Place of amniocentesis in the assessment of preterm labour

European Journal of Obstetrics & Gynecology and Reproductive Biology 93 (2000) 19–25

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Original Article

Place of amniocentesis in the assessment of preterm labour a, b a Vassilis Tsatsaris *, Bruno Carbonne , Dominique Cabrol a

b

Maternity Baudelocque, Port Royal, Cochin Hospital, Paris, France Department of Obstetrics and Gynecology, Saint-Antoine Hospital, Paris, France Received 2 August 1999; accepted 2 December 1999

Abstract Objective: To evaluate the benefits and indications for amniocentesis in cases of preterm labor with or without preterm rupture of membranes. Method: A review of the literature on amniocentesis in cases of intra-amniotic infection. Results: Amniocentesis is an invasive method that allows the diagnosis of intra-amniotic infection. However, no randomized trials have been performed from which we can assess the benefits and complications of amniocentesis in preterm labor. Conclusion: The published data do not justify the routine practice of amniocentesis in preterm labor. More data are needed to evaluate the benefits and complications of this practice. Only randomized trials of patients in preterm labor, comparing those who undergo amniocentesis with those who do not, will clarify the indications for this procedure.  2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Preterm labor; pPROM; Infection; Amniocentesis; Antibiotic

1. Introduction Intrauterine infection is one of the main causes of preterm births [1]. Studies published by Romero and Mazor [2–4], based on systematic amniocentesis of patients in preterm labor, have helped illuminate to the pathophysiology of such labor following intrauterine infection. Other studies have demonstrated that infection is associated with prematurity in more than 50% of all cases [1]. Intrauterine infection may also be responsible for such neonatal neurological complications as periventricular leukomalacia [5]. To reduce the consequences of prematurity, some units are currently performing amniocentesis on all patients admitted for preterm labor, both with intact membranes and preterm premature rupture of the membranes (pPROM), so that adequate antibiotic therapy can be provided in cases of intrauterine infection. More recently, *Corresponding author. Present address: 6 Place Nungesser et Coli, 94130 Nogent sur Marne, France. Tel. / fax: 133-1-4877-2100. E-mail address: [email protected] (V. Tsatsaris).

amniocentesis has been proposed in cases of pPROM without preterm labor, to allow intentional delivery when infection is found in the amniotic fluid. Thus degenerative neurological complications might be avoided. Are these procedures useful in everyday practice? And if so, what are their indications? In order to answer these questions we did a review of the literature ( MEDLINE search from 1967 to 1999 with the following search terms: preterm labor, infection, amniocentesis, antibiotic).

2. Intrauterine infection and prematurity

2.1. In preterm labor with intact membranes Several reviews have examined intrauterine infections in cases of preterm labor [6,7]. They indicate that the prevalence of infected amniotic fluid reported in these cases is 13%, but there is a wide range between authors (3–48%). Part of the explanation for these differences lies in the tests performed: not all studies tested for chlamydia

0301-2115 / 00 / $ – see front matter  2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00298-5

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or mycoplasma, even though they are known to be the most frequently detected infectious agents. Moreover, inclusion criteria and populations differed (for example, some authors did not include severe preterm labor, others did). Note that more than half these intrauterine infections were silent, but most of them nevertheless led to preterm delivery. Prevention of such deliveries may be an indication for antibiotics. Some authors have reported successful antibiotic treatment of intrauterine infections with intact membranes that delayed delivery until term, but no randomized trials offer evidence to encourage this procedure. Intrauterine infection, because it is associated with preterm birth in 86% of cases, is a major prognostic factor for it [8].

2.2. In cases of preterm rupture of membranes Patients with pPROM have a high rate of intrauterine infection. The overall prevalence of positive cultures in amniotic fluid is 35% (range: 14–56%) [9], and this rate is even higher in patients with pPROM and preterm labor than in those with only pPROM (39% compared with 26%, P,0.05) [10]. The pathophysiologic hypothesis is that bacteria near the amnion produce phospholipase A 2 , which in turn metabolizes membrane phospholipids and initiates prostaglandin synthesis, thereby weakening membranes, which can eventually rupture [8]. Patients with pPROM and infected amniotic fluid have a greater rate of chorioamnionitis, endometritis, and neonatal sepsis than do patients with pPROM without intra-amniotic infection. Neonatal respiratory distress syndrome is also twice as frequent when amniotic fluid is infected [11]. It is now clear that pPROM is related to intrauterine infection and is a major prognostic factor for preterm labor. Guinn et al. [12] evaluated the usefulness of antibiotics in preventing rupture of the membranes in cases of preterm labor. This randomized study included 253 patients in preterm labor with intact membranes. Overall, pPROM occurred in 17.4% of cases. Among those patients, both preterm birth (P50.036) and positive amniotic fluid cultures (P50.00007; OR: 27) were more likely than among other patients with preterm labor. Antibiotic treatment combining ampicillin and erythromycin was unable to prevent pPROM. Published results about preventing pPROM in patients with preterm labor are inconsistent, and the usefulness of antibiotics has not been proved.

3. Antibiotics for prevention or treatment of asymptomatic intrauterine infections

3.1. Antibiotics for preterm labor and intact membranes Ten randomized trials have studied the effects of antibiotics given to women admitted with intact membranes for preterm labor (Fig. 1). Five trials found that

antibiotics neither improved perinatal morbidity nor prolonged gestation [13–17]. The other five concluded that gestation was significantly prolonged when patients received antibiotics [18–22]. One trial also observed a reduction in perinatal infectious morbidity [20]. In a meta-analysis including seven trials and 795 patients, Egarter et al. [23] showed that antibiotic administration did not reduce perinatal morbidity. This study did not assess the prolongation of gestation. Unfortunately, it is difficult to compare the published trials: the study groups are small, their inclusion criteria dissimilar, and management quite diverse, especially concerning the use of antibiotics, steroids, and tocolytic drugs. In another meta-analysis published in the Cochrane Database of Systematic Reviews in 1998 [24], the authors concluded that: ‘This review fails to demonstrate a clear overall benefit from antibiotic treatment for preterm labor with intact membranes on neonatal outcomes and raises concerns about increased perinatal mortality for those receiving antibiotics. This treatment cannot therefore be currently recommended for routine practice. Further research is required to identify a subgroup of women (and their babies) who are more likely to experience benefit from antibiotic treatment for preterm labor prior to membrane rupture.’ It is not currently possible to draw any conclusions from the literature. Five of ten trials (including the more recent ones) did find that antibiotics had a positive effect on the rate of preterm labor complications, but results from larger randomized trials are needed to propose clear guidelines.

3.2. Antibiotics after pPROM Sixteen randomized trials have analyzed the effects of antibiotic treatment of patients with pPROM [39–47] (Fig. 2). Recent studies have shown that antibiotics reduce neonatal and infectious morbidity [25–30]. Although these trials differ methodologically, three meta-analyses [31–33] confirm the beneficial effects of antibiotics (Fig. 3). Egarter et al. [32] performed a meta-analysis based on seven randomized trials (657 patients) that compared the effects of antibiotics and placebo on perinatal morbidity. Treatment was given to women admitted for pPROM and not receiving tocolytic drugs or steroids. Antibiotics significantly reduced neonatal sepsis, by 68% (OR 0.32; CI [0.16–0.65], P,0.001), and intraventricular hemorrhage by 50% (OR 0.50; CI [0.28–0.89], P50.019). In contrast, antibiotics had no significant effect on neonatal mortality (OR 0.92, CI [0.46–1.81]), respiratory distress syndrome (OR 0.84, CI [0.58–1.22]), or necrotizing enterocolitis (OR 1.27, CI [0.61–2.62]). In another meta-analysis, Mercer and Arheart [31] analyzed 13 randomized controlled trials of systemic antimicrobial therapy to prolong gestation in woman with pPROM but not in labor. Steroids for fetal pulmonary

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Fig. 1. Randomized trials comparing antibiotics versus placebo given to patients admitted for preterm labor (* P,0.05).

maturation and tocolysis were used in five of the trials. In this meta-analysis, antibiotic therapy significantly reduced the risk of: • delivering within 1 week after pPROM (62 vs. 76%; OR50.51; CI: 0.41–0.68) • chorioamnionitis (12 vs. 23%; OR50.63; CI: 0.33– 0.60) • post-partum infection (8 vs. 12%; OR50.63; CI: 0.41– 0.97) • neonatal sepsis (5 vs. 9%; OR50.57; CI: 0.36–0.88) • neonatal pneumonia (1 vs. 3%; OR50.32; CI: 0.11– 0.96) • intraventricular hemorrhage (9 vs. 14%; OR50.65; CI: 0.45–0.92) The third meta-analysis, by Ananth et al. [33], examined

nine randomized controlled trials to explore the effects of antibiotic therapy on pPROM. The outcome variables studied were endometritis, chorioamnionitis, perinatal mortality, neonatal respiratory distress syndrome, neonatal necrotizing enterocolitis, latency between membrane rupture and onset of labor .48 h, latency period .7 days, and neonatal sepsis. Patients received steroids for fetal lung maturation in two studies and tocolysis in five. The patients receiving antiobiotics differed significantly from the placebo group, with a reduction in chorioamnionitis (OR50.54; CI: 0.31–0.95) and in neonatal mortality (OR50.50; CI: 0.29–0.85) and an increase in the number of patients with a latency period .48 h (OR52.18; CI: 1.25–3.80) and .7 days (OR53.53; CI: 2.13–5.85). In conclusion, it appears that, independently of tocolytics or steroids, antibiotics given to patients with pPROM delay delivery and reduce perinatal morbidity.

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Fig. 2. Randomized trials comparing antibiotics versus placebo given to patients admitted for pPROM (* P,0.05).

4. Indications for amniocentesis in preterm labor. Authors who recommend amniocentesis in cases of preterm labor stress the importance of identifying bacterial agents so that antimicrobial therapy can begin promptly. Patients with intra-amniotic infections have an increased risk of neonatal sepsis. Because asymptomatic intra-amniotic infections seem quite frequent in this population,

amniocentesis may be able to select a group of patients who might benefit from antibiotics. In addition, microbial agents in amniotic fluid are correlated with those found in neonatal samples. It is therefore argued that amniocentesis allows early bacteriological diagnosis and prompt effective antibiotic therapy. Moreover, intra-amniotic infection is an important neonatal prognostic factor. Knowledge of an intra-amniotic

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Fig. 3. Meta-analysis comparing antibiotics versus placebo given to patients admitted for pPROM.

infection allows better patient management. A possible attitude could be to interrupt pregnancy prematurely in order to avoid perinatal infection. However, the benefit effect of such attitude has not been demonstrated yet. Rapid diagnostic tests of infection are also under study. For example, high levels of interleukin-6 in amniotic fluid predicts intra-amniotic infection with 100% sensitivity and 83% specificity. Romero [11] has concluded that interleukin-6 is the best marker of intra-amniotic infection. Recent reports also indicate that high levels of interleukin6 in vaginal secretions have a good predictive value for intra-amniotic infection [34]. Does this herald the end of routine invasive procedures in these circumstances? Several arguments oppose the systematic use of amniocentesis in cases of preterm labor or pPROM. Amniocentesis is invasive and may cause iatrogenic intra-amniotic infection, pPROM, preterm delivery, and sometimes severe maternal complications. In 1976, Brinsmead [35] described maternal and fetal morbidity associated with amniocentesis and pointed out the need to consider the risks of the procedure. Although it has become technically easier, it remains invasive, as the recently-reported fatal maternal complication attests [36]. Severe complications due to umbilical vessel injury have also been reported in cases of oligohydramnios [37], which occurs frequently with pPROM. More importantly, only 13% of the amniocenteses performed in cases of preterm labor with intact membranes reveal intra-amniotic infection, and half of these are asymptomatic. Therefore, nearly 90% of the amniocenteses performed in this situation are futile. The advantages of discovering the infection are not currently established, since it has not been demonstrated that antibiotics reduce perinatal morbidity (preterm delivery, neonatal infection).

Moreover, Romero [3] showed that the interval between amniocentesis and delivery is 6 h (2–224 h) when amniotic fluid is infected. This mean delay is not long enough to allow an antibiogram, and bacterial identification often occurs after delivery. Moreover, amniotic fluid cultures may be an insensitive test to detect infection that begins in the decidua or amnion [38]. Similarly, in cases of pPROM, it is unnecessary to perform routine amniocentesis; in this instance, the reason is that the systematic administration of antibiotics such as ampicillin significantly reduces perinatal morbidity, regardless of any other treatment or procedure. Finally, the usefulness of amniocentesis in reducing perinatal morbidity is not shown by any data. Therefore its performance should be limited to clinical trials. Only randomized trials comparing patients in preterm labor (those with intact membranes or those with pPROM) who undergo amniocentesis to a comparable group that does not, can assess the impact of amniocentesis on preterm delivery and neonatal morbidity.

5. Conclusion After this review of the literature, we can distinguish two situations: First, in patients with preterm labor and intact membranes; the rate of intra-amniotic infection is low (13%), and antibiotic administration (systematic or targeted at a specific germ) does not appear to prevent preterm labor or membrane rupture or neonatal morbidity. Routine amniocentesis does not seem justified in this situation. Second, intra-amniotic infection is more common (30%) in patients in labor with preterm rupture of membranes and

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is accompanied by a high risk of chorioamnionitis and preterm delivery. Neonatal prognosis is compromised. An amniocentesis to reveal intra-amniotic infection might be indicated. But what can we do with the results? Is antibiotic therapy necessary? For how long? Is a follow-up amniocentesis required? Or must we deliver the fetus to protect against neurological complications? Unfortunately, no evaluation of such a practice is available, and it is currently impossible to answer these questions. The systematic prescription of antibiotics, however, does seem effective in reducing perinatal morbidity. Amniocentesis for patients in preterm labor, with either intact or ruptured membranes, must be evaluated in randomized controlled trials and compared with noninvasive techniques, to see whether perinatal complications are reduced. Moreover, if the goal of amniocentesis is to reveal an intra-amniotic infection, new noninvasive techniques such as assays for cytokines in vaginal smears, may be safer, more efficacious, or both.

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