Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality

Some previous studies suggested that prophylactic antibiotics given during pregnancy improved maternal and perinatal outcomes, some did not show any benefit and some even reported adverse effects.

To determine the effect of prophylactic antibiotics during second and third trimester of pregnancy on maternal and perinatal outcomes.

The Cochrane Pregnancy and Childbirth Group trials register (April 2002), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) and reference lists of articles were searched.

Randomized controlled trials comparing prophylactic antibiotic treatment with placebo or no treatment for women in the second or third trimester of pregnancy before labour.

Trial quality assessment and data extraction were done by the reviewers.

BACKGROUND

Maternal genital tract infection or colonization by some infectious organisms can cause maternal and perinatal mortality and morbidity.

Preterm delivery is the most common cause of perinatal morbidity and mortality in the world. Moreover, prematurity is implicated in at least two thirds of early infant deaths (Cunningham 1997).

A wide spectrum of medical and demographic factors have been implicated in the etiology of preterm birth. These can be categorized into three groups: 1. medical and obstetric complications (eg hypertensive disorders, placental hemorrhage); 2. lifestyle factors (eg cigarette smoking, poor nutrition); 3. amniotic fluid infection caused by a variety of microorganisms located in the genital tract; 4. cervical incompetence. Approximately one third of preterm births were associated with chorioamniotic infection (Lettieri 1993).There are many microorganisms that have been proposed to be the cause of preterm prelabour rupture of membranes, preterm labour, or both, eg bacterial vaginosis, Trichomonas vaginalis, Neisseria gonorrhoeae, Ureaplasma urealyticum, Chlamydia trachomatis, Group B streptococci (Hillier 1995; Hardy 1984; Braun 1971; Gravett 1986; Regan 1981). Case detection and treatment in pregnant women are problematic and expensive, underscoring the need for other strategies.

Infections and related complications in pregnancy and childbirth are potentially preventable. However, the appropriate intervention is yet to be identified. Routine antenatal detection and treatment of infections, especially in countries with high prevalence, would be the most reasonable approach. Limited laboratory facilities make this strategy unrealistic in low resource settings. Diagnosis algorithms including clinical signs and symptoms and behavioral pattern are at times used for quick identification of infections for prompt care. Unfortunately, despite the fact that this approach may be useful in countries with limited resources, diagnostic algorithms have low sensitivity, predictive values and validity. In a situation where there is a scarcity of realistic options, a strategy of routine antibiotic prophylaxis might be a worthwhile alternative.

The available body of literature on prophylactic antibiotics in pregnancy has yielded conflicting results. While some studies demonstrated that prophylactic antibiotic administration in pregnancy improved maternal and perinatal morbidity and mortality, other studies could not confirm this finding (Eschenbach 1991; McCormack 1987; Morales 1994; Newton 1989; Romero 1993; Oleszczuk 2000; Romero 1988). It is in view of this uncertainty that there is a need for a systematic review of the results of randomized controlled trials of antibiotic prophylaxis in pregnancy.

To determine whether the routine administration of prophylactic antibiotics in the second or third trimester of pregnancy reduces adverse pregnancy outcomes.

This review has drawn on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The full list of journals and conference proceedings as well as the search strategies for the electronic databases, which are searched by the Group on behalf of its reviewers, are described in detail in the 'Search strategies for the identification of studies section' within the editorial information about the Cochrane Pregnancy and Childbirth Group. Briefly, the Group searches on a regular basis MEDLINE, the Cochrane Controlled Trials Register and reviews the Contents tables of a further 38 relevant journals received via ZETOC, an electronic current awareness service.

Relevant trials, which are identified through the Group's search strategy, are entered into the Group's specialised register of controlled trials. Please see Review Group's details for more detailed information. Date of last search: April 2002.

In addition, The Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) was searched using the terms "(antibio* or antimicrob*) and pregnan*". We selected trials in which the administration of antibiotics was done before documentation of any infections or complications of pregnancy which is the principle of antibiotic prophylaxis. Reference lists of identified studies were examined for additional trials.

All trials were assessed for eligibility in accordance with the specified criteria. Trials were assessed for methodological quality using the standard Cochrane criteria of allocation concealment (A = adequate; B = unclear; C = inadequate; D = allocation concealment was not used). Note was made of whether the trials were placebo controlled, and information on the blinding of outcome assessment and loss to follow up was collected. The effect of trial quality will be assessed in sensitivity analyses. Categorical data will be compared using Peto odds ratio and 95% confidence intervals. The following data were extracted from each publication:

1) information on the study setting (eg country, type of population, and socio-economic status);
2) detailed description of the antibiotic regimen used (including type of drug, dose, frequency, and timing);
3) definition of the outcomes. An 'intention to treat' analysis was performed. A summary of the odds ratio was calculated using a fixed effects model (as long as there is no significant heterogeneity among the trials);
4) effects of routine use of antibiotics during pregnancy in their allocated groups (unselected or unspecified risk; high risk or specified risks).

High risk pregnant women were defined as previous spontaneous preterm delivery, history of low birth weight (< 2,500 gm) or pre pregnancy weight less than 50 kg; or associate with bacterial vaginosis (BV) in that current pregnancy.

There were eight randomized controlled trials to assess the effect of antibiotics administration during pregnancy. We excluded two trials because of the timing of antibiotic administration during the current pregnancy in the first and second half of pregnancy in one trial (Gray 2001). Another trial was studied in twin gestation which has a higher risk of adverse pregnancy outcome with some different mechanisms from single pregnancy (Peters 1995). Six trials met the inclusion criteria for this review.

For a detailed description of studies see the table of 'Characteristics of included studies'. Three of the studies (Hauth 1995; McGregor 1990; Vermeulen 1999) were conducted in high income countries (USA, Netherlands) while the remaining three (Temmerman 1995; Gichangi 1997; Paul 1997) were reports from low and middle income countries (Kenya, India). Three trials (Hauth 1995; Gichangi 1997; Vermeulen 1999) enrolled only high risk pregnant women. All studies described adequately the characteristics of the women admitted into the study.

The antibiotics used in these studies were oral erythromycin, metronidazole, cefetamet-pivoxil, and parenteral ceftriaxone, and clindamycin vaginal cream.

The earliest of the six studies reviewed was published in 1990, four others were published in 1995 to 1997 and the latest one was published in 1999.

For the detailed information on methods see the table of 'Characteristics of included studies'.

The methodological quality of the trials was satisfactory. In all, the methods of randomisation were adequate. They were all placebo controlled double blind randomized trials. A large drop out was noted in one study (Temmerman 1995: 166 (41.5%) out of 400 women enrolled). The losses for some outcomes were higher than the figures given in the characteristics of studies tables (Temmerman 1995; Gichangi 1997). This might have influenced the results. However, there was no evidence that these drop outs occurred preferentially in one or the other arm of the trial. There were high drop out rates in the other studies too (Gichangi 1997 21%; Paul 1997 22%; Vermeulen 1999 15.5%). These high loss rates have the potential to introduce bias.

Six randomized controlled trials with a total of 2184 women were included to detect the effect of prophylactic antibiotic administration in the second or third trimester on pregnancy outcomes. There were many studies of antibiotic use to prevent preterm delivery, but other than the included studies, they were studies of antibiotic treatment after there was evidence of infection or complications of pregnancy eg, detected bacterial vaginosis (BV) or premature rupture of membranes before administration of antibiotics. They were thus trials of treatment, not prophylaxis. The time of included studies' publication occupied a range of almost ten years (1990 to 1999). Three trials with 1112 women (Hauth 1995; Gichangi 1997; Vermeulen 1999) enrolled only high risk pregnant women which was defined as previous spontaneous preterm delivery, history of low birth weight, association with BV in the current pregnancy or pre pregnancy weight less than 50 kg. Four studies used oral antibiotics: erythromycin alone (McGregor 1990; Paul 1997), erythromycin plus metronidazole (Hauth 1995), cefetamet-pivoxil (Gichangi 1997). One study used ceftriaxone intramuscular injection (Temmerman 1995) and one used clindamycin vaginal cream application (Vermeulen 1999).

Results from trials for women with unspecified risk or unselected women:

Studies of antibiotic prophylaxis during the second or third trimester (range 26 to 34 weeks of gestational age) in unselected pregnant women reported the following outcomes: preterm prelabour rupture of membranes, prelabour rupture of membranes, preterm delivery, chorioamnionitis, postpartum endometritis, low birth weight, mean birth weight, congenital abnormality, small for gestational age, perinatal mortality. There was only a significant risk reduction for prelabour rupture of membranes (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14 to 0.73) in one trial (McGregor 1990). There was almost risk reduction on postpartum endometritis (OR 0.49, 95% CI 0.23 to 1.06) from the data of two trials (McGregor 1990; Temmerman 1995).

Results from trials for women specified as at high risk:

High risk group trials reported the following outcomes: preterm delivery, postpartum endometritis, gonococcal infection (postpartum detected), mean gestational age, low birth weight, mean birth weight, neonatal sepsis. Postpartum detected gonococcal infection is a non-prespecified outcome assessed. There was a significant risk reduction in preterm delivery (OR 0.48, 95% CI 0.28 to 0.81) in pregnant women with previous preterm delivery associated with BV during the current pregnancy but there was no risk reduction in pregnant women with previous preterm delivery without BV in that current pregnancy (OR 1.06, 95% CI 0.68 to 1.64). There was a risk reduction on postpartum endometritis (OR 0.46, 95% CI 0.24 to 0.89), gonococcal infection (detected postpartum) (OR 0.35, 95% CI 0.13 to 0.89) and low birth weight (OR 0.48, 95% CI 0.27 to 0.84) in pregnant women with a history of preterm delivery. There was also a significant increase in mean gestational age (weighted mean difference (WMD) 0.70, 95% CI 0.01 to 1.39) and higher mean birth weight (WMD 155.00 95% CI 6.22 to 303.78) on prophylactic antibiotic use in women with a previous low birth weight baby (< 2500 gm).

Vaginal antibiotic prophylaxis did not prevent adverse pregnancy outcomes but increased the risk of neonatal sepsis (OR 8.07, 95% CI 1.36 to 47.77).

Other results:

The included studies did not report any serious adverse effects of antibiotic prophylaxis. There were no data reported on some maternal outcomes that we planned to assess, including preterm labor, intrapartum fever needing treatment with antibiotics, puerperal sepsis, wound infection, urinary tract infection, serious maternal complications (puerperal infection requiring laparotomy for infection, hysterectomy, death), maternal side effects, duration of hospitalization and satisfaction with care. There were limited data to assess congenital abnormality and perinatal mortality. We also found limited data to evaluate the effect of antibiotics on low birth weight in unselected women. There were two trials in this analysis; one reported in unselected and another one reported in high risk group, which have effects in opposite directions. There were no data on the following neonatal outcomes: blood culture confirming sepsis, admission to neonatal intensive care unit, ophthalmia neonatorum and abnormal neurological development.

We found one study that reported compliances with medication which were different between the groups (73% in treatment group versus 84% in control group). In this trial, the treatment and control group received the identical-appearing treatment bottles and tablets that were either erythromycin base or placebo.

The methodological quality of the six included trials was satisfactory. They were all randomized double blind placebo controlled trials with satisfactory methods of randomisation. They were from both high income and low and middle income countries. The sample size for unselected pregnant women might not be enough to demonstrate differences for important uncommon outcomes.

The results of this study showed that antibiotic prophylaxis during the second or third trimester of pregnancy were effective in reducing risk of prelabour rupture of membranes in unselected pregnant women and low birth weight, postpartum endometritis and gonococcal infection (detected postpartum) in high risk pregnant women. We need more data to evaluate whether routine use antibiotics in pregnant women can prevent other substantive adverse pregnancy outcomes.

The authors thank Dr Metin Gulmezoglu for his suggestions and encouragement to complete this review.

None known.