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.

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

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

I. Introduction IN THE adult ovary, folliculogenesis starts when follicles leave the pool of resting follicles (RF) to enter the growth phase. From there, the early growing follicle undergoes a developmental process including a dramatic course of cellular proliferation and differentiation. In primates, only one follicle commonly reaches the preovulatory stage every cycle; most follicles fail to complete this maturation scheme, dying in the process termed atresia. In recent years, a picture has emerged depicting the classic endocrine control of ovarian function by LH and FSH, entangled in a maze of regulatory systems hinging on cell-cell interactions between follicular cells, via action of a variety of molecules (1–3). Different types of cell-cell interactions have been described. In paracrine regulations, a molecule synthesized by one cellular type is released into the interstitial milieu to act directly on another cellular type. In autocrine regulations, molecules synthesized by one cellular type are rel...

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Regulation of ovarian follicular development in primates: facts and hypotheses.

Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.

Background. Low-back pain (LBP) is a commonly observed symptom during pregnancy. Despite its high frequency the extent of the problem is less well documented and detailed studies concerning related risk factors are scarce. Furthermore, efforts to address the problem are hampered by the inability to predict accurately which pregnancies are at risk. This study was conducted in order to assess the frequency, manifestations and the contribution of various factors to the development of LBP during pregnancy.Methods. The study included 449 pregnant women who were consecutively referred for an antenatal ultrasonographic examination for various reasons. A simple questionnaire which consisted of several items along with ultrasonographic measurements was devised to evaluate the incidence of and risk factors for LBP during pregnancy.Results. 246 (54.8%) women reported LBP in the present pregnancy. Factors which were found to be significantly associated with an increased risk to develop LBP during pregnancy included l...

Low-back pain of pregnancy.

Cytokines—involvement in reproduction

Sixteen patients with polycystic ovarian syndrome (PCO) were treated by in-vitro fertilization (26 treatment cycles). The results were compared with 37 normo-ovulatory women with tubal disease (37 treatment cycles). The oestradiol and progesterone levels were higher during the follicular phase in the PCO patients, but were statistically significantly higher only on the day after human chorionic gonadotrophin administration. Although more oocytes were recovered per cycle from the PCO group (19.3 +/- 6.1) than from the control group (5.4 +/- 2.9) with P less than 0.004, the mean numbers of embryos per cycle were similar in both groups (3.7 +/- 2.4 versus 3.6 +/- 2.2, respectively). The pregnancy rate was also comparable in both groups (30.7 versus 29.7%, respectively). The fact that more oocytes are recovered from PCO patients, balances their lower fertilization and cleavage rates. We conclude, therefore, that IVF treatment may be a viable solution for PCO patients resistant to an in-vivo protocol treatment regimes.

The treatment of patients with polycystic ovarian syndrome by in-vitro fertilization and embryo transfer: a comparison of results with those of patients with tubal infertility

The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer

Objective To assess the frequency of menarche and menstrual disturbances among women suffering from insulin-dependent diabetes mellitus, and to evaluate their correlation to the onset of diabetes, its duration, and complications. Research design and methods Retrospective analysis of the menstrual regularity and gynecologic and fertility history of 100 women suffering from insulin-dependent diabetes mellitus. These data were compared with information obtained from the patients' medical records regarding the age at onset of diabetes, its management, control, and complications. Results The average age at menarche was 13.5 years. Delayed menarche tended to appear in girls whose diabetes was diagnosed before the age of menarche, and before the age of 10 years. Menstrual disturbances, such as oligomenorrhea, amenorrhea, and polymenorrhea, occurred in 32% of the women. A significant correlation was found between late menarche and menstrual disturbances. Furthermore, patients with diabetic complications had a higher incidence of menstrual disorders compared with uncomplicated diabetic patients. Conclusions It appears that women with insulin-dependent diabetes mellitus who had been diagnosed prior to menarche had a higher probability of delayed menarche, and were at higher risk for development of menstrual disturbances, including amenorrhea with subsequent fertility disorders.

Zion Ben-Rafael

Papers

Low-back pain of pregnancy.

Cytokines—involvement in reproduction

The treatment of patients with polycystic ovarian syndrome by in-vitro fertilization and embryo transfer: a comparison of results with those of patients with tubal infertility

The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer

Menstrual characteristics of women suffering from insulin-dependent diabetes mellitus.