 18 and 24 weeks is a better predictor for PTB compared to serial measurements.²⁰ The International Federation of Gynecology and Obstetrics (FIGO) recommends universal screening, but there is no universal agreement on this strategy. PTB is a syndrome of many etiologies and experts argue that this would reduce the preterm birth rate only marginally.²¹ There is also no consensus about the threshold to trigger intervention and a concern for medicating the majority of women with false positive screen results.²¹

Fetal Fibronectin

Fetal fibronectin is a glycoprotein in the extracellular matrix between the amniotic membranes and decidua. It is thought that damage to the membranes causes a higher concentration in cervicovaginal secretions. It is used to predict delivery within 7 days in symptomatic women. A positive fetal fibronectin test is strongly associated with PTB before 35 weeks with a relative risk of 8.2. However, it has a low sensitivity (23%)¹⁹ and has limited use in asymptomatic and low-risk women. There is also insufficient evidence for use in women who have uterine anomalies, in multiple pregnancies or in those who have had excisional procedures to the cervix.¹⁹

PREVENTION OF PTB

Prevention of PTB is an important goal of obstetric care. The United Nations Millennium Development Goal 4 had a two-thirds reduction in PTB between 1990 and 2015, but did not achieve this objective. This is despite extensive research and advancements in the understanding of this syndrome over several decades.

The approach towards prevention should be holistic and encompass multiple social, clinical and administrative avenues.

Antenatal care and education. Access to early and comprehensive care is vital to PTB prevention. Regular antenatal visits allow healthcare providers to identify and address risk factors and provide appropriate interventions and monitor the health of both mother and fetus. Education about lifestyle modification like smoking cessation, nutrition and importance of compliance to medical advice are proactive steps toward prevention.

Management of high-risk pregnancies. Identification of women who have had previous PTB, multiple pregnancies and medical comorbidities requires specialist care. This allows effective interventions to be instituted in a timely manner like low-dose aspirin for pre-eclampsia prevention, progesterone supplementation or cerclage placement. Close monitoring of fetal growth can also help to mitigate the risks of PTB in these women.

Addressing infection and inflammation. Infection and inflammation are significant contributors to PTB. Early detection and treatment of infection such as urinary tract infection, bacterial vaginosis, periodontal disease and sexually transmitted infections can help to reduce PTB risk.

Progesterone, cerclage or pessary. Progesterone is a hormone that is essential for maintenance of pregnancy. It has been used in various forms throughout the years for PTB prevention with conflicting results. However, in 2018, an individual patient data meta-analysis was conducted and conclusively demonstrated that vaginal micronized progesterone in singleton asymptomatic women with a sonographically short cervix significantly reduced PTB rates by 38%.²²

A cerclage is a surgical procedure where a suture is used to secure the cervix to prevent dilatation and shortening. The NICE guidelines recommend that women who have risk factors be offered either cervical cerclage placement or vaginal progesterone.²³ However, if the history includes previous premature prelabor rupture of membranes or cervical trauma, then a cerclage is preferable.¹⁹

The cervical pessary is a flexible silicon device that is folded and inserted into the vagina to hold the cervix together. Its exact mechanism of action is unknown, but it may redistribute the weight of the uterus away from the internal os. The studies that have evaluated its use have mixed results and for this reason, it cannot be recommended until more conclusive results of efficacy can be demonstrated.¹⁹

There is still uncertainty as to whether multiple modalities can be used together, what the frequency of cervical length measurements should be after treatment to assess whether therapy is effective and what should be the optimal algorithm for management.

Psychosocial support. Psychosocial factors such as stress, depression and anxiety have also been associated with an increased risk of PTB through uncertain mechanisms. Antenatal care should incorporate mental health screening and provide appropriate support. This could include counseling, support groups or referral to specialized mental health professionals.

IMPROVING NEONATAL OUTCOMES

Tertiary interventions to improve PTB outcomes are taken when the process of preterm parturition has already begun.

Early identification of PTB may be improved by using cervical length measurements and fetal fibronectin to triage women who will benefit from interventions.

Antibiotic treatment for all women in preterm labor to reduce the risk of group B streptococcus infection has been effective in improving neonatal outcomes in the UK.²⁴

Administration of antenatal corticosteroids reduces neonatal mortality and morbidity by reducing respiratory distress from accelerated lung maturation. It also reduces rates of necrotizing enterocolitis, intraventricular hemorrhage and mortality in randomized controlled trials.²⁴

Magnesium sulfate given to the mother has proven to be a fetal cerebral protection agent. Its mechanism of action is by reducing intraventricular hemorrhage (IVH) and periventricular leukomalacia in the premature brain that predisposes to cerebral palsy. Most guidelines now recommend magnesium sulfate when delivery is imminent within 24 hours, for gestations less than 30 weeks it is given as a 4 g bolus and 1 g per hour until delivery for no more than 24 hours.

ONGOING RESEARCH

There are many developments in the continued search for effective means to improve PTB outcomes. There are promising new biomarkers that may be used at 12 weeks as screening for PTB. Probiotics as a preventative strategy have been researched with mixed results. There are also ongoing trials evaluating low-dose aspirin in PTB prevention.

UNSOLVED ISSUES

• The etiology of PTB remains multifactorial and although risk factors have been identified, they only account for a fraction of those who deliver too soon. Genetic predisposition, uterine anomalies, hormonal imbalance and environmental factors play a role but their intricate interaction and contributions remain poorly understood. In the past, obstetricians and epidemiologists have combined all births between 22 and 37 weeks as preterm for statistical purposes. This has complicated efforts to study different etiologies and pathways separately.
• It is now clear that PTB is a syndrome and the causes vary according to gestational age and may even be a continuum from early pregnancy as there is considerable overlap with those at risk of miscarriage.
• Predictive markers remain elusive despite extensive research. Cervical length, fetal fibronectin and biomarker analysis have shown promise in certain groups of women but lack accuracy and specificity for widespread clinical use.
• Prevention of PTB remains the major challenge despite current strategies like progesterone supplementation, cerclage and pessary placement which appear beneficial in only specific subgroups of women. The development of universally effective measures has proved challenging leaving clinicians with limited options for effectively reducing the incidence of PTB.
• Collaborative research is imperative to unravel all the mysteries of PTB. Interdisciplinary studies involving obstetricians, neonatologists, geneticists and epidemiologists are crucial in understanding this complex syndrome.

Important areas of research include:

• A better understanding of placental implantation and development.
• The need for better early diagnostic tests to discriminate the many pathways to PTB.
• The development of intervention strategies to target unique initiators of PTB.

PRACTICE RECOMMENDATIONS

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