Why preterm birth

The disproportionate representation of preterm infants among infection-related neonatal deaths may be due to their immature immune systems Wynn et al. Preterm infants have deficiencies in both innate and adaptive immunity, and in the interaction between these two systems Durandy, ; Strunk et al. Preterm infants' immune systems may be further compromised, however, by factors associated with preterm birth.

A variety of common pre- and postnatal events associated with preterm birth have the potential to modulate immunity. At the time of term birth, the immune system has not fully matured. The inexperienced adaptive immune system must still develop specificity and memory, which is completed only in the early childhood years Hannet et al. As such, normal term neonates rely heavily on their innate immune response but this too is immature Marodi, Immaturity of the immune system is more pronounced in infants born preterm Figure 1.

Figure 1. Leukocyte development begins in the yolk sac before moving to the liver and finally the bone marrow. The development and maturation of primary lymphoid organs blue and peripheral blood leukocytes red occur throughout gestation but is not complete until after birth. Based on a figure from Durandy Soluble proteins and peptides have the ability to opsonize pathogens to aid in phagocytosis and to directly kill pathogens through their antimicrobial properties.

There is limited production of soluble factors, such as immunoglobulin Ig , by the fetus so it must rely on maternal supply. Antigen-specific IgG is transferred across the placenta from the maternal circulation in large amounts after 32 weeks of gestation van den Berg et al.

Transfer increases with fetal age; so preterm infants have low levels of circulating maternal IgG Heininger et al. APPs act through various mechanisms to destroy pathogens, such as iron binding using the bacterium's source of iron , enzymatic destruction, zinc depravation and membrane pore formation Levy, The production of APPs is positively correlated with gestational age Strunk et al.

The classical, alternative and lectin complement pathways are all reduced in their pathogen-killing abilities in preterm infants Fietta et al. Complement proteins act through various mechanisms to activate the C3 protein and induce phagocytosis. Preterm neonates are deficient in the production of C1, C4 classical pathway and factor B alternative pathway compared to term neonates McGreal et al. Preterm infants are also deficient in the pattern-recognition receptor mannose-binding lectin MBL , for which production increases as gestational age increases Strunk et al.

MBL is produced by hepatocytes, and opsonizes pathogens, aiding activation of the complement system through the lectin pathway.

Associated with MBL, L-ficolin production and function is also reduced in preterm neonates Swierzko et al.

These deficiencies in non-cellular responses to pathogens can lead to reduced phagocytosis and impaired pathogen clearance by phagocytes Driscoll et al. Preterm infants have a reduced pool of neutrophils and monocytes, and their precursors, due to reduced granulocyte colony-stimulating factor G-CSF and granulocyte-macrophage colony-stimulating factor GM-CSF levels Carr and Modi, The relative monocytopenia and neutropenia of preterm compared to term neonates can greatly affect infants' ability to fight infection Correa-Rocha et al.

Neutrophils are among the first responders to infection and have an important role in bacterial clearance. In response to an invading pathogen neutrophils migrate to the sight of infection to digest and kill these microorganisms Abbas and Lichtman, Neutrophils of preterm infants may have difficulty in migrating to sites of infection due to a reduction in the expression of adhesion molecules such as L- and E-selectin Nussbaum and Sperandio, Neutrophils ingest, through phagocytosis, and kill pathogens by releasing enzymes from their cytoplasmic granules Witko-Sarsat et al.

Impairment in neutrophil function phagocytosis, generation of oxygen radicals and intracellular killing of pathogens is a risk factor for the development of sepsis Carr, Extracellular pathogen killing is also limited in neonates, with reduced ability to produce neutrophil extracellular traps NETs Yost et al.

NETs are lattices made of DNA bound to granular and cytoplasmic protein, which are released from neutrophils to trap and kill pathogens Brinkmann and Zychlinsky, Monocytes are phagocytic blood-borne cells that differentiate into macrophages or DCs in tissue.

Monocytes are capable of phagocytosis, have bactericidal mechanisms and are involved in antigen presentation to T cells Abbas and Lichtman, The monocytes of preterm infants have reduced cytokine production, but a similar efficiency in phagocytosis and intracellular killing of pathogens as term neonates Currie et al.

Adaptive immunity, involving lymphocytes B and T cells , is pathogen-specific and requires acquisition of immunological memory. Genetic recombination of lymphocyte cell surface receptors results in an increased repertoire of pathogen recognition. Recognition of a pathogen results in lymphocyte activation, pathogen clearance and memory lymphocyte production, leading to swifter adaptive immune responses on subsequent encounters with the same pathogen.

Maturation of adaptive immunity occurs mostly after term birth, so all newborn infants have deficiencies in T cell activation and cytokine production, B cell immunoglobulin production, and interactions between T and B cells, relative to adults. At birth lymphocyte subpopulations are lower than in adults, and require clonal expansion. This occurs in the first few weeks of postnatal life, with both term and preterm infants following the same pattern of expansion; but preterm infants have lower absolute numbers of circulating lymphocytes Walker et al.

A reduction in lymphocyte subpopulations is evident in children born preterm at 7 months Berrington et al. The increased proportion of naive T cells is a result of inefficient DC antigen uptake and presentation, and is contributed to by a reduction in MHC II expression on antigen-presenting cells Strunk et al. During fetal life, cytokine responses are driven toward a Th2 phenotype.

The Th2 bias is thought to be a preventative measure against fetal rejection by the maternal immune system, with increased Th1 cytokine production linked to an increased risk of spontaneous abortion Szekeres-Bartho, Conversely, IL-8 production and baseline Toll-like receptor TLR -4 expression is greater for monocytes from neonates compared to adults. IL-8 production is lower in monocytes from preterm neonates compared to term neonates but monocyte TLR-4 expression is comparable Levy et al.

Immunoglobulins IgM and IgD are co-expressed on naive B cells; upon activation the B cells class-switch to express another antibody isotype and lose IgD expression. B cells, when activated, secrete antibodies to fight the pathogen by opsonization Liu and Banchereau, In neonates the ability to class-switch is reduced, resulting in B cells secreting mainly IgM antibodies.

Neonatal T cells have reduced expression of CD40L, even when activated, resulting in a reduced production of the antibodies IgG and IgA by neonatal compared to adult B cells Nonoyama et al.

Intrauterine inflammation is the principal cause of preterm birth Hagberg et al. Intrauterine inflammation can be caused by bacterial infection, which can occur by ascent of bacteria from the birth canal, crossing of the placenta or membranes by microbes, or inadvertent pathogen transfer into the amniotic cavity during amniocentesis Hagberg et al. Intrauterine inflammation can increase the risk of infant mortality Hagberg et al.

Clinical and experimental studies demonstrate that bacteria or pro-inflammatory mediators in amniotic fluid can be inspired or swallowed by the fetus to elicit a fetal inflammatory response FIRS Gotsch et al.

In sheep, intrauterine inflammation increases the risk of perinatal neurological injury Duncan et al. The fetal sheep lung has increased surfactant production and improved compliance after exposure to inflammation Moss et al.

However, at least in the sheep, lung structure is simplified Moss et al. Simplified lung structure arising from prenatal exposure to inflammation could contribute to a potential increase in the risk of bronchopulmonary dysplasia BPD in human neonates Been et al.

There is evidence of monocyte and neutrophil activation in addition to increased numbers of these cells in the fetal circulation after exposure to inflammation in humans and sheep Kallapur et al.

Lymphocytes are activated during infections in utero in humans, indicating the fetal adaptive immune response is at least partly responsive Duggan et al. Intrauterine inflammation also increases production of these cytokines Romero et al. Animal experimentation has been valuable for understanding the immune consequences of intrauterine inflammation. Immune cells including monocytes, neutrophils, and lymphocytes in fetal sheep lung tissue significantly increase in response to intra-amniotic lipopolysaccharide LPS infusion Kallapur et al.

Peripherally, activation of leukocytes resulting in MHC II up-regulation would aid in eliminating the threat. The increased number of lymphocytes and expression of MHC II may indicate that the fetus is capable of reacting to infection with an adaptive immune response, along with these innate responses, consistent with observations in humans Duggan et al. Responsiveness of the preterm immune system to intrauterine inflammation is demonstrated further by the observation that repeated pro-inflammatory exposures induce tolerance in preterm sheep.

Repeated doses of LPS into the amniotic cavity of sheep, at 2 and 7 days before preterm delivery, cause a reduction in IL-6 secretion in fetal sheep when compared to a single dose of LPS Kallapur et al. This tolerance effect clearly demonstrates modulation of the immune system in response to the initial stimulus. Deficiencies in preterm immune function have implications for the eradication of postnatal infections. Particularly important are nosocomial infections, which occur more frequently in preterm infants due to their extended hospital stays.

Mortality associated with early-onset sepsis is increased in preterm infants, and rates correlate inversely with gestational age. Of the infants born after exposure to chorioamnionitis, 4. Intrauterine inflammation increases the risk of early-onset sepsis, likely because at least some of these postnatal infections originated in utero. However, intrauterine inflammation decreases the risk of late-onset sepsis Strunk et al. In , Liggins used the synthetic glucocorticoid, dexamethasone, to induce preterm labor in pregnant ewes and found that the lambs born after dexamethasone were able to breathe spontaneously, whereas preterm lambs that had not received dexamethasone could not Liggins, Since this time, numerous randomized controlled trials have demonstrated beneficial effects on the preterm respiratory, central nervous, and gastrointestinal systems of antenatal glucocorticoids Roberts and Dalziel, Glucocorticoids are used in adults to modify immune responses in allergy and autoimmune diseases but the equivalent effects on the fetal immune system are not well-understood Tuckermann et al.

The hypothalamic-pituitary-adrenal HPA axis regulates many physiological processes, including the immune system. An increase in pro-inflammatory cytokines causes activation of the HPA axis, which increases cortisol.

Cortisol suppresses the immune system, by acting on glucocorticoid receptors of leukocytes, which causes translocation to the nucleus Beato et al. Interference with these transcription factors reduces cytokine production and prevents the immune system overwhelming the body with inflammation Barnes, Glucocorticoids can also induce apoptosis of DCs and lymphocytes Barnes, The effect of an increase in endogenous glucocorticoids via stress or maternal administration of exogenous glucocorticoids on the developing immune system has not been extensively studied in humans or other animals but the limited data show lasting effects.

Glucocorticoid exposure results in long-lasting alterations to physiological and cellular responses to infection and inflammation in the offspring. In pigs, maternal cortisol treatment during pregnancy caused an increased febrile response of female offspring to LPS challenge de Groot et al. Administration of adrenocorticotropic hormone to pregnant Rhesus monkeys over a 2-week period alters immune responses of the juvenile offspring, reducing their febrile and cytokine responses to IL-1 Reyes and Coe, Induction of maternal stress causing an increase in maternal corticosterone in rats resulted in a reduction in proliferation of certain subgroups of lymphocytes after mitogenic stimulation, in offspring at 8—9 weeks postnatal age Kay et al.

Human clinical studies have observed a reduction in lymphocyte number in preterm neonates after antenatal glucocorticoids Chabra et al.

Meta-analysis shows that antenatal glucocorticoids may reduce the risk of neonatal sepsis Dembinski et al. However, an association between increased early-onset neonatal sepsis and multiple-course maternal betamethasone treatment has been observed in one study Vermillion et al. A recent study showed that the ability of neonatal cord blood leukocytes to produce cytokines is not altered with antenatal glucocorticoid treatment Kumar et al. Intravenous administration of dexamethasone to fetal sheep, in a dose approximating that used antenatally in women at risk of preterm birth, results in an increase in total leukocytes between three and 12 h after administration due to an increase in neutrophils, but a reduction in lymphocytes Edelstone et al.

In contrast, maternal intravenous dexamethasone administration does not alter fetal circulating leukocyte counts but increases maternal neutrophils and decreases maternal lymphocytes Edelstone et al. Similarly, pregnant women administered antenatal glucocorticoids have increased circulating neutrophils coupled with a decrease in lymphocytes Wallace et al. Betamethasone administration to pregnant rats on gestational days 19 and 20 term 22 days caused a reduction in lymphocyte proliferation and IL-2 production in late-gestation fetuses and for up to six days after birth Murthy and Moya, Natural killer NK cells also had reduced cytotoxicity, particularly those from male offspring Kay et al.

Functional changes are also observed in monocytes of lambs born after maternal betamethasone injection. Phagocytosis of apoptotic neutrophils, but not bacteria, by preterm sheep monocytes was initially decreased after maternal betamethasone but was increased 3-fold seven days after Kramer et al.

These differences in phagocytic capacity may be explained by the observation that TLR-4 expression is not altered by glucocorticoids Cepika et al. Similar results are seen in adult monocytes exposed to glucocorticoids. Human monocytes are altered to an anti-inflammatory phenotype aiding in the resolution of infections Tsianakas et al. In murine monocytes, glucocorticoids increase the expression of receptors responsible for the phagocytosis of apoptotic neutrophils Nilsson et al.

From the available studies it appears likely that antenatal glucocorticoids have a modulating effect on preterm immune function. What is unknown is whether these effects are transient or persist into childhood and beyond. Rates are highest on average for low-income countries However, relatively high preterm birth rates are seen in many individual high-income countries where they contribute substantially to neonatal mortality and morbidity.

Of the 1. The uncertainty ranges in Figure 3 are indicative of another problem -- the huge data gaps for many regions of the world. Although these data gaps are particularly great for Africa and Asia, there also are gaps in data from high-income countries.

While data on preterm birth-associated mortality are lacking in these settings, worldwide there are almost no data currently on acute morbidities or long-term impairment associated with prematurity, thus preventing even the most basic assessments of service needs. The maps in Figure 4 depict preterm birth rates and the absolute numbers of preterm birth in by country. Estimated rates vary from around 5 in several Northern European countries to Preterm births in Source: Blencowe, H.

Mortality rates increase with decreasing gestational age, and babies who are both preterm and small for gestational age are at even higher risk [ 61 ].

Across all regions, mortality and morbidity are highest among those babies although improvements in medical care have led to improved survival and long-term outcomes among very and extremely preterm babies in high-income countries [ 62 ]. In all settings, these very or extremely preterm babies account for the majority of deaths, especially in low-income countries where even simple care is lacking [ 64 ].

Absolute numbers and rates of preterm birth for 65 countries in Europe, the Americas and Australasia from to for these countries suggest an increasing burden of preterm birth [ 5 ]. Despite a reduction in the number of live births, the estimated number of preterm births in these countries increased from 2.

Preterm birth rate trends for low- and middle-income countries suggest an increase in some countries e. In , approximately 15 million babies were born preterm, and more than 1 million died due to complications in the first month of life, more from indirect effects, and millions have a lifetime of impairment. The burden of preterm birth is highest in low-income countries, particularly those in South Asia.

Yet unlike many other global health issues, preterm birth is truly a global problem with a high burden being found in high-income countries as well e.

However, while the risk of preterm birth is high for both the poorest and the richest countries, there exists a major survival gap in some regions for babies who are preterm. In high-income settings, half of babies born at 24 weeks may survive, but in low-income settings half of babies born at 32 weeks still die due to a lack of basic care [ 64 ]. Preterm birth rates appear to be increasing in most of the countries where data are available. Some of this increase may be accounted for by improved registration of the most preterm babies associated with increased viability and by improved gestational assessment, with change to near universal ultrasound for dating pregnancies in these settings.

It may, however, represent a true increase. Possible reasons for this include increases in maternal age, access to infertility treatment, multiple pregnancies and underlying health problems in the mother, especially with increasing age of pregnancy and changes in obstetric practices with an increase in provider-initiated preterm births in moderate and late preterm infants who would not have otherwise been born preterm [ 46 ]. In the s and s, the increases seen in many high-income countries were attributed to higher multiple gestation and preterm birth rates amongst assisted conceptions after treatment for sub-fertility.

Recent changes in policies limiting the number of embryos that can be implanted have led to a reduction in preterm births due to assisted fertility treatments in many countries [ 63 ]. However, in many middle-income regions with newer, relatively unregulated assisted fertility services, a similar increase may be seen if policies to counteract this are not introduced and adhered to.

A reduction in preterm birth was reported from the s to s in a few countries e. Finland, France, Scotland , and this was attributed, in part, to improved socioeconomic factors and antenatal care. For the majority of countries in low- and middle-income regions, it is not possible to estimate trends in preterm birth over time as there are not sufficient data to provide reliable evidence of a time trend for preterm birth overall. Some countries in some regions e. South and Eastern Asia have data suggesting possible increases in preterm birth rates over time, but this may represent measurement artifact due to increases in data and data reliability.

Distinguishing spontaneous and provider-initiated preterm birth is of importance to programs aiming to reduce preterm birth. For spontaneous preterm births, the underlying causes need to be understood and addressed while in the case of provider-initiated preterm births both the underlying conditions e.

The proportion of neonatal deaths attributed to preterm births is inversely related to neonatal mortality rates, because in countries with very high neonatal mortality, more deaths occur due to infections such as sepsis, pneumonia, diarrhea and tetanus as well as to intrapartum-related "birth asphyxia" [ 2 ].

However, although the proportion of deaths due to preterm birth is lower in low-income countries than in high-income countries, the cause-specific rates are much higher in low- and middle-income than in high-income countries.

For example, in Afghanistan and Somalia, the estimated cause-specific rate for neonatal deaths directly due to preterm birth is 16 per 1, compared to Japan, Norway and Sweden where it is under 0. This is due to the lack of even simple care for premature babies resulting in a major survival gap for babies depending on where they are born [ 64 ]. Preterm birth can result in a range of long-term complications in survivors, with the frequency and severity of adverse outcomes rising with decreasing gestational age and decreasing quality of care Table 1.

Most babies born at less than 28 weeks need neonatal intensive care services to survive, and most babies 28 to 32 weeks will need special newborn care at a minimum. The availability and quality of these services are not yet well established in many low- and middle-income countries.

Many middle-income countries, currently scaling up neonatal intensive care, are just beginning to experience these long-term consequences in survivors. These effects are most marked amongst survivors born extremely preterm; however, there is increasing evidence that all premature babies regardless of gestational age are at increased risk.

Most of these infants will survive with adequate supportive care and without needing neonatal intensive care. However, even babies born at 34 to 36 weeks have been shown to have an increased risk of neonatal and infant death when compared with those born at term and contribute importantly to overall infant deaths [ 68 ].

Babies born at 34 to 36 weeks also experience increased rates of short-term morbidity associated with prematurity e. In the longer term, they have worse neurodevelopmental and school performance outcomes and increased risk of cerebral palsy [ 72 , 73 ]. On a global level, given their relatively larger numbers, babies born at 34 to 36 weeks are likely to have the greatest public health impact and to be of the most importance in the planning of services e.

We have highlighted the differences in preterm birth rates among countries, but marked disparities are also present within countries. For example, in the United States in , reported preterm birth rates were as high as Disparities within countries need to be better understood in order to identify high-risk groups and improve care.

The economic costs of preterm birth are large in terms of the immediate neonatal intensive care and ongoing long-term complex health needs frequently experienced. These costs, in addition, are likely to rise as premature babies increasingly survive at earlier gestational ages in all regions. This survival also will result in the increased need for special education services and associated costs that will place an additional burden on affected families and the communities in which they live [ 74 ].

An increased awareness of the long-term consequences of preterm birth at all gestational ages is required to fashion policies to support these survivors and their families as part of a more generalised improvement in quality of care for those with disabilities in any given country.

In many middle-income countries, preterm birth is an important cause of disability. The estimates from the Born Too Soon report represent a major step forward in terms of presenting the first-ever national preterm birth estimates [ 77 ].

However, action is required to improve the availability and quality of data from many countries and regions and, where data are being collected and analysed, to improve consistency among countries. These are vital next steps to monitor the progress of policies and programs aimed at reducing the large toll of preterm birth Table 4. Efforts in every country should be directed to increasing the coverage and systematic recording of all preterm births in a standard reporting format. Standardisation of the definition in terms of both the numerator the number of preterm births and the denominator the number of all births is essential if trends and rankings are to be truly comparable.

Collecting data on both live and stillbirths separately will allow further quantification of the true burden, while data focusing on live births only are required for monitoring of neonatal and longer-term outcomes.

These estimates indicate the large burden amongst live-born babies. Distinguishing between live births and stillbirths may vary depending on local policies, the availability of intensive care and perceived viability of babies who are extremely preterm. If estimates for live-born preterm babies were linked to estimates for stillbirths, this would improve tracking among countries and over time. Achieving consensus around the different types of preterm birth and comparable case definitions, whilst challenging, are required where resources allow to further understand the complex syndrome of preterm birth [ 23 ].

In many low- and middle-income countries without wide-scale vital registration, no nationally representative data are available on rates of preterm birth. Substantial investment and attention are required to improve vital registration systems and to account for all birth outcomes [ 78 ].

In the meantime, the amount of population-based data available in high-burden countries could be dramatically increased to better inform future estimates and monitor time trends if data on preterm birth rates were able to be included in nationally representative surveys such as the Demographic and Health Surveys DHS , but this will require developing, testing and training in the use of preterm-specific survey-based tools which are not currently available.

The advent of inexpensive portable ultrasound machines makes inclusion of routine early ultrasound scans in demographic surveillance sites or representative cohorts a promising route to increase data availability in these settings in the short term.

Innovation for simpler, low-cost, sensitive and specific tools for assessing gestational age could improve both the coverage and quality of gestational age assessment. Data from hospital-based information systems would also be helpful, but potential selection and other biases must be taken into account.

Simpler standardized tools to assess acute and long-term morbidities-associated preterm birth also are critically important to inform program quality improvement to reduce the proportion of survivors with preventable impairment. Preterm birth: Inflammation, fetal injury and treatment strategies.

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