Abstract

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The risk of preterm labour in the presence of maternal infection is 30% to 50%. Antibiotics may induce a significant 12-20% reduction in neonatal infections following preterm rupture of the membranes and also may prolong pregnancy significantly. Aiming to evaluate the effectiveness of using antibiotics at any time during pregnancy to prevent preterm birth, we searched the Cochrane Library, MEDLINE, BIOSIS, EMBase, and CINAHL and we applied no language restrictions. We selected reviews and RCT’s assessing the use of antibiotics during pregnancy with outcome data on preterm labour and birth.

45 randomised controlled trials published between 1966 and the present day were included, showing mild decrease in the incidence of preterm birth before 37 weeks with the use of antibiotics and an average 34% less maternal infective morbidity with the use of antibiotics compared to placebo or no treatment for all antibiotic groups, all indications, and all gestational ages.

18 reviews published between 1993 and the present day were included, showing an average 30% decrease in the incidence of neonatal morbidity, 45% less maternal infective morbidity and an average 17% increase in the maternal adverse effects with the use of antibiotics compared to placebo or no treatment for all indications and all gestational ages.

In both trials and reviews, there is a noticeable increase in preterm births with the use of Metronidazole compared to placebo or no treatment

The result of this umbrella review does not supports the use of antibiotics during pregnancy except when there is a clear evidence of infection with extreme caution, regular follow ups and monitoring of the patient.

We do not support the use of metronidazole during pregnancy.

Background

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Preterm labour is a clinical syndrome characterized by regular uterine contractions, cervical ripening with progressive changes, and / or membrane rupture occurring after the gestational age of viability (20 weeks,500 grams weight) and before 37 completed weeks (259 days) of pregnancy [Cram 2002; Gonc 2002; Haram 2003; Taraa 2004]. Preterm birth is one of the most important problems in medicine today with an alarming frequency and economic impact [Hollier 2005]. With an incidence in most developed countries of 5-10% prematurity has major neonatal implications and is the single most common cause of perinatal death with an overall neonatal mortality rate of 41/1000 live births [Taraa 2004]. In spite of the advances in obstetric care, the rate of prematurity has not decreased over the past 40 years. In fact, most studies in the industrialized countries states that preterm labour and delivery has increased slightly. Neonatal mortality rates have declined in recent years largely because of improved neonatal intensive care and better access to these services [Goldenberg 2002; Haram 2003]. With appropriate medical care, neonatal survival dramatically improves as gestational age progress, with over 50% of neonates surviving at 25 weeks gestation, and over 90% surviving by 28-29 weeks gestation. However, these premature infants are often left with long term neurological impairment [Goldenberg 2002; Taraa 2004]. Short term morbidities associated with preterm delivery include respiratory distress syndrome,intraventricular haemorrhage, periventricular leuckomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and patent ductus arteriosus. Long term morbidities include cerebral palsy, mental retardation, and retinopathy of prematurity [Cram 2002; Goldenberg 2002]. The risk for these morbidities is directly related to the gestational age and birth weight. For example, cerebral palsy, defined as non progressive motor dysfunction with origin around the time of birth, complicates around 2/1000 of all live births. The relative risk for a preterm infant to develop cerebral palsy is 40 times that for term infants. Approximately 8-10% of surviving newborns weighing less than 1000 grams at birth will develop cerebral palsy. These infants also have substantial higher rates of mental retardation and visual disabilities, as well as neurobehavioral dysfunction and poor school performance [Goldenberg 2002]. Economically preterm birth account for 57% of the initial care of the USA neonates or nearly $6 billion annually [Hollier 2005]. The lifetime costs per preterm birth have been estimated at £511,614 [Riggs 2004].

Preterm labour has 3 obstetrical antecedents:

1. Spontaneous preterm labour which accounts for 50% of cases.
2. Spontaneous membrane ruptures which almost always result in delivery with in 1 week and account for 30% of cases.
3. Indicated preterm birth which is the decision of the obstetrician to induce labor or perform a caesarean section because of fetal or maternal indication, and this accounts for 20% of cases [Goldenberg 2002; Goldenberg 2005; Hollier 2005].

Infection has emerged during the last 20 years as an important and frequent mechanism of disease in preterm labour. Indeed, it is the only pathological process for which a firm causal link with prematurity has been established and for which a defined molecular pathophysiology is known. Moreover, fetal infection has been implicated in the genesis of fetal and neonatal injury leading to cerebral palsy and chronic lung disease [Kurki 1998; Lamont 2003a; Mertz 2001; Romero 2002].

The following evidence implicates infection as the cause of almost 40-50% of preterm birth:

1. Histological chorioamnionitis is consistently increased in cases of preterm birth.
2. Clinical infection is increased in the infant and the mother after preterm birth.
3. Several genital tract isolates are associated with preterm birth.
4. 10-15% of amniotic fluid cultures from preterm labour patients are positive for microorganisms.
5. Infection cause cytokines and prostaglandin production
6. Bacteria and bacterial products induce preterm birth in animal models [Gibbs 1997].

The infection may be either generalized or more commonly a local urogenital tract infection. Generalized infections (for example; pneumonia, pyelonephritis, malaria, typhoid fever, periodontal disease, etc.) has been associated with preterm labour and delivery. Yet, many of these conditions are rare in developed countries. Thus, the risk attributable to systemic maternal infection for prematurity is considered to be low [Kurki 1998; Romero 2002]. It has been estimated that at least 40% of all preterm births occur to mothers with intrauterine infection. Moreover, the lower the gestational age at delivery the greater the frequency of intrauterine infection (Figure 1) [Gonc 2002; Romero 2002].

Microorganisms may gain access to the amniotic cavity and the fetus through the following pathways:

1. Ascending from the vagina and the cervix.
2. Haematogenous dissemination through the placenta.
3. Retrograde seeding from the peritoneal cavity through the fallopian tubes.
4. Accidental introduction at the time of invasive procedures, such as amniocentesis, percutaneous fetal blood sampling, chorionic villous sampling or shunting [Gonc 2002; Romero 2002; Ville 2001].

The most common pathway of intrauterine infection is the ascending route. Evidence in support of this includes:

1. Histological chorioamnionitis is more common and sever at the site of membrane rupture than in other locations, such as the placental chorionic plate or the umbilical cord.
2.In virtually all cases of congenital pneumonia chorioamnionitis is present.
3. Bacteria identified in cases of congenital infections are similar to those found in the lower genital tract.
4. In twin gestations, histological chorioamnionitis is more common in the firstborn twin and has not been demonstrated only in the second twin, as the membranes of the first twin are generally opposed to the cervix, this is taken as evidence in favour of an ascending infection [Gonc 2002; Romero 2002].

Ascending intrauterine infection is considered to have four stages (Figure 2).

Stage I consists of a change in the vaginal/cervical microbial flora or the presence of pathologic organisms in the cervix, bacterial vaginosis may be an early manifestation of this initial stage. Once microorganisms gain access to the intrauterine cavity, they reside in the decidua (stage II). A localized inflammatory reaction leads to deciduitis. Microorganisms may then reside in the chorion and amnion. The infection may invade the fetal vessels (choriovasculitis) or proceed through the amnion (amnionitis) into the amniotic cavity, leading to microbial invasion of the amniotic cavity or an intra-amniotic infection (stage III). Rupture of the membranes is not a prerequisite for intraamniotic infection, as microorganisms are capable of crossing intact membranes. Once in the amniotic cavity, the bacteria may gain access to the fetus through various ports of entry (stage IV). Seeding from any of these sites to the fetal circulation may result in fetal bacteraemia and sepsis [Epstein 2000; Gonc 2002; Romero 2002]. Stage IV is the most advanced and serious stage with overall mortality rate ranges between 25% and 90% [Gonc 2002; Romero 2002]. The mean rate of positive amniotic fluid cultures for microorganisms in patients with preterm labour and intact membranes is 12.8%, and those inpatients with preterm premature rupture of membranes is 32.4% [Romero 2002].

Microorganisms produce different bioactive substances helping them to induce preterm labour and the pathway can be summarized as follows (Figure 3):

The presence of sialidases facilitates bacterial attachment and break down of mucin while mucinases assist microbial ascent into the decidua (uterine tissue). Metalloproteolytic enzymes and other microbial bioactive substances act directly on cervical collagen and amnionchorion leading to premature cervical ripening and weakening the fetal membranes with subsequent preterm premature rupture of the membranes. Microorganisms stimulate the maternal monocytes and macrophages resulting in the production of phospholipase A2 which is an enzyme that liberate arachidonic acid from the phospholipids of the membranes leading to the synthesis of prostaglandins E2 and F2α by the placental membranes. Similarly, protease toxins activate the deciduas and fetal membranes to produce Cytokines such as Tumour Necrosis Factor (TNF), Interleukin (IL1a, IL1b, IL6, IL8), and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). In response to the activation of local inflammatory reaction Prostaglandins synthesis and release are stimulated leading to stimulate uterine contractions. Moreover, in infected foetuses, there is an increase in both fetal hypothalamic and placental production of corticotrophin releasing hormone leading to increase in fetal corticotrophin secretion, which in turn increases fetal adrenal cortisol production leading to increased production of prostaglandins. Also, when the fetus is infected, there is a high increase in the production of cytokines and marked decrease in the delivery time [Epstein 2000; Goldenberg 2002; Keelan 1997; Klein 2004; Mertz 2001; Romero 2002].

In pregnancy, the genital tract flora is more abundant with an increase in the number of aerobes and a decrease in the number of anaerobes. As pregnancy advances, the genital tract flora becomes progressively more benign, until at term, the upper vaginal flora is composed mainly of organisms of low virulence which threaten no significant hazard to the fetus [Lamont 1999]. Bacterial vaginosis is a polymicrobial condition caused by the increased prevalence of anaerobes including Gardnerella vaginalis, Bacteroides spp., and Mobiluncus and Mycoplasma hominis. There is an associated reduction in hydrogen peroxide producing Lactobacilli and a dramatic increase in the anaerobe to aerobe ratio.

The criteria used to diagnose bacterial vaginosis are:

a. Vaginal PH >4.5.
b. Grey homogenous vaginal discharge.
c. Presence of clue cells in a wet mount preparation of vaginal fluid.
d. Positive amine test in which a fishy odour is released after the addition of 10% potassium hydroxide (KOH) to the vaginal fluid [Chaim 1997; Cram 2002; Haram 2003; Lamont 2003a; Taraa 2004; VIPS 1995].

The current recommendation by the centre for disease control and prevention (CDC) {Atlanta, GA, USA} and the UK drug and therapeutics bulletin is to screen and treat bacterial vaginosis in high risk pregnancies [Ugwumadu 1999]

Asymptomatic bacteriuria, defined as more than 100,000 colonies of a single bacterial species per ml of urine, cultured from midstream sample, is present in 2-7% of pregnant women. The most commonly isolated bacteria are escherichia coli. Pregnancy does not increase the incidence of asymptomatic bacteriuria; however, pyelonephritis develops in 20-40% of pregnant women with untreated asymptomatic bacteriuria and if not treated will cause preterm labour [Cram 2002; Weismiller 1999].

The centers for disease control and prevention (CDC) recommends that pregnant women with bacteriuria be treated at the time of diagnosis [Cram 2002].

Because infection is clearly associated with preterm births, it has been logical to ask whether antibiotics can prevent prematurity. Antibiotics may induce a significant 12-20% reduction in neonatal infections following preterm rupture of the membranes and also may prolong pregnancy significantly [Kurki 1998; Lamont 2003a]. Moreover antibiotics may be used prophylactically for those women at high risk of preterm birth, or may be given as adjuvant therapy with tocolytics for those women who are in preterm labour [Lamont 2003a].

Objectives

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To evaluate the effectiveness of using antibiotics at any time during pregnancy to prevent preterm birth.

Criteria for considering studies for this review

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Types of studies

All reviews assessing the use of antibiotics during pregnancy with outcome data on preterm labour and birth.

Also, all randomised clinical trials assessing the use of antibiotics during pregnancy with outcome data on preterm labour and birth.

Types of participants

Pregnant women.

Types of interventions

Antibiotics versus placebo, no treatment, or any other intervention to prevent preterm labour and birth.

Types of outcome measures

Main;

1. Preterm birth before 34 weeks.
2. Neonatal morbidity (includes; intraventricular haemorrhage, neonatal sepsis, pneumonia, ophthalmia neonatorum, and necrotizing enterocolitis).

Other outcomes of interest;

1. Preterm birth before 28 weeks.
2. Preterm birth before 37 weeks.
3. Maternal infective morbidity (includes; any infection diagnosed by fever, blood culture, urine culture, high vaginal swab, or any other method of diagnosis and classified by author
as infective morbidity).
4. Maternal adverse effects (includes; palpitation, flushes, nausea, vomiting, diarrhoea, abdominal pain, rashes, headache, and dizziness).

Search strategy for identification of studies

We searched the Cochrane Library, MEDLINE, BIOSIS, EMBase, and CINAHL.
Reviews and Randomised clinical trials identified through the searching activities and fit to the criteria for selecting studies mentioned above included.
We did not apply any language restrictions.

Methods of the umbrella review

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Methods for the reviews

Selection of reviews: We assessed for inclusion all potential reviews we identify as a result of the search strategy. We resolved any disagreement through discussion.

Data extraction and management: We designed a form to extract data from the reviews. Two review authors extracted the data using the agreed form. We resolved discrepancies through discussion. When information regarding any of the above is unclear, we attempted to contact authors of the original studies to provide further details.

Measures of treatment effect: We carried out a statistical analysis using fixed effect meta-analysis for combining data in the absence of heterogeneity if reviews are sufficiently similar. Heterogeneity was found and explored by sensitivity analysis followed by random effect meta-analysis.

Assessment of methodological quality of included reviews:

Methods used in each review and its quality was described. We assessed the validity and quality of each study using the following criteria;

1. Quality assessment: We designed a form to assess the quality of the reviews based on the QUOROM reviews quality checklist [Moher 2000], with score of 1 point for each yes and 0 score for each no (with the exception of restriction of search where no scores1 and yes scores 0) the maximum score is 27. We will assign each review using the following criteria;

A. Excellent quality: score of 24 or more (out of 27 points).
B. Good quality: score of 20 to 23.
C. Fair quality: score of 16 to 19.
D. Poor quality: score of 15 or less.

2. Presence of studies assessment: (as stated in the inclusion and exclusion criteria of the review e.g. randomised controlled trials, observational studies). We assessed the presence of studies in each review using the following criteria:

1. There are studies included in the review.
2. There are no studies included in the review.

Assessment of heterogeneity: We applied tests of heterogeneity between reviews, using the I² statistic. We identify high levels of heterogeneity among the reviews, (exceeding 50%); a random-effects meta-analysis was used as an overall summary. We carried out sensitivity analysis to explore the effect of reviews quality. This involved analysis based on an A, B, C, or D rating of the quality assessment and 1, or 2 in the presence of studies assessment. Reviews of poor quality (those rating D) or with no studies included (those rating 2) were excluded in the analysis, in order to assess for any substantive difference to the overall result.

Methods for the randomised clinical trials

Selection of studies: We assessed for inclusion all potential studies we identify as a result of the search strategy.

Data extraction and management:We designed a form to extract data. At least two review authors extracted the data using the agreed form. We resolved discrepancies through discussion.
When information regarding any of the above is unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of methodological quality of included studies:Methods used for generation of the randomisation sequence was described for each trial. We assessed the validity of each study using the following criteria;

1. Selection bias (randomisation and allocation concealment) We assigned a quality score for each trial, using the following criteria:

A. Adequate concealment of allocation: such as telephone randomisation, consecutively numbered sealed opaque envelopes;
B. Unclear whether adequate concealment of allocation: such as list or table used, sealed envelopes, or study does not report any concealment approach;
C. Inadequate concealment of allocation: such as open list of random number tables, use of case record numbers, dates of birth or days of the week.
D. Randomisation not used.

2. Attrition bias (loss of participants, e.g. withdrawals, dropouts, protocol deviations). We assessed completeness to follow up using the following criteria:

A. less than 5% loss of participants;
B. 5% to 9.9% of loss of participants;
C. 10% to 19.9% loss of participants;
D. More than 20% loss of participants.

3. Performance bias (blinding of participants, researchers and outcome assessment) We assessed blinding using the following criteria:

1. Blinding of participants (yes/no/unclear);
2. Blinding of caregiver (yes/no/unclear);
3. Blinding of outcome assessment (yes/no/unclear).

Measures of treatment effect: We used fixed-effect meta-analysis for combining data in the absence of significant heterogeneity if trials are sufficiently similar. Heterogeneity was found this was explored by sensitivity analysis followed by random effect meta-analysis.

Unit of analysis issues: We planed to include cluster-randomised trials in the analyses along with individually randomised trials. Their sample sizes was to be adjusted using the methods described in Gates 2005 using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), or from another source. If ICC's from other sources are used, this was to be reported and sensitivity analyses conducted to investigate the effect of variation in the ICC. If we identify both cluster randomised trials and individually randomised trials, we plan to synthesise the relevant information. We consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We also acknowledge heterogeneity in the randomisation unit and perform a separate meta-analysis. Therefore the meta-analysis was to be performed in two parts as well.

Dealing with missing data: We analysed data on all participants with available data in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants are not analysed in the group to which they were randomised, and there is sufficient information in the trial report, we attempted to restore them to the correct group.

Assessment of heterogeneity: We applied tests of heterogeneity between trials, using the I² statistic. We identified high levels of heterogeneity among the trials, (exceeding 50%); a random-effects meta-analysis was used as an overall summary.
We carried out sensitivity analysis to explore the effect of trial quality. This involved analysis based on an A, B, C, or D rating of selection bias and attrition bias. Studies of poor quality were excluded in the analysis (those rating D) in order to assess for any substantive difference to the overall result.

Subgroup analyses
We carried out the following subgroup analyses;

• According to the indication for the use of the antibiotics;

- Dental indications.
- Genital infections including sexually transmitted diseases.
- Urinary tract infections.
- Other indications.

• According to the antibiotic group;

- Penicillins and Cephalosporins.
- Macrolide antibiotics.
- Metronidazole.
- Other antibiotics.
- Combination of two or more of the groups mentioned above.

• According to the stage of pregnancy

- Less than 16 weeks.
- 16 weeks or more.
- Mixed or not stated. 

Description of studies

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56 Randomised controlled trials published between 1966 and the present day were considered for this umbrella review, 45 were included and 11 excluded due to being a subgroup analysis of one of the included trials [Goldenberg 2001; Kigozi 2003; Rosenstein 2000], not using antibiotics in the trial [Lopez 2002], or not being a proper intention to treat analysis with the loss of more than 20% of the participants [Andrews 2005; Gordon 1995; Jacobson 2001; McCaul 1992; McGregor 1986; Paul 1998; Wing 1999]. For detailed characteristics of excluded trials see (Figure 4)

33 reviews published between 1993 and the present day were considered for this umbrella review, 18 were included and 14 excluded due to poor quality [Carey 2001; Kirschbaum 1993; Klein 2004; Lewis 1995], synthesis of opinion based on different data and not on meta-analysis of studies [Gibbs 1997; Lamont 2003; Lamont 2005; Mertz 2001; Tebes 2003], using outcomes not included in this umbrella review [Orton 2005; Thorp 2002; Young 2001], or not including any studies [Peyron 1999; Walker 2001]. For detailed characteristics of excluded reviews see (Figure 4. One review is ongoing [Crowther 2005]. For detailed characteristics of this ongoing review see (Figure 4).

Methodological quality of included studies

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26 of the included trials were multicenter trials. Only one randomised trial used antibiotic control to compare the use of 3 antibiotics versus 2 antibiotics [Maberry 1991]. For detailed description of the included trials see (Figure 4).

4 of the included reviews were not Cochran reviews [Egarter 1996; Guise 2001; Leitich 2003; Turrentine 1995]. For detailed description of the included reviews see (Figure 4).

Results

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Results of included randomised controlled trials meta-analysis:

There is an average 9% decrease in the incidence of preterm birth before 37 weeks with the use of antibiotics compared to placebo or no treatment for all antibiotic groups, all indications, and all gestational ages {Risk Ratio (RR) 0.93, 95% Confidence Interval (95%CI) 0.89, 0.98, and Probability (P) 0.003 for all antibiotics versus placebo or no treatment, RR 0.90, 95%CI 0.84, 0.97, P 0.006 for all indications versus placebo or no treatment, RR 0.90, 95%CI 0.84, 0.97, P 0.005 for all gestational ages versus placebo or no treatment}.

There is an average 34% less maternal infective morbidity with the use of antibiotics compared to placebo or no treatment for all antibiotic groups, all indications, and all gestational ages {RR 0.67, 95%CI 0.50, 0.90, P 0.009 for all antibiotics versus placebo or no treatment and all indications versus placebo or no treatment, RR 0.64, 95%CI 0.49, 0.85, P 0.002 for all gestational ages versus placebo or no treatment}.

For the rest of the outcomes in the subgroups analysis the results are not statistically significant.

Although not statistically significant, (Figure 5), there is a noticeable increase in preterm births with the use of Metronidazole compared to placebo or no treatment {RR 1.19, 95%CI 0.88, 1.61, P 0.26 before 37 weeks, RR 1.17, 95%CI 0.90, 1.51, P 0.24 before 34 weeks, RR 2.61, 95%CI 0.71, 9.62, P 0.15 before 28 weeks}.

Results of included reviews meta-analysis:

There is an average 30% decrease in the incidence of neonatal morbidity with the use of antibiotics compared to placebo or no treatment for all antibiotic groups, all indications, and all gestational ages {RR 0.77, 95%CI 0.59, 1.00 for all antibiotics versus placebo or no treatment, RR 0.69, 95%CI 0.53, 0.89 for all indications versus placebo or no treatment, RR 0.64, 95%CI 0.51, 0.81 for all gestational ages versus placebo or no treatment}.

There is an average 45% less maternal infective morbidity with the use of antibiotics compared to placebo or no treatment for all antibiotic groups, all indications, and all gestational ages {RR 0.59, 95%CI 0.47, 0.70 for all antibiotics versus placebo or no treatment, RR 0.53, 95%CI 0.40, 0.70 for all indications versus placebo or no treatment, RR 0.53, 95%CI 0.40, 0.70 for all gestational ages versus placebo or no treatment}.

There is an average 17% increase in the maternal adverse effects with the use of antibiotics compared to placebo or no treatment for all indications, and all gestational ages {RR 1.17, 95%CI 1.00, 1.37 for all indications versus placebo or no treatment and all gestational ages versus placebo or no treatment}. In the case of all antibiotics versus placebo or no treatment maternal adverse effects increased with antibiotics to 16% but did not reach statistical significance {RR 1.16, 95%CI 1.00, 1.35, P 0.06}.

For the rest of the outcomes in the subgroups analysis the results are not statistically significant.

Although not statistically significant, (Figure 5), there is a noticeable increase in preterm births with the use of Metronidazole compared to placebo or no treatment {RR 1.02, 95%CI 0.89, 1.17, P 0.81 before 37 weeks, RR 1.07, 95%CI 0.79, 1.45, P 0.66 before 34 weeks, no studies compared metronidazole to placebo or no treatment before 28 weeks}.

Discussion

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By comparing the above results we can see that regardless of the antibiotic group, indication, and gestational age there is 39% decrease in the maternal infective morbidity with the use of antibiotics during pregnancy compared to placebo or no treatment, which is accompanied by 17% increase in the maternal adverse effects.

Again regardless of the antibiotic group, indication, and gestational age there is 9% decrease in the incidence of preterm birth before 37 weeks with the use of antibiotics compared to placebo or no treatment, but there is no significant effect for antibiotics use to prevent preterm birth before 34 weeks which is more important clinically.

There is 30% decrease in the incidence of neonatal morbidity with the use of antibiotics compared to placebo or no treatment regardless of the antibiotic group, indication, and gestational age. This Decrease in neonatal morbidity is noticed in infants up to the age of 6 weeks, but recent study [Kenyon 2008b] followed up the long-term effects on children after exposure to antibiotics that were given to there mothers when they were in spontaneous preterm labour with intact membranes and without overt signs of clinical infection, in this follow up study they found that the prescription of antibiotics for these women was associated with an increase in functional impairment among their children at 7 years of age and The risk of cerebral palsy was increased.

There is a positive association between using metronidazole and increase the incidence of preterm labour this results supports the previous findings by other researchers [Carey 2000, Kigozi 2003, Klebanoff 2001, Shennan 2005, Simcox 2007]. 

Conclusion

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The results of this umbrella review proves that the use of antibiotics during pregnancy have no effect in preventing preterm labour before 34 weeks, but also may increase the risk of preterm labour specially metronidazole, and this is accompanied by an increase in the maternal adverse effects including palpitation, flushes, nausea, vomiting, diarrhoea, abdominal pain, rashes, headache, and dizziness.

Implications for practice

The result of this umbrella review does not supports the use of antibiotics during pregnancy except when there is a clear evidence of infection with extreme caution, regular follow ups and monitoring of the patient.

We do not support the use of metronidazole during pregnancy.

Implications for research

There is a real need for a randomised controlled trial designed to test antibiotics versus antibiotics, the trials should be appropriately sized and Outcomes should include preterm labour and birth at clinically significant gestational ages, neonatal and maternal infective morbidity and adverse effects.

Effects of metronidazole on pregnancy needs further investigation.

Long term effects of antibiotics on infants and children needs further investigation.

References

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References to included randomised controlled studies

Andrews 2003 {published data only}

Andrews WW, Sibai BM, Thom EA, Dudley D, Ernest JM, McNellis D, Leveno KJ, Wapner R, Moawad A, O’Sullivan MJ, Caritis SN, Iams JD, Langer O, Miodovnik M, and Dombrowski M. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstetrics and Gynaecology 2003; 101(5):847-854.

Antsaklis 1997 {published data only}

* Antsaklis A, Daskalakis G, Michalas S, Aravantinos D. Erythromycin treatment for subclinical Ureaplasma urealyticum infection in preterm labor. Fetal Diagnosis and Therapy 1997; 12:89-92.

Carey 2000 {published data only}

* Carey JC, Klepanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, Heine RP, Nugent RP, Fischer ML, Leveno KJ, Wapner R, Varner M. metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. The New England Journal of Medicine 2000; 342(8):534-540.

Cox 1996 {published data only}

* Cox SM, Bohman VR, Sherman L, Leveno KJ. Randomized investigation of antimicrobials for the prevention of preterm birth. American Journal of Obstetrics and Gynecology 1996; 174(1part1):206-210.

Elder 1971 {published data only}

* Elder HA, Santamarina BAG, Smith S, Kass EH. The natural history of asymptomatic bacteriuria during pregnancy: the effect of tetracycline on the clinical course and the outcome of pregnancy. American Journal of Obstetrics and Gynecology 1971; 111(3):441-462.

Eschenbach 1991 {published data only}

* Eschenbach DA, Nugent RP, Rao AV, Cotch MF, Gibbs RS, Lipscomb KA, Martin DH, Pastorek JG, Rettig PJ, Carey JC, Regan JA, Geromanos KL, Lee MLF, Poole WK, Edelman R,. A randomized placebo-controlled trial of erythromycin for the treatment of ureaplasma urealyticum to prevent premature delivery. American Journal of Obstetrics and Gynecology 1991; 164(3):734-742.

Gray 2001 {published data only}

* Gray RH, Wabwire-Mangen F, Kigozi G, Sewankambo NK, Serwadda D, Moulton LH, Quinn TC, O’Brien KL, Meehan M, Abramowsky C, Robb M, and Wawer MJ. Randomized trial of presumptive sexually transmitted disease therapy during pregnancy in Rakai, Uganda. American Journal of Obstetrics and Gynecology 2001; 185:1209-1217.

Guaschinoa 2002 {published data only}

* Guaschinoa S, Riccib E, Franchic M, Frated GD, Tibaldie C, Santoa DD, Ghezzic F, Benedettoe C, Setaa FD, Parazzinib F. Treatment of asymptomatic bacterial vaginosis to prevent pre-term delivery: a randomised trial. Obstetrics and Gynaecology 2002; 110:149-152.

Hauth 1995 {published data only}

* Hauth JC, Goldenberg RL, Andrews WW, Dubard MB, Copper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. New England Journal of Medicine 1995; 333(26):1732-1736.

Hawkinson 1966 {published data only}

* Hawkinson JA, Schulman H. Prematurity associated with cevicitis and vaginitis during pregnancy. American Journal of Obstetrics and Gynecology 1966; 94(7):898-902.

Jeffcoat 2003 {published data only}

* MK Jeffcoat, JC Hauth, NC Geurs, MS Reddy, SP Clive, PM Hodgkins, RL Goldenberg. Periodontal disease and preterm birth: results of a pilot intervention study. Journal of Periodontology 2003; 74(8):1214-1218.

Joesoef 1995 {published data only}

* Joesoef MR, Hillier SL, Wiknjosastro G, Sumampouw H, Linnan M, Norojono W, Idajadi A, Utomo B. Intravaginal clindamycin treatment for bacterial vaginosis: Effect on preterm delivery and low birth weight. American Journal of Obstetrics and Gynecology 1995; 173(5):1527-1531.

Kekki 2001 {published data only}

* Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, and Paavonen J. Vaginal clindamycin in preventing preterm birth and Peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstetrics and Gynaecology 2001; 97(5 part1):643-648.

Kenyon 2001a {published data only}

* Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. The Lancet 2001; 357:979-988.

Kenyon 2001b {published data only}

* Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. The Lancet 2001; 357:989-994.

Keuchkerian 2004 {published data only}

Keuchkerian SE, Sosaa CG, Fernandez A, Alonso JG, Labordea, f A, Cuadroa JC. Effect of amoxicillin sulbactam in threatened preterm labour with intact membranes: a randomised controlled trial. Obstetrics and Gynaecology 2004; 119:21-26.

Kiss 2004 {published data only}

* Kiss H, Petricevic L and Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004; 329:371-376.

Klebanoff 1994 {published data only}

* Klebanoff MA, Regan JA, Rao AV, Nugent RP, Blackwelder WC, Eschenbach DA, Pastorek JG, Williams S, Gibbs RS, Carey JC. Outcome of the Vaginal Infections and Prematurity Study: results of a clinical trial of erythromycin among pregnant women colonized with group B streptococci. American Journal of Obstetrics and Gynecology 1994; 172(5):1540-1545.

Klebanoff 2001 {published data only}

* Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Thom EA, Ernest JM, Heine RP, Nugent RP, Leveno KJ, Wapner R, Trout W, Moawad A. failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic trichomonas vaginalis infection. New England Journal of Medicine 2001; 345(7):487-493.

Kurkinen-Raty 2000 {published data only}

* Kurkinen-Raty M, Vuopala S, Koskela M, Kekki M, Kurki T, Paavonen J, Jouppila P. A randomised controlled trial of vaginal clindamycin for early pregnancy bacterial vaginosis. British Journal of Obstetrics and Gynaecology 2000; 107:1427-1432.

Lamont 2003 {published data only}

Lamont RF, Duncan SLB, Mandal D, and Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstetrics and Gynaecology 2003; 101(3):516-522.

Little 1966 {published data only}

* Little PJ. The incidence of urinary infection in 5000 pregnant women. The Lancet 1966:925-928.

Maberry 1991 {published data only}

* Maberry MC, Gilstrap LC, Bawdon R, Little BB, Dax J. Anaerobic coverage for intra-amnionic infection: maternal and perinatal impact. American Journal of Perinatology 1991; 8(5):338-341.

Martin 1997 {published data only}

* Martin DH, Eschenbach DA, Cotch MF, Nugent RP, Rao AV, Klebanoff MA, Lou Y, Rettig PJ, Gibbs RS, Pastorek IJG, Regan JA, Kaslow RA. Double-blind placebo-controlled treatment trial of chlamydia trachomatis endocervical infections in pregnant women. Infectious Diseases in Obstetrics and Gynaecology 1997; 5:10-17.

McDonald 1997 {published data only}

* McDonald HM, O'Loughlin JA, Vigneswaran R, Jolley PT, Harvey JA, Bof A, McDonald PJ. Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomised, placebo controlled trial. British Journal of Obstetrics and Gynaecology 1997; 104:1391-1397.

McGregor 1990 {published data only}

* McGregor JA, French JI, Richter R, Vuchetich M, Bachus V, Seo K, Hillier S, Judson FN, McFee J, Schoonmaker J, Todd JK. Cervicovaginal microflora and pregnancy outcome: results of a double-blind, placebo-controlled trial of erythromycin treatment. American Journal of Obstetrics and Gynecology 1990; 163(5part1):1580-1591.

McGregor 1991 {published data only}

* McGregor JA, French JI, Seo K. Adjunctive clindamycin therapy for preterm labor: Results of a double-blind, placebo-controlled trial. American Journal of Obstetrics and Gynecology 1991; 165(4part1):867-875.

McGregor 1994 {published data only}

* McGregor JA, French JI, Jones W, Milligan K, McKinney PJ, Patterson E, Parker R. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream.. American Journal of Obstetrics and Gynecology 1994; 170(4):1048-1060.

Morales 1988 {published data only}

* Morales WJ, Angel JL, O'Brien WF, Knuppel RA, Finazzo M. A randomized study of antibiotic therapy in idiopathic preterm labor. Obstetrics and Gynecology 1988; 72(6):829-833.

Morales 1994 {published data only}

* Morales WJ, Schorr SJ, Albritton J. Effect of metronidazole in patients with history of preterm birth and bacterial vaginosis. American Journal of Obstetrics and Gynecology 1994; 171(2):345-349.

Newton 1989 {published data only}

* Newton ER, Dinsmoor MJ, Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor. Obstetrics and Gynaecology 1989; 74(4):562-566.

Newton 1991 {published data only}

* Newton ER, Shields L, Ridgway 3rd LE, Berkus MD, Elliott BD. Combination antibiotics and indomethacin in idiopathic preterm labor: a randomized double-blind clinical trial. American Journal of Obstetrics and Gynecology 1991; 165:1753-1759.

Norman 1994 {published data only}

* Norman K, Pattinson RC, deSouza J, deJong P, Moller G, Kirsten G. Ampicillin and metronidazole treatment in preterm labour: a multicentre randomised controlled trial. British Journal of Obstetrics and Gynaecology 1994; 101:404-408.

Odendaal 2002 {published data only}

* Odendaal HJ, Popov I, Schoeman J, Smith M, Grove D. Preterm labour--is bacterial vaginosis involved? South African Medical Journal 2002; 92(3):231-234.

Ogasawara 1999 {published data only}

* Ogasawara KK and Goodwin TM. Efficacy of azithromycin in reducing lower genital ureaplasma urealyticum colonization in women at risk for preterm delivery. The Journal of Maternal-Fetal Medicine 1999; 8:12-16.

Oyarzun 1998 {published data only}

* Oyarzún E, Gómez R, Rioseco A, González P, Gutiérrez P, Donoso E, Montiel F. Antibiotic treatment in preterm labor and intact membranes: a randomized, double-blinded, placebo-controlled trial.. The Journal of Maternal-Fetal Medicine 1998; 7:105-110.

Purwar 1997 {published data only}

* Purwar MB, Sarodey C, Karale S. Ampicillin and metronidazole in preterm labor management: an RCT. Journal of Clinical Epidemiology 1997; 50(1):22S.

Romero 1993 {published data only}

* Romero R, Sibai B, Caritis S, Paul R, Depp R, Rosen M, Klebanoff M, Sabo V, Evans J, Thom E. Antibiotic treatment of preterm labor with intact membranes: a multicenter, randomized, double-blinded, placebo-controlled trial. American Journal of Obstetrics and Gynecology 1993; 171(3):865-866.

Saez-Llorens 1995 {published data only}

* Saez-Llorens X, Ah-Chu MS, Castano E, Cortes L, Torres A, Suarez M, Bissot A, Reyes W, Karp WB, McCracken GH SaSaez-Llorens X, Ah-Chu MS, Castano E, Cortes L, Torres A, Suarez M, Bissot A, Reyes W, Karp WB, McCracken GH. Intrapartum prophylaxis with ceftriaxone decreases rates of bacterial colonization and early-onset infection in newborns. Clinical Infectious Diseases 1995; 21:876-880.

Shennan 2005 {published data only}

* Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G, Poston L. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET study. BJOG 2005; 113:65-74.

Svare 1997 {published data only}

* Svare J, Langhoff-Roos J, Andersen LF, Kryger-Baggesen N, Borch-Christensen H, Heisterberg L, Kristensen J. Ampicillin-metronidazole treatment in idiopathic preterm labour: a randomised controlled multicentre trial. British Journal of Obstetrics and Gynaecology 1997; 104:892-897.

Thomsen 1987 {published data only}

* Thomsen AC, Morup L, Hansen KB. Antibiotic elimination of group-B streptococci in urine in prevention of preterm labour. The Lancet 1987; 1(8533):591-593.

Ugwumadu 2003 {published data only}

Ugwumadu A, Manyonda I, Reid F, Hay P A Ugwumadu, I Manyonda, F Reid, P Hay. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. The Lancet 2003; 361:983-988.

Vermeulen 1999 {published data only}

* Vermeulen GM, Bruinse HW. Prophylactic administration of clindamycin 2% vaginal cream to reduce the incidence of spontaneous preterm birth in women with an increased risk: a randomised placebo-controlled double-blind trial. British Journal of Obstetrics and Gynaecology 1999; 106:652-657.

Watts 1994 {published data only}

* Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Randomized trial of antibiotics in addition to tocolytic therapy to treat preterm labor. Infectious Diseases in Obstetrics and Gynecology 1994; 1:220-227.

References to included reviews

Brocklehurst 1998 {published data only}

* Brocklehurst P, Rooney G. Interventions for treating genital chlamydia trachomatis infection in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 4, 1998.

Brocklehurst 2002 {published data only}

* Brocklehurst P. Antibiotics for gonorrhoea in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 2, 2002.

Egarter 1996 {published data only}

* Egarter C, Leifich H, Husslein P, Kaider A, and Schemper M. Adjunctive antibiotic treatment in preterm labor and neonatal morbidity. Obstetrics & Gynecology 1996; 88(2):303-309.

Flenady 2002 {published data only}

* Flenady V, King J. Antibiotics for prelabour rupture of membranes at or near Term. In: The Cochrane Database of Systematic Reviews, Issue 3, 2002.

Garner 2002 {published data only}

* Garner P, Gülmezoglu AM. Drugs for preventing malaria-related illness in pregnant women and death in the newborn. In: The Cochrane Database of Systematic Reviews, Issue 4, 2002.

Guise 2001 {published data only}

* Guise JM, Mahon SM, Aickin M, Helfand M, Peipert JF, Westhoff C. Screening for Bacterial Vaginosis in Pregnancy. American Journal of Preventive Medicine 2001; 20(3S):62-72.

Gülmezoglu 2002 {published data only}

* Gülmezoglu AM. Interventions for trichomoniasis in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 3, 2002.

Hopkins 2002 {published data only}

* Hopkins L, Smaill F. Antibiotic regimens for management of intraamniotic infection. In: The Cochrane Database of Systematic Reviews, Issue 3, 2002.

Kenyon 2003 {published data only}

* Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. In: The Cochrane Database of Systematic Reviews, Issue 2, 2003.

King 2002 {published data only}

* King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. In: The Cochrane Database of Systematic Reviews, Issue 4, 2002.

Leitich 2003 {published data only}

* Leitich H, Brunbauer M, Bodner-Adler B, Kaider A, Egarter C, and Husslein P. Antibiotic treatment of bacterial vaginosis in pregnancy. American Journal of Obstetrics and Gynecology 2003; 188(3):752-758.

McDonald 2005 {published data only}

* McDonald H, Brocklehurst P, Parsons J. Antibiotics for treating bacterial vaginosis in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.

Raynes-Greenow 2004 {published data only}

* Raynes-Greenow CH, Roberts CL, Bell JC, Peat B, Gilbert GL. Antibiotics for ureaplasma in the vagina in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 1, 2004.

Smaill 2001 {published data only}

* Smaill F. Antibiotics for asymptomatic bacteriuria in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 2, 2001.

Thinkhamrop 2002 {published data only}

* Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality. In: The Cochrane Database of Systematic Reviews, Issue 4, 2002.

Turrentine 1995 {published data only}

* Turrentine MA, and Newton ER. Amoxicillin or erythromycin for the treatment of antenatal chlamedial infection. Obstetrics & Gynecology 1995; 86(6):1021-1025.

Vazquez 2003 {published data only}

* Vazquez JC, Villar J. Treatments for symptomatic urinary tract infections during pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 4, 2003.

Villar 2000 {published data only}

* Villar J, Widmer M, Lydon-Rochelle MT, Gülmezoglu AM, Roganti A. Duration of treatment for asymptomatic bacteriuria during pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 2, 2000.

References to excluded randomised controlled trials

Goldenberg 2001 {published data only}

* Goldenberg RL, Klebanoff M, Carey JC, and MacPherson C. Metronidazole treatment of women with a positive fetal fibronectin test result. American Journal of Obstetrics and Gynecology 2001; 185:485-486.

Gordon 1995 {published data only}

* Gordon M, Samuels P, Shubert P, Johnson F, Gebauer C, and Iams J. A randomized, prospective in preterm labor study of adjunctive ceftizoxime. American Journal of Obstetrics and Gynecology 1995; 172:1546-1552.

Jacobson 2001 {published data only}

* Jacobson GF, Autry AM, Kirby RS, Liverman EM, Motley RU. A randomized controlled trial comparing amoxicillin and azithromycin for the treatment of chlamydia trachomatis in pregnancy. American Journal of Obstetrics and Gynecology 2001; 184(7):1352-1356.

Kigozi 2003 {published data only}

* Kigozi G, Brahmbhatt H, Wabwire-Mangen F, Wawer MJ, Serwadda D, Sewankambo N, and Gray RH. Treatment of Trichomonas in pregnancy and adverse outcomes of pregnancy: A subanalysis of a randomized trial in Rakai, Uganda. American Journal of Obstetrics and Gynecology 2003; 189(5):1398-1400.

Lopez 2002 {published data only}

* Lopez NJ, Smith PC, Gutierrez J. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: a randomized controlled trial. Journal of Periodontology 2002; 73(8):911-924.

McCaul 1992 {published data only}

* McCaul JF, Perry KG Jr, Moore JL Jr, Martin RW, Bucovaz ET, Morrison JC. Adjunctive antibiotic treatment of women with preterm rupture of membranes or preterm labor. International Journal of Gynecology and Obstetrics 1992; 38:19-24.

McGregor 1986 {published data only}

* McGregor JA, French JI, Reller LB, Todd JK, Makowski EL. Adjunctive erythromycin treatment for idiopathic preterm labor: results of a randomized, double-blinded, placebo-controlled trial. American Journal of Obstetrics and Gynecology 1986; 154(1):98-103.

Paul 1998 {published data only}

* Paul VK, Singha UM, Bucksheeb K. Erythromycin treatment of pregnant women to reduce the incidence of low birth weight and preterm deliveries. International Journal of Gynecology and Obstetrics 1998; 62:87-88.

Rosenstein 2000 {published data only}

* Rosenstein I.J, Morgan D.J, Lamont R.F, Sheehan M, Dore C.J, Hay P.E, Taylor- Robinson D. Effect of intravaginal clindamycin cream on pregnancy outcome and on abnormal vaginal microbial flora of pregnant women. Infectious Diseases in Obstetrics and Gynecology 2000; 8:158-165.

Wing 1999 {published data only}

*Wing DA, Hendershott CM, Debuque L, and Millar LK. Outpatient Treatment of Acute Pyelonephritis in Pregnancy after 24 Weeks. Obstetrics & Gynecology 1999; 94(5part1):683-688.

References to excluded reviews

Carey 2001 {published data only}

* Carey JC, Klebanoff MA. Bacterial vaginosis and other asymptomatic vaginal infections in pregnancy. Current Women’s Health Reports 2001; 1:14-19.

Gibbs 1997 {published data only}

* Gibbs RS, and Esehenbaeh DA. Use of antibiotics to prevent preterm birth. American Journal of Obstetrics and Gynecology 1997; 177(2):375-380.

Kirschbaum 1993 {published data only}

* Kirschbaum T. Antibiotics in the treatment of preterm labor. American Journal of Obstetrics and Gynecology 1993; 168(4):1239-1246.

Klein 2004 {published data only}

* Klein LL, Gibbs RS. Use of microbial cultures and antibiotics in the prevention of infection-associated preterm birth. American Journal of Obstetrics and Gynecology 2004; 190:1493-1502.

Lamont 2003 {published data only}

* Lamont RF. Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth. BJOG 2003; 110(20):71-75.

Lamont 2005 {published data only}

* Lamont RF. Can antibiotics prevent preterm birth--the pro and con debate? BJOG 2005; 112(1):67-73.

Lewis 1995 {published data only}

* Lewis R, Mercer BM. Adjunctive care of preterm labor--the use of antibiotics. Clinical Obstetrics and Gynaecology 1995; 38(4):755-770.

Mertz 2001 {published data only}

* Mertz HL, Ernest JM. Antibiotics and preterm labor. Current Women’s Health Reports 2001; 1:20-26.

Orton 2005 {published data only}

* Orton L, Garner P. Drugs for treating uncomplicated malaria in pregnant women. In: The Cochrane Database of Systematic Reviews, Issue 3, 2005.

Peyron 1999 {published data only}

* Peyron F, Wallon M, Liou C, Garner P. Treatments for toxoplasmosis in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 3, 1999.

Tebes 2003 {published data only}

* Tebes CC, Lynch C, Sinnott J. The effect of treating bacterial vaginosis on preterm labor. Infectious Diseases in Obstetrics and Gynaecology 2003; 11(2):123-129.

Thorp 2002 {published data only}

* Thorp JM Jr, Hartmann KE, Berkman ND, Carey TS, Lohr KN, Gavin NI, and Hasselblad V. Antibiotic therapy for the treatment of preterm labor: A review of the evidence Antibiotic therapy for the treatment of preterm labor: A review of the evidence Antibiotic therapy for the treatment of preterm labor: A review of the evidence. American Journal of Obstetrics and Gynecology 2002; 186(3):587-592.

Walker 2001 {published data only}

* Walker GJA. Antibiotics for syphilis diagnosed during pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 3, 2001.

Young 2001 {published data only}

* Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy. In: The Cochrane Database of Systematic Reviews, Issue 4, 2001.

 

References to ongoing reviews

Crowther 2005 {published data only}

Crowther CA, Thomas N, Middleton P, Chua M, Esposito M. Treating periodontal disease for preventing preterm birth in pregnant women. In: The Cochrane Database of Systematic Reviews, Issue 2, 2005.

* indicates the primary reference for the study

Other references

Chaim 1997

Chaim W, Mazor M, Leiberman JR. The relationship between bacterial vaginosis and preterm birth. Archives of Gynecology and Obstetrics 1997; 257:51-58.

Cram 2002

Cram LF, Zapata MI, Toy EC, and Baker B III. Genitourinary Infections and Their Association with Preterm Labor. American Family Physician 2002; 65(2):241-248.

Epstein 2000

Epstein F. Intrauterine infection and preterm delivery. New England Journal of Medicine 2000; 342(20):1500-1507.

Gibbs 1997

Gibbs RS, and Esehenbaeh DA. Use of antibiotics to prevent preterm birth. American journal of obstetrics and gynaecology 1997; 177(2):375-380.

Goldenberg 2002

Goldenberg RL. The Management of Preterm Labor. Obstetrics & Gynecology 2002; 100(5):1020-1037.

Goldenberg 2005

Goldenberg RL, Culhane JF. Prepregnancy Health Status and the Risk of Preterm Delivery. Archives of pediatric and adolescent medicine 2005; 159:89-90.

Gonc 2002

Gonc LF, Alves CT, and Romero R. Intrauterine infection and prematurity. Mental retardation and developmental disabilities 2002; 8:3-13.

Haram 2003

Haram K., Mortensen JHS And Wollen AL. Preterm delivery: an overview. Acta Obstetricia et Gynecologica Scandinavica 2003; 82:687-704.

Hollier 2005

Hollier LM. Preventing Preterm Birth: What Works, what does not. Obstetrical and gynaecological survey 2005; 60(2):124-131.

Keelan 1997

Keelan J A.; Coleman M; Mitchel M. The Molecular Mechanisms of Term and Preterm Labor: Recent Progress and Clinical Implications. Clinical Obstetrics and Gynaecology 1997; 40(3):460-478.

Klein 2004

Klein LL, Gibbs RS. Use of microbial cultures and antibiotics in the prevention of infection-associated preterm birth. American Journal of Obstetrics and Gynecology 2004; 190:1493-1502.

Kurki 1998

Kurki T. A survey of etiological mechanisms and therapy of preterm labor. Acta Obstetricia et Gynecologica Scandinavica 1998; 77:137-141.

Lamont 1999

Lamont RF. The prevention of preterm birth with the use of antibiotics. European journal of paediatrics 1999; 158(1):2-4.

Lamont 2003a

Lamont RF. Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth. BJOG: an international journal of obstetrics and gynaecology 2003; 110(20):71–75.

Mertz 2001

Mertz HL and Ernest JM. Antibiotics and Preterm Labor. Current Women’s Health Reports 2001; 1:20-26.

Moher 2000

Moher D, Cook DJ, Eastwood S, Olkin I, Ronnie D, Stroup DF. Improving the quality of reports of meta-analysis of randomised controlled trials: the QUOROM statement. British journal of surgery 2000; 87(11):1448-1454.

Riggs 2004

Riggs MA, Klebanoff MA. Treatment of vaginal infections to prevent preterm birth: a meta-analysis. Clinical Obstetrics and Gynaecology 2004; 47(4):796-807.

Romero 2002

Romero R, Espinoza J, Chaiworapongsa T and Kalache K. Infection and prematurity and the role of preventive strategies. Seminars in Neonatology 2002; 7:259-274.

Taraa 2004

Taraa P.N., Thornton S. Current medical therapy in the prevention and treatment of preterm labour Current medical therapy in the prevention and treatment of preterm labour. Seminars in Fetal & Neonatal Medicine 2004; 9:481-489.

Ugwumadu 1999

Ugwumadu AHN, Hay P. Bacterial vaginosis: sequelae and management. Current Opinion in Infectious Diseases 1999; 12(1):53-59.

Ville 2001

Ville Y. Premature delivery and inflammation. Journal of Gynecology, Obstetrics and Biological Reproduction 2001; 30(1):12-16.

VIPS 1995

Vaginal infections and prematurity study group. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. New England Journal of Medicine 1995; 333(26):1737-1742.

Weismiller 1999

Weismiller DG. Preterm Labor. American family physician 1999; 59(3):3-18. 

Source(s) of Funding

---

Scholarship from Saudi Goverment

Competing Interests

---

None what so ever