https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(08)60074-4.pdf

Epidemiology and causes of preterm birth

Background
Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless. Liggins and Howie published the first randomised controlled trial in humans in 1972 and many others followed.

Objectives
To assess the effects of administering a course of corticosteroids to the mother prior to anticipated preterm birth on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life.

Search methods
We searched Cochrane Pregnancy and Childbirth's Trials Register (17 February 2016) and reference lists of retrieved studies.

Selection criteria
We considered all randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co-morbidity, for inclusion in this review. Most women in this review received a single course of steroids; however, nine of the included trials allowed for women to have weekly repeats.

Data collection and analysis
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.

Main results
This update includes 30 studies (7774 women and 8158 infants). Most studies are of low or unclear risk for most bias domains. An assessment of high risk usually meant a trial had potential for performance bias due to lack of blinding. Two trials had low risks of bias for all risk of bias domains.

Treatment with antenatal corticosteroids (compared with placebo or no treatment) is associated with a reduction in the most serious adverse outcomes related to prematurity, including: perinatal death (average risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.89; participants = 6729; studies = 15; Tau² = 0.05, I² = 34%; moderate-quality); neonatal death (RR 0.69, 95% CI 0.59 to 0.81; participants = 7188; studies = 22), RDS (average RR 0.66, 95% CI 0.56 to 0.77; participants = 7764; studies = 28; Tau² = 0.06, I² = 48%; moderate-quality); moderate/severe RDS (average RR 0.59, 95% CI 0.38 to 0.91; participants = 1686; studies = 6; Tau² = 0.14, I² = 52%); intraventricular haemorrhage (IVH) (average RR 0.55, 95% CI 0.40 to 0.76; participants = 6093; studies = 16; Tau² = 0.10, I² = 33%; moderate-quality), necrotising enterocolitis (RR 0.50, 95% CI 0.32 to 0.78; participants = 4702; studies = 10); need for mechanical ventilation (RR 0.68, 95% CI 0.56 to 0.84; participants = 1368; studies = 9); and systemic infections in the first 48 hours of life (RR 0.60, 95% CI 0.41 to 0.88; participants = 1753; studies = 8).

There was no obvious benefit for: chronic lung disease (average RR 0.86, 95% CI 0.42 to 1.79; participants = 818; studies = 6; Tau² = 0.38 I² = 65%); mean birthweight (g) (MD -18.47, 95% CI -40.83 to 3.90; participants = 6182; studies = 16; moderate-quality); death in childhood (RR 0.68, 95% CI 0.36 to 1.27; participants = 1010; studies = 4); neurodevelopment delay in childhood (RR 0.64, 95% CI 0.14 to 2.98; participants = 82; studies = 1); or death into adulthood (RR 1.00, 95% CI 0.56 to 1.81; participants = 988; studies = 1).

Treatment with antenatal corticosteroids does not increase the risk of chorioamnionitis (RR 0.83, 95% CI 0.66 to 1.06; participants = 5546; studies = 15; moderate-quality evidence) or endometritis (RR 1.20, 95% CI 0.87 to 1.63; participants = 4030; studies = 10; Tau² = 0.11, I² = 28%; moderate-quality). No increased risk in maternal death was observed. However, the data on maternal death is based on data from a single trial with two deaths; four other trials reporting maternal death had zero events (participants = 3392; studies = 5; moderate-quality).

There is no definitive evidence to suggest that antenatal corticosteroids work differently in any pre-specified subgroups (singleton versus multiple pregnancy; membrane status; presence of hypertension) or for different study protocols (type of corticosteroid; single course or weekly repeats).

GRADE outcomes were downgraded to moderate-quality. Downgrading decisions (for perinatal death, RDS, IVH, and mean birthweight) were due to limitations in study design or concerns regarding precision (chorioamnionitis, endometritis). Maternal death was downgraded for imprecision due to few events.

Authors' conclusions
Evidence from this update supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids could be considered routine for preterm delivery. It is important to note that most of the evidence comes from high income countries and hospital settings; therefore, the results may not be applicable to low-resource settings with high rates of infections.

There is little need for further trials of a single course of antenatal corticosteroids versus placebo in singleton pregnancies in higher income countries and hospital settings. However, data are sparse in lower income settings. There are also few data regarding risks and benefits of antenatal corticosteroids in multiple pregnancies and other high-risk obstetric groups. Further information is also required concerning the optimal dose-to-delivery interval, and the optimal corticosteroid to use.

We encourage authors of previous studies to provide further information, which may answer any remaining questions about the use of antenatal corticosteroids in such pregnancies without the need for further randomised controlled trials. Individual patient data meta-analysis from published trials is likely to answer some of the evidence gaps. Follow-up studies into childhood and adulthood, particularly in the late preterm gestation and repeat courses groups, are needed. We have not examined the possible harmful effects of antenatal corticosteroids in low-resource settings in this review. It would be particularly relevant to explore this finding in adequately powered prospective trials.

/pdf/antenatal-corticosteroids-for-accelerating-fetal-lung-1rk6f4kj70.pdf

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

A controlled trial of betamethasone therapy was carried out in 282 mothers in whom premature delivery threatened or was planned before 37 weeks9 gestation, in the hope of reducing the incidence of neonatal respiratory distress syndrome by accelerating functional maturation of the fetal lung. Two hundred and thirteen mothers were in spontaneous premature labor. When necessary, ethanol or salbutamol infusions were used to delay delivery while steroid or placebo therapy was given. Delay for at least 24 hours was achieved in 77% of the mothers. In these unplanned deliveries, early neonatal mortality was 3.2% in the treated group and 15.0% in the controls (p 0.01). There were no deaths with hyaline membrane disease or intraventricular cerebral hemorrhage in infants of mothers who had received betamethasone for at least 24 hours before delivery. The respiratory distress syndrome occurred less often in treated babies (9.0%) than in controls (25.8%, p 0.003), but the difference was confined to babies of under 32 weeks9 gestation who had been treated for at least 24 hours before delivery (11.8% of the treated babies compared with 69.6% of the control babies p. 0.02). There may be an increased risk of fetal death in pregnancies complicated by severe hypertensionedema-proteinuria syndromes and treated with betamethasone, but no other hazard of steroid therapy was noted. We conclude that this preliminary evidence justifies further trials, but that further work is needed before any new routine procedure is established.

A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants

Intrauterine growth restriction.

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

/pdf/endocrine-and-paracrine-regulation-of-birth-at-term-and-4igz1kdkru.pdf

Endocrine and paracrine regulation of birth at term and preterm

Dexamethasone caused premature delivery when infused into foetal lambs at rates of 0\m=.\06-4\m=.\0mg./24 hr. but it had no effect when administered to pregnant ewes at the rate of 4\m=.\0mg./24 hr. Infusions into the foetus of deoxycorticosterone or corticosterone were ineffective; mixtures of dexamethasone and deoxycorticosterone did not cause parturition more rapidly than dexamethasone alone. Thus, the ability of corticosteroids to cause premature parturition appears to depend on glucocorticoid rather than mineralocorticoid activity. Parturition induced by dexamethasone was not delayed by administration of 100 mg. progesterone/24 hr. to the ewe or to the foetus. This suggests either that withdrawal of inhibitory effects of progesterone on the myometrium can occur independently of the progesterone concentration in peripheral plasma, or that the mechanism of parturition provoked by corticosteroids in the foetus can override any regulatory influence of progesterone

Premature delivery of foetal lambs infused with glucocorticoids.

Publisher Summary
This chapter discusses the mechanism of initiation of parturition in the ewe. The chapter also describes a study that has been carried out on sheep to determine the extent to which the lamb shares in the mechanisms of initiation of parturition, to elucidate the means of its participation, and to unravel the intricate endocrine relationship between the conceptus and the mother. The chapter explains that the concentration of total unconjugated estrogen in the peripheral plasma of pregnant sheep is low. The acute effect of estrogen on uterine smooth muscle in vitro is usually inhibitory and its stimulatory action in vivo is the result of the release of an oxytocic material. Coincident with the rise in circulating levels of unconjugated estrogen, there is an increase in the concentration of PGF2α in myometrium. Moreover, administration of stilbestrol to the ewe is associated with the increased levels of PGF2α in the myometrium and uterine vein blood. Distention of the cervix and vagina by descent of the fetus reflexly stimulates the release of oxytocin from the posterior pituitary gland. Responsiveness of this reflex is increased by the prior fall in circulating levels of progesterone and the rise in levels of unconjugated estrogen. Complete delivery of the lamb is rapidly accomplished through the combined efforts of uterine contractions augmented by oxytocin and reflexly excited contraction of the maternal abdominal musculature.

The mechanism of initiation of parturition in the ewe.

The glucocorticoids, cortisol and corticosterone, have a unique function in the fetus in inducing a wide range of enzymes before birth that have little or no function during fetal life but on which survival after birth is dependent. The loss of the placenta at birth deprives the fetus of a source of oxygen, glucose and heat (among many other things) for which alternatives must be available immediately if survival is to be assured. In anticipation of these needs several organs undergo maturational changes in late pregnancy aimed at meeting these requirements. The lungs mature structurally and functionally, becoming distensible and capable of coping with high surface tension when air enters the alveoli with the first breath. In the liver, glycogen accumulates and gluconeogenesis is initiated to meet the demands for glucose until feeding begins. There is an increase in the production of tri-iodothyronine and catecholamines in preparation for the sharp increase in metabolic rate and thermogenesis associated with breathing and the cold environment. All these dramatic maturational events are regulated by cortisol as are numerous others in most organ systems that contribute to neonatal well-being but on which survival is less dependent. Pharmacological manipulation of these systems before birth has made a substantial contribution to improving human health.

The role of cortisol in preparing the fetus for birth

Adrenocortical-related maturational events in the fetus.

The discovery in 1910 (see Liggins, 1988, for historical review) of the dependence of continuing pregnancy in rodents on the corpus luteum and the subsequent isolation of progesterone seemed to provide a sound basis for the mechanism initiating parturition. The ‘progesterone withdrawal’ hypothesis gained widespread acceptance regardless of whether the maintenance of pregnancy was corpus luteum dependent or placenta dependent. Because the luteotrophic complex of hormones in rodents is of maternal origin, little reason existed to depart from the traditional view that the mechanism resided in the mother rather than the conceptus. However, the 1950s saw increasing awareness of the evidence that fetal genotype in farm animals and certain fetal malformations in both man and farm animals influence the duration of pregnancy. With the unequivocal demonstration in 1967 that hypophysectomy in fetal sheep abolishes the initiation of parturition, the pendulum swung decisively away from maternal control towards fetal control and the fetal endocrine system became the focus of attention of most investigators.

G. C. Liggins

Papers

Premature delivery of foetal lambs infused with glucocorticoids.

The mechanism of initiation of parturition in the ewe.

The role of cortisol in preparing the fetus for birth

Adrenocortical-related maturational events in the fetus.

Initiation of parturition.