040706.359_366.tp

J. Perinat. Med. 34 (2006) 359–366 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2006.073 Guidelines for the management of spontaneous
preterm labor
Gian Carlo Di Renzo1,*, Lluis Cabero Roura2
of respiratory distress syndrome may be exploited by and the European Association of Perinatal
delay. Delay may also permit transfer of the fetus in utero Medicine-Study Group on ‘‘Preterm Birth’’**
to a center with neonatal intensive care unit facilities.
There is considerable variation in the way that spon- 1 Department of Obstetrics and Gynecology, University taneous preterm labor (SPTL) is diagnosed, managed 2 Department of Obstetrics and Gynecology, Hospital The development of clinical guidelines requires an evi- dence-based approach to improve outcome and allowmore efficient use of resources. With recent advances in Abstract
our understanding of the etiology and mechanisms ofSPTL and the availability of safer, more specific tocoly- Preterm birth is defined as delivery at -37 completed tics, it was felt that guidelines should be developed to weeks of pregnancy (World Health Organization). Spon- achieve, if possible, an European consensus in patient taneous preterm birth (SPB) includes preterm labor, pre- diagnosis, management and treatment.
term spontaneous rupture of membranes, pretermpremature rupture of membranes (PPROM) and cervical Keywords: Atosiban; cervical assessment; corticoste-
weakness; it does not include indicated preterm delivery roids; European guidelines; fibronectin; spontaneous pre- for maternal or fetal conditions. Early SPB (-32 weeks’ gestation) is associated with an increased higher peri-natal mortality rate, inversely proportional to gestationalage. The pathophysiologic events that trigger SPB are Myths to dispel
(abruption), mechanical factors (uterine overdistention or It may be worth pointing out that the incidence of SPB cervical incompetence), and hormonal changes (perhaps has not changed because we are now including more mediated by fetal or maternal stress). In addition, several babies born at very early gestational age, at extremely cervicovaginal infections have been associated with pre- low birth weight, and at the limits of viability, who were term labor. SPB is also the leading cause of long-term never included in our previous statistics. There is also an morbidity, including neurodevelopmental handicap, cer- increasing trend towards elective preterm delivery as ebral palsy, seizure disorders, blindness, deafness and neonatal intensive care has improved, and finally, that non-neurological disorders, such as bronchopulmonary term delivery per se is not a good indicator of outcome dysplasia and retinopathy of prematurity. Delaying bearing in mind that each day of delay between 22 and delivery may reduce the rate of long-term morbidity by 28 weeks’ gestation increases survival by 3% without the facilitating the maturation of developing organs and sys- tems. The benefits of administration of antepartum In addition, the myth that tocolytics only work for 48 h glucocorticosteroids to reduce the incidence and severity arose from the inaccurate interpretation of the meta-anal-ysis of beta-agonists which found that 48 h was the only consistent finding among the 16 papers analyzed to allow comparison, but many tocolytics have been shown Professor and ChairmanDepartment of Ob/Gyn and Center for Perinatal to work beyond 48 h. With respect to the claim that no tocolytic has been shown to reduce the incidence of peri- natal mortality and morbidity, it should be noted that no study on tocolytics has ever been carried out with a suf- ficient statistical power (sample size) to show such a Fax: q39 0755729271E-mail: [email protected] The diagnosis of spontaneous preterm labor
** Members: A. Antsaklis (Greece), G. Breborowicz (Poland), P.
Husslein (Austria), R. Lamont (UK), A. Mikhailov (Russia), S.C.
Robson (UK), C. Sen (Turkey), H. Van Geijn (Netherlands), Y. Ville On admission with suspected SPTL, the accuracy of the expected date of confinement should be re-checked 360 Di Renzo et al., Guidelines for the management of spontaneous preterm labour scrupulously because the best estimate will influence fFN in addition to clinical assessment. A second algo- whether or not intervention should take place.
rithm is for the subset of facilities which have regular The diagnosis of SPTL on clinical grounds should access to reliable transvaginal ultrasound. Both algo- rithms provide the same outcome: determination of theoptimum disposition of women who present with signs 1. Contractions that are painful, palpable, last longer and symptoms of preterm labor. This document can be than 30 s and occur at least four times per 20 min; 2. Evidence of a change in the position, consistency, length and/or dilatation of the cervix.
The management and treatment of spontaneous
preterm labor
When compared with digital examination and transab- dominal scanning, transvaginal ultrasound has a higher Tocolytic therapy (see also Table 1)
sensitivity for the detection of cervical shortening and the agents have been advocated as suppressing uterine con- tractions. Those in current use include beta-agonists, Oncofetal fibronectin (fFN) may be considered to com- calcium channel blockers, prostaglandin synthetase plement the clinical assessment. The availability of fFN inhibitors, nitric oxide donors, and oxytocin receptor testing was associated with a reduction in hospital antagonists. There is little reliable information about cur- admissions, length of hospital stay, and overall hospital rent clinical practice but it is likely that ritodrine hydro- chloride, a beta-agonist, remains the most widely used fFN testing supplemented by ultrasonography to deter- mine cervical length, may be useful in defining women at The primary aims of tocolytic therapy are to delay high risk for preterm labor. However, their clinical useful- delivery to allow the administration of a complete course ness may rest primarily with their negative predictive val- of antepartum glucocorticosteroids in order to primarily ue given the lack of proven treatment options to prevent reduce the incidence and severity of idiopathic respira- SPB. Bearing in mind the excellent negative predictive tory distress syndrome and to arrange in utero transfer value of such tests (when fibronectin is negative and cer- to a center with neonatal intensive care unit facilities.
vical length by transvaginal ultrasound is )2.5 cm), we The secondary aim of tocolytic therapy is to delay recommend that tocolytic therapy should be withheld if delivery to reduce the perinatal mortality and morbidity fetal fibronectin or transvaginal ultrasound scan indicate associated with severe prematurity. A full comparison of costs has not been reported but this should also take Perceptions of uterine contractions have always been into account the costs of administering each drug against interpreted by pregnant women as evidence for impend- any benefits or adverse effects, primarily the costs of ing SPTL. The majority of these women will present to SPB itself, savings on midwifery care and the compari- their local hospitals for assessment of labor, resulting in son of obstetric and tocolytic budgets to other hospital over half being admitted, treated and released without delivering after a few days. With the use of biochemical Atosiban represents an advance in currently available markers and sonographic evaluation of the cervix, it is tocolytics, and should be considered a first-line tocolytic possible to identify the majority of women who are not Atosiban is licensed in Europe for treatment of SPTL.
Standardization of assessment and disposition of The recommended dosage and administration schedule patients presenting with the signs and symptoms of PTL for atosiban is a three-step procedure (see Table 1).
will: 1) Allow for timely interventions for preterm labor; Duration of treatment should not exceed 48 h and the 2) maintain maternal-fetal safety; 3) minimize the need for total dose given during a full course should preferably hospitalization only for those patients at greater risk of not exceed 330 mg of atosiban. In the early gestational preterm delivery; and 4) promote effective transport of age with or without PPROM, the use of atosiban can be preterm labor patients to higher, more appropriate levels prolonged for a further few days without any significant An example of a clinical methodology that was devel- The risk of adverse events associated with b-agonists oped to determine the optimal disposition of women who in the management of SPTL requires close monitoring of present with signs and symptoms of PTL can be found the mother in a high dependency unit (Table 2).
in the March of Dimes Preterm Labor Assessment Toolkit, Common adverse effects, when beta-agonists are endorsed by the American Society of Maternal Fetal compared to no treatment or placebo, include palpitation Medicine in 2005. This toolkit was developed with the (68% with beta-agonists vs. 5% with controls), tremor dual aim of 1) the recommendations being evidence (39% vs. 4%), nausea (20% vs. 12%), headache (23% based and 2) the information can be utilized effectively vs. 6%) and chest pain (10% vs. 1%). Rare, but serious at all levels of facilities receiving PTL patients. As such, and potentially life threatening adverse effects have been the toolkit contains two algorithms. One algorithm uses reported following beta-agonists use and a few maternal Di Renzo et al., Guidelines for the management of spontaneous preterm labour thyroid functionhypokalemia, tremor,nervousness, nauseaor vomiting,hypokalemia of 50–100 mg/min,i.v., increase 50 mg/min every 10 minuntil contractionscease or sideeffects developMaximumdoses350 mg/min hyperbilirubinemia,necrotizingenterocolitis intramuscularly,then 30 mgintramuscularlyevery 6=48 h thrombocytopenia,NSAID-sensitiveasthma, othersensitivity to NSAID 362 Di Renzo et al., Guidelines for the management of spontaneous preterm labour 10 mg patch forevery 12 hcontinuing until an infusion of18 mg/h for 3 h andthen 6 mg/h forup to 45 h.
deaths associated with the use of these drugs were menting serious maternal cardiovascular and pulmonary reported. Pulmonary edema is a well-documented com- adverse events. It has been recommended that nicardi- plication, usually associated with aggressive intravenous pine should only be used in a clinical trial setting. Doc- hydration. A systematic review reported one case of pul- monary edema among 850 women (1/425 with beta-ago- lightheadedness, headache, flushing, nausea, and tran- nists vs. 0/427 with placebo). For the other tocolytic sient hypotension. The combination of magnesium sul- drugs (magnesium sulphate, indomethacin and atosiban), phate and nifedipine should be avoided because of fewer types of adverse effects were reported and these reported cases of symptomatic hypocalcemia, neuro- occurred less frequently. For atosiban, the only docu- muscular blockade, and cardiac toxicity, including mater- mented adverse effect is nausea (11% with atosiban vs.
nal death. There is an increasing number of case reports 5% with placebo) but this is only of short duration and of adverse feto-maternal events with the use of nifedi- only in association within about a minute during which pine, particularly in twin pregnancies. In addition, there is the bolus dose is administered. The same study reported a case report of a myocardial infarction in a 29-year-old no increase in vomiting (3% with atosiban vs. 4% with woman who received nifedipine immediately after intra- placebo), headache (5% vs. 7%), chest pain (1% vs.
venous ritodrine therapy. The evidence pertaining to nife- dipine for the treatment of SPTL is based largely upon a Among unlicensed tocolytic therapy, calcium channel small number of poor quality investigator-led studies of blockers, such as nifedipine and nicardipine, inhibit the small sample size. A systematic review has identified influx of calcium ions into myometrial cells, and the serious concerns with respect to the topic and method- decreased intracellular calcium results in decreased specific conduct and, hence, because of the quality of myometrial activity. Recent reviews of the evidence per- such studies they should not be used to guide practice.
taining to the use of nicardipine or nifedipine suggest that Magnesium sulphate is ineffective at delaying birth or the safety profiles of these drugs are incomplete and preventing SPB after preterm labor, and its use is asso- should lead to careful consideration before use. Partic- ciated with an increased infant mortality. Magnesium sul- ularly, a number of studies have been published docu- phate is popular for tocolysis in the USA and some otherparts of the world, but is rarely used for this indication in The recommended guidelines for monitoring i.v.
Europe and it is not recommended for tocolysis.
Indomethacin and other prostaglandin synthesis inhib- itors are effective in delaying preterm labor and increas- • Maternal pulse and BP should be monitored every 15 min ing birth weight; result in shorter stays in neonatal • Chest auscultation should be performed every 4 h intensive care units and shorter intervals of mechanical • Strict input/output charts should be measured for fluid ventilation. However, contradictory evidence exists that indomethacin fails to prolong gestation and infants are • Urea, electrolytes, and hematocrit should be measured delivered prematurely. Potential fetal adverse effects include premature closure of the ductus arteriosus, nec- Maternal blood glucose should be measured 4-hourly rotizing enterocolitis, respiratory distress syndrome and (From reference: Royal College of Obstetricians and Gynecolo- gists. Clinical Green Top Guidelines. Tocolytic Drugs for Womenin Preterm Labor (1B)-Oct 2002. http://www.rcog.org.uk/guide- increased risk of development of periventricular leuko- malacia (at a daily dose of 200 mg).
Di Renzo et al., Guidelines for the management of spontaneous preterm labour Nitric oxide donors (glyceryl trinitrate or isosorbide) doses of 6 mg dexamethasone given intramuscularly have been shown to act as tocolytic agents. Major side 12 h apart. It should be pointed out that the fetal bio- effects are maternal headache and hypotension. Their physical variables recorded by cardiotocography or ultra- use is still limited by low compliance of the patients.
sound may be significantly modified by the corticosteroid If a tocolytic agent is used, ritodrine no longer seems administration, particularly betamethasone, and mothers the best choice. Alternatives such as atosiban appear to should be informed on reduction of fetal movements in have comparable effectiveness in terms of delaying deliv- the 48 h subsequent to drug injection. In the case of ery for up to seven days and are associated with consid- impending SPTL, betamethasone was administered in erably fewer maternal and fetal adverse effects.
12 mg, 12 h apart, showing the same beneficial effects.
Maintenance treatment after threatened preterm
Key guidelines:
• Administration of one single-course of antenatal glu- Maintenance tocolysis is not recommended for rou-
cocorticosteroids is the most important treatment to tine practice
prevent brain injury and increase survival that can be insufficient evidence to show whether or not oral beta- provided by the obstetrician to patients at risk of pre- agonists, or any other maintenance therapy will prevent term delivery at 24–34 weeks of gestation SPB and its consequences after SPTL. In addition, one • Based on observational clinical and animal studies, trial has compared subcutaneous terbutaline with pla- betamethasone is preferable to dexamethasone cebo: although the b-agonists delayed the next episode • Multiple courses of corticosteroids should be avoided of threatened labor, there is insufficient evidence for firm • There is no direct evidence that tocolytic treatment conclusions about the effects on other more substantive per se might affect the risk of perinatal brain injury or outcomes. Therefore, there is insufficient evidence for any firm conclusions about whether or not maintenancetocolytic therapy following SPTL is worthwhile. Mainte-nance therapy cannot be recommended for routine The role of infection and use of antibiotics in preterm
labor The following investigations should be routine in
most units:
The administration of antepartum glucocorticoste-
1. Full blood count and group and save serum for fur- Prolonging gestation with tocolytic therapy allows for the administration of antepartum glucocorti- costeroids to reduce the incidence and severity of res- piratory distress syndrome and hence to reduce neonatal 3. High vaginal swab for culture microscopy and sen- A single course of antepartum glucocorticoids (GC) to 4. Low vaginal swab and rectal swab to be cultured in pregnant women, at risk of preterm delivery within Granada or selective broth medium for Group B 7 days, should be administered between 24–34 weeks’ A meta-analysis of 18 randomized trials demonstrates In the presence of PPROM, the ORACLE study that antenatal corticosteroids significantly reduce the showed that prophylactic erythromycin was of benefit occurrence of neonatal respiratory distress syndrome but not amoxicillin-clavulanic acid (co-amoxiclav). Apart (OR 0.53, 95% CI 0.44–0.63) and neonatal death (OR from these two antibiotics no other antibiotics were test- 0.6, 95% CI 0.48–0.75). Furthermore, a significant reduc- ed in the ORACLE study. Erythromycin is not active tion of intraventricular hemorrhage (IVH) diagnosed both against anerobes, Group B streptococcus (SGB), or at autopsy (OR 0.29, 95% CI 0.14–0.61) and by ultra- many of the organisms associated with bacterial vagi- sound (OR 0.48, 95% CI 0.32–0.72) was shown. One nosis. Similarly co-amoxiclav, while it is active against single course of antenatal GC may also reduce periven- anerobes and being of broad spectrum, may not be tricular leukomalacia (PVL) and cerebral palsy.
active against the more fastidious organisms like Myco- Betamethasone and dexamethasone are the two most plasma hominis associated with bacterial vaginosis.
widely used GC for antenatal prophylaxis, but no ran- Intrapartum chemoprophylaxis for SGB should be by domized controlled studies exist comparing the efficacy intravenous penicillin given intravenously at 4 h and if the of these agents. Even though betamethasone seems to patient is allergic to penicillin, then a combination of affect fetal heart rate variation and fetal movements more erythromycin and cleritromycin or clindamycin is recom- than dexamethasone, it seems to offer several advant- assessed as part of the ORACLE study, however.
The treatment should consist of two doses of 12 mg Topical vaginal chlorexidine (0.5%) in gel or vaginal betamethasone given intramuscularly 24 h apart or four douches have been proposed and found as a valid alter- 364 Di Renzo et al., Guidelines for the management of spontaneous preterm labour native to parental antibiotics for SGB prophylaxis or Absolute contraindications are those in which prolon- gation of pregnancy is contraindicated per se, e.g., clin- Among women with PPROM, the use of antibiotics ically apparent intrauterine infection, known lethal fetal was associated with a statistically significant intrapartum congenital malformation, fulminating proteinuric pre- eclampsia and any other urgent fetomaternal indication 0.37–0.86). The numbers of babies born within 48 h (OR 0.71, 95% CI 0.58–0.87) and seven days of randomiza- Relative contraindications are those in which a debate tion (OR 0.80, 95% CI 0.71–0.90) were reduced, as were exisits about the risks and benefits of intervention such the following markers of neonatal morbidity: neonatal as antepartum hemorrhage, ruptured membranes, non- infection (OR 0.68, 95% CI 0.53–0.87), use of surfactant reassuring fetal heart rate pattern on cardiotocography, (OR 0.83, 95% CI 0.72–0.96), oxygen therapy (OR 0.88, intrauterine growth restriction, insulin-dependent diabe- 95% CI 0.81–0.96), and abnormal cerebral ultrasound scan prior to discharge from the hospital (OR 0.82, 95% Tocolytics should not be used if there is a significant CI 0.68–0.98) (this meta-analysis included 12 trials and antepartum hemorrhage, especially if there are signs and 6294 babies). The reduction of cerebral sonographic symptoms of abruptio placentae. Following a mild bleed- abnormalities indicates a protective effect. Antibiotic ing due to placenta previa, it is acceptable to use toco- treatment following PROM is recommended.
lytics because they may help to stop uterine contractionsand the stretch they induce, leading to further separationof the placenta and hemorrhage.
Overall management
In the presence of ruptured membranes, tocolytics are rarely indicated after 36 weeks’ gestation. At an earlier As soon as the diagnosis has been reached, it is rec- gestation, tocolytics may be administered when the risk- ommended that neonatologists involved in management benefit balance is in favor of delaying delivery to allow a decisions are informed to ensure that a neonatal inten- full course of glucocorticosteroids to be administered or sive care cot is available on site or that an in utero trans- arrangements to transfer the woman to a center with fer to a center with intensive care unit facilities may be Tocolytics to delay delivery of the preterm infant are In the absence of clear evidence that tocolytic drugs contraindicated when non-reassuring fetal heart rate pat- improve outcome following preterm labor, it is reasonable terns on cardiotocography occur in association with a not to use them. Women who are more likely to benefit significant hemorrhage or with signs of fetomaternal from tocolysis are those at a still very preterm gestational age, those needing transfer to a hospital that can provide Well-controlled insulin-dependent diabetic women with neonatal intensive care, or those who have not yet com- SPTL can safely be treated with atosiban. Close moni- pleted a full course of corticosteroids to promote fetal toring is required in case other tocolytics are used lung maturity. For these women, tocolytic drugs should because both glucocorticosteroids and tocolytics are If time permits, an ultrasound scan should be arranged Twins and higher-order multiple births are associated to check for fetal viability, fetal morphology, fetal number, with a greater and expanded maternal plasma volume fetal presentation, placental site, an estimate of fetal and secondary hyperaldosteronism when compared with weight and amniotic fluid volume index, all of which singleton pregnancies. Beta-agonists are known to might affect management. Appropriate analgesia follow- increase both aldosterone and renin levels in twin preg- ing discussion with an anesthetist should be arranged nancies, which may potentiate the risk of pulmonary ede- and opiates should be avoided, if possible, to prevent ma. Beta-agonists are therefore contraindicated in central fetal and neonatal respiratory depression.
multiple pregnancies, and alternative tocolytics should If intervention is contraindicated or unsuccessful, then be used. Also, calcium channel blockers potentiate neg- the mode of delivery of a preterm infant should be indi- ative effects on maternal cardiovascular balance, espe- vidualized according to gestational age, fetal presenta- cially in multiples, and therefore are contraindicated in tion, number of fetuses and the presence or absence of non-reassuring fetal heart tracing on cardiotocography.
Contraindicated intervention in the management
of spontaneous preterm labor
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