Preterm labour. Pharmacological prevention of prematurity

The acute treatment of premature labour is successful for delaying delivery for short periods of time. Acute tocolysis does not have a significant impact on perinatal outcome. This is likely to be because the process leading to labour occurs over a longer timeframe and therefore therapies instigated as preventative measures are more likely to be successful in delaying delivery. Identification of women at risk of preterm birth is essential to ensure therapies are targeted appropriately. Risk assessments for prediction include previous obstetric history, previous episode of threatened preterm labour, fetal fibronectin status and cervical length. Several groups of pharmacological agents have been studied for the prophylactic treatment of preterm labour. There is no evidence to support the use of tocolytics such as beta-mimetics and oxytocin receptor antagonists. Current studies of calcium channel blockers are too small to draw final conclusions. Non-steroidal anti-inflammatory drugs are associated with side effects on the fetal renal system and ductus arteriosus, making them suitable only for long term use in pregnancy with close ultrasound surveillance. Antibiotics used early in pregnancy in women with abnormal vaginal flora may reduce the risk of preterm birth; however, in women with other risk factors for preterm birth, metronidazole may be associated with an increased risk. The use of progesterone in women with a history of very early preterm labour is likely to be beneficial for preventing preterm labour.     

Medical legal issues in the prevention of prematurity

Preterm birth remains the leading cause of neonatal morbidity and mortality in the world today. This article discusses ways the treatment team can inform parents of probable outcomes and help them reach decisions about treatment for the newborn under emotionally fraught conditions. In addition to supporting the patient, these approaches may help the clinician avoid malpractice litigation.     

Efficient prevention of prematurity - the Thuringian model

In two prospective projects, the effectiveness of the self-care programme for prematurity prevention developed by Saling was prevented. Pregnant women in Erfurt were shown how to perform self-measurements of their vaginal pH by means of test gloves twice a week in order to screen for any disturbances in the vaginal millieu. The women were instructed to see their physician immediately, if abnormal values (ph > or = 4.7) or other risk factors were present, in order to start Lactobacillus acidophilus therapy or, in cases of bacterial vaginosis, treatment with intravaginal clindamycin cream. Patients who were not interested in the programme, served as a control group. 73 out of 381 women in the intervention group were identified as risk cases. In this study, the prematurity rate was 8.1% in the self-measurement/intervention group versus 12.3% in the control group (p < 0.05, n = 2,341); 0.3 versus 3.3% of the neonates belonged to the group of very early prematures with a gestational age of <32 + 0 weeks (p < 0.01). Starting on March 1, 2000, a similar statewide pH screening programme was initiated in order to reduce prematurity in the State of Thuringia. According to the study design, a significant decrease in prematurity was hypothetically expected for the second half of 2000. Data from 16,276 women are available. On this basis, a significant reduction of early prematurity from 1.58 to 0.99% was seen (p < 0.001). Comparing low birth weights, a significant reduction of cases was also achieved in all groups. On the basis of data obtained, we recommend that the campaign should be extended to the whole of Germany. This recommendation is also supported by the observation that after the campaign had been discontinued the prematurity rates monitored in 2002 were as high as they had been prior to the introduction of the statewide programme.     

A paradigm shift in the prevention of retinopathy of prematurity

For more than 50 years it has been known that oxygen therapy can lead to retinopathy of prematurity (ROP). Recent clinical research has led many neonatologists to lower the target oxygen saturation alarm limits to 85-93% and to titrate the inspired oxygen in small increments. Despite efforts to optimize oxygen therapy, the number of cases of severe ROP remains high as more extremely low birth weight infants survive. Based on new insights into the pathogenesis of ROP, there are multiple interventions, in addition to optimizing oxygen therapy that may help decrease severe ROP. Interventions that have the potential to prevent phase I ROP (birth to ≤32 weeks PMA) include increasing retinal erythropoietin (exogenous rHuEPO) and serum IGF-1 (breast milk and/or exogenous IGF-1), maintaining serum glucose below 120 mg, and providing omega-3 supplements. Interventions with potential to prevent proliferative ROP in phase II (infants >32-34 weeks PMA) include treating anemia with a liberal policy of transfusion in premature infants with stage III ROP, photopic adaptation, vitamin E supplements (>34 weeks PMA), and omega-3 supplements. The WINROP algorithm has shown promise as a biomarker in the early identification of extremely low birth weight infants at high risk for proliferative ROP. As there is interplay of multiple factors in the causation of ROP, we suggest that the simultaneous application of some combination of multiple interventions, mentioned above, may reduce the burden of ROP in the most vulnerable infants. These concepts need study in well-designed randomized clinical trials before being incorporated into clinical practice.     

Current aspects of the Thuringia prematurity prevention campaign 2000

In two prospective investigations the effectiveness of the self- care program for prematurity prevention, developed by Saling, was investigated. Pregnant women in Erfurt have been offered to perform self-measurements of their vaginal pH by means of test gloves (Careplan VpH) twice a week. The women were instructed to see their physician immediately, if abnormal values (pH > or = 4.7) or other risk factors were present. 73 out of 381 women in the intervention group have been identified as risk cases. 58 of them were treated with a lactobacillus preparation, and 24 with clindamycin cream for bacterial vaginosis, 3 patients refused to have any therapy. In this study the prematurity rate was 8.1 % in the self-measurement/intervention group vs. 12.3 % in the control group (N=2 341, P < 0.05); 0.3 % vs. 3.3 % of the neonates belonged to the group of early prematures with a gestational age of < 32 + 0 weeks (P < 0.01). PROM was registered in 22.8 % vs. 30.8 % (P < 0.001) respectively. Starting March 1, 2000 a similar statewide pH-screening program was initiated in Thuringia. According to the study design a significant decrease of prematurity was hypothetically expected for the second half of the year 2000. In Erfurt an overall decrease of prematurity from 7.68 to 6.81 % and a reduction of cases < 32 + 0 weeks from 3.22 to 2.39 % was observed (N=1,600). Data from 16,276 women are available for the state of Thuringia. On this basis a significant reduction of early prematurity from 1.58 to 0.99 % was seen respectively (P < 0.001). Comparing low birthweights a significant reduction of cases was achieved as well in all groups. On the basis of the data obtained we recommend the extension of the campaign in the whole of Germany.     

Corticosteroid treatment for prevention of prematurity complications

Objective: To investigate of efficiency to corticosteroid treatment for prevention of respiratory distress syndrome and other prematurity complications. Materials and Methods: One thousand and six babies born at 26–36^th gestational age were investigated for following parameters; the development of respiratory distress syndrome, necessity of surfactant therapy, mean duration of daily ventillatory support, rates of Grade III or IV intraventricular hemorrhage, and periventricular leukomalacia, necrotizing enterocolitis, proven neonatal sepsis and neonatal death. Antenatal steroids were administered in the form of two 12-mg intramuscular doses of betamethasone 12 h apart as a total 24 mg in the 24 h and repeat courses of two 12 mg of betamethasone every 7 days after the first dose of the last course if undelivered. Babies were divided into 4 groups based on betamethasone treatment: The first group or control group didn’t received treatment; the second group received treatment and delivered within 12 h after first injection; the third group delivered 12–24 h after first injection; and fourth group delivered at least 24 h after first injection. The patients ongoing pregnancy at least 1 week were divided into two groups as a single dose and multiple courses in once a week. Results: Significant difference for development of respiratory distress syndrome between fourth group and others was found (p=0.029). There were significant difference for respiratory distress syndrome rate in hypertansive and premature rupture of membranes groups between fourth group and control group (p=0.002, p=0.041). There weren’t significant difference for RDS between repeat doses and single dose groups (p>0.05). Conclusion: Single dose corticosteroid is an effective treatment for the development of RDS and the prevention of other prematurity complications. Received: 25 September 2001 / Accepted: 30 October 2001 Correspondence to C. Celik     

Short-term neonatal morbidity associated with prematurity and the effect of a prematurity prevention program on expected incidence of morbidity

With recent advances in neonatal medicine, the risk of mortality for premature newborns has been markedly reduced. Attention has shifted to the morbidity associated with preterm delivery. Consideration of anticipated neonatal morbidity at a particular gestational age plays an important part in the decision of whether or not to treat preterm labor. We have assessed eight indices of short-term morbidity in 170 liveborn infants delivered between 26 and 35 completed weeks of gestation and calculated the gestational age-specific rates of each measure of morbidity. Five measures of short-term morbidity were significantly reduced by extending the gestation from 34 to 35 weeks. To illustrate the effect of prolonged pregnancy on the incidence of short-term neonatal morbidity, the actual incidence of morbidity from a group of preterm labor patients who were part of a preterm birth prevention program was compared to the anticipated incidence of these same morbidity factors has birth occurred when preterm labor was first diagnosed. There was a significant decrease in the number of observed, as opposed to anticipated, neonatal deaths and in morbidity occurrences in four of the six factors tested. Implications for considering short-term neonatal morbidity in the decision to initiate treatment for preterm labor after 33 weeks gestation are discussed.     

The role of the obstetrician in the prevention of retinopathy of prematurity

This review underlines the important role that obstetricians play in the prevention of retinopathy of prematurity. Efforts predominately focus on predicting which pregnant women are at highest risk of preterm birth, instigating treatments to prevent pre-eclampsia, fetal growth restriction and maternal infection which could lead to iatrogenic or spontaneous preterm birth, and optimizing care when preterm birth is inevitable. More broadly, optimizing maternal health pre-conception through stopping smoking, improving diet, reducing obesity with its associated gestational diabetes, and treating hypertension may reduce preterm birth and other pregnancy complications. This is a message that all healthcare professionals including obstetricians, neonatologists and GPs, nursing and midwifery staff need to communicate all women and men who are contemplating having a baby.     

Rickets of prematurity: controversies in causation and prevention

Metabolic bone disease in the growing premature infant is an important disorder owing to inadequate intake of calcium or phosphorus over an extended period of time. Prevention of serious bone disease is an important goal in the care of the VLBW infant. Attempts to reproduce intrauterine bone accretion rates in intrauterine life may be unnecessary and may result in potential complications.     

Obstetric inertia: an obstacle to the prevention of prematurity

Traditional obstetric beliefs regarding diagnoses leading to premature birth constitute a significant barrier to successful clinical application of current knowledge about the pathophysiology of preterm delivery. Progress in reducing prematurity will be limited unless obstetricians assume a leadership role in changing attitudes about preterm birth among patients, providers, and society in general.     

Evaluation of the efforts in prenatal care for the prevention of prematurity]

A retrospective analysis was done in 341 singleton premature deliveries to assess the practised activities in antenatal care for the prevention of premature delivery. This analysis, expressed in terms of adequacy revealed that 56% were adequate whereas 23% were conditionally adequate and 21% were inadequate. Clinically these activities were reflected in suppression of uterine contractions (80%/57%/40%-effective tocolysis), achieved prolongation of pregnancy (25d/8d/2d) and a lowered rate of premature delivery before the 32nd week of gestation (17%/31%/33%), respectively. A prospective study depending on these results (n = 450) done in 4 centers for antenatal care (under constant supervision to keep the respective recommended activities) showed a significant reduction in the rate of premature delivery compared to a similar control group (n = 458) in the year 1988. Simultaneously, we could demonstrate the influence of patient explanation and the growing patient satisfaction which resulted in reduction of premature delivery.     

Changes in the pathogenesis and prevention of chronic lung disease of prematurity

With the increasing survival of extremely premature infants there is a large number of them who are developing chronic lung disease (CLD), but the severity of the lung damage is considerably less than that observed in the classic form of bronchopulmonary dysplasia (BPD). Because many of these infants have only a mild initial respiratory distress and therefore do not receive aggressive ventilation, it is clear that factors other than oxygen toxicity and barotrauma are involved in the pathogenesis of this new milder type of CLD. CLD results from the interaction of multiple factors that can injure the immature lung. For this reason the prevention must be based on the elimination of all the factors implicated in its pathogenesis. Clinical and epidemiological data strongly suggest that infections, either prenatal or nosocomial, and the presence of a patent ductus arteriosus (PDA) play a major role in the development of CLD in these infants. For this reason, efforts to prevent CLD in extremely low birth weight infants should include an aggressive approach to the prevention and treatment of prenatal and neonatal infections and an early closure of the PDA.     

Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity

Retinopathy of Prematurity (ROP) is a preventable neovascular retinal disease with a lifetime impact on vision and ocular morbidities. Retinal vessel immaturity and oxygen therapy, influenced or modulated by several risk factors including oxidative stress, intermittent hypoxia and desaturations, inflammation, infection, malnutrition, retinal growth factor deficiencies or excesses, and others are determinant factors of pathologic retinal angiogenesis and ROP. These factors are pharmacologic targets for prevention and/or rescue therapy. These drugs, include intravitreal anti-vascular endothelial growth factor drugs, erythropoietin, ocular propranolol, caffeine, antioxidants, insulin-like growth factor-I, and omega 3 poly-unsaturated fatty acids, and are promising therapies to prevent ROP, but require further studies. Topical ocular non-steroidal anti-inflammatory drugs (NSAIDs) target inflammatory cascade but the best, safest, and most effective ocular NSAID and formulation remain to be developed. Timing of drug intervention appears critical. Moreover, the complex interactions of the various pathophysiologic mechanisms resulting in aberrant angiogenesis thence ROP strongly suggest that drug combinations and synergisms may be required for effective prevention of ROP and a lifetime of blindness.     

Apnea of prematurity.

Apnea is a common, treatable disorder of respiration in premature infants, which usually resolves over time. The definition and classification of apnea are discussed, as well as its epidemiology and natural history. The pathophysiology of apnea is considered in detail, including the chemosensory and reflex input that modulates respiration and the involvement of upper airway control in the etiology of obstructive apnea. Finally, diagnosis and therapy are reviewed, and the relationship of apnea of prematurity to the underlying disorder in sudden infant death syndrome is considered.     

Prevention of prematurity.

Although only about 8 per cent of pregnancies end prematurely, as much as 75 per cent of perinatal deaths are due to prematurity. Since it is difficult to identify the predisposing factors in individual cases and to prevent the premature onset of labor, it is necessary to try to arrest such labor when it occurs. A theoretical scheme for the mechanism of labor in the human subject is presented. This permits the identification of four possible points of attack: (1) replacement of progesterone to reduce the myometrial sensitivity to oxytocin, (2) administration of beta-mimetic agents to relax the uterus and make it unresponsive to stimuli, (3) administration of ethanol to block oxytocin secretion, and (4) administration of anti-inflammatory drugs to inhibit prostaglandin synthesis. Results obtained with ritodrine, a beta-mimetic agent, and with ethanol are presented as illustration. Ritodrine gave somewhat better results than ethanol, possibly because the treatment was continued after discharge of the patients.     

Retinopathy of prematurity prevention,screening and treatment programmes: Progress in India

India is home to largest number of preterm births and neonates at risk of developing retinopathy of prematurity. Being a large heterogenous country, different approaches including training of local ophthalmologists, tele-screening by ophthalmic technicians carrying wide-angle retinal cameras and use of low-cost retinal cameras by neonatal unit healthcare providers are being tested to expand the coverage of screening.     

Preterm labour. Myometrial function in prematurity

The primary function of the uterus during gestation is to harbour the growing conceptus in a largely quiescent environment. Upon maturation of the fetus to a point sufficient for extrauterine survival, the uterus must remodel itself sufficiently to generate forceful contractions during labour. During preterm delivery, the process of remodelling of the myometrium occurs early due to a number of different causes, although the underlying basis for myometrial contraction remains the same. This review summarises the anatomical, physiological and molecular basis for contraction. We describe the fibre structure of the human uterus and how this relates to the spread of electrical excitation during a contraction. The process of excitation within a single myometrial cell is described, as well as how this relates to contraction. We then focus on how excitation-contraction coupling is modulated by intercellular communication, pharmacomechanical-coupling and hormonal milieu. Lastly, we consider the actions of the commonly accepted uterine agonists oxytocin, prostaglandin F(2alpha), and prostaglandin E(2), and the tocolytic ritodrine.