Ronald F. Lamont

Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth

The association between infection and spontaneous preterm labour is now well established and thought to be responsible for preterm birth in up to 40% of cases. Preterm labour that is due to infection is refractory to the use of tocolytic agents. So the knowledge that infection may be the cause is unhelpful once a woman is admitted in spontaneous preterm labour, since by that time there may be irreversible changes in the uterine cervix, which renders futile those attempts to inhibit the process. It would be much more logical to use the association between infection and spontaneous preterm labour to identify a group of women at risk and to intervene using antibiotic prophylaxis. It is important to record, that the earlier in gestation at which abnormal genital tract colonisation is detected, the greater is the risk of an adverse outcome. For example, abnormal genital tract flora at 26–32 weeks gestation is associated with preterm birth with an odds ratio (OR) of 1.4 to 2, whereas abnormal genital tract flora at 7–16 weeks gestation carries an OR of 5 to 7.5. Intervention studies have used different antibiotics in different dosage regimes by different routes of administration to patients of differing risks at different gestational ages. Not surprisingly this has led to differing results. If intervention is to be successful, the antibiotics chosen should be active against bacterial vaginosis or bacterial vaginosis‐related organisms and should be used early in pregnancy in those women with the greatest degree of abnormal genital tract flora. While there is logic in using intravaginal antibiotics to deliver a heavy antibiotic load to the vagina where heavy abnormal colonisation exists, there is also logic in considering systemic antibiotics to eradicate those organisms, which have already gained access to the decidua. It may be that the greatest chance of benefit would exist if both routes of administration were combined. Yet no study has evaluated the combination of both intravaginal and systemic antibiotics to eradicate abnormal genital tract flora for the prevention of preterm birth.

Maternal and Fetal Characteristics Associated With Meconium-Stained Amniotic Fluid

OBJECTIVE: To estimate the rates of meconium-stained amniotic fluid (AF) and adverse outcome in relation to gestational age and racial group, and to investigate the predictors of meconium-stained AF. METHODS: We studied 499,096 singleton births weighing at least 500 g, at 24 or more weeks of gestation, from 1988 to 2000. The predictors of meconium-stained AF from 37 weeks of gestation onward were determined using multiple logistic regression. RESULTS: The crude meconium-stained AF rates in preterm, term, and postterm births were 5.1% (95% confidence interval [CI] 4.9–5.4), 16.5% (95% CI 16.4–16.6), and 27.1% (95% CI 26.5–27.6), respectively; the rates in blacks, South Asians, and whites were 22.6% (95% CI 22.2–23.1), 16.8% (95% CI 16.5–17.1), and 15.7% (95% CI 15.6–15.8), respectively. Independent predictors of meconium-stained AF included being black (odds ratio [OR] 8.4, 95% CI 2.4–28.8), vaginal breech delivery (OR 4.7, 95% CI 4.2–5.3), being South Asian (OR 3.3, 95% CI 1.3–8.3), and being in an advancing week of gestation (OR 1.39, 95% CI 1.38–1.40). More blacks (17.9%, 95% CI 17.3–18.4) and South Asians (11.8%, 95% CI 11.5–12.1) with good outcome and no risk factors for fetal hypoxia had meconium-stained AF than did whites (11.2%, 95% CI 11.1–11.4). Using white neonates born at 40 weeks as reference, the absolute risk of adverse outcome at 41 and 42 weeks were 2% and 5% in whites, 3% and 7%, in South Asians, and 7% and 11% in blacks. CONCLUSION: Meconium-stained AF rates are different among races and across gestational age, and overall risk of adverse outcomes in meconium stained AF is low. LEVEL OF EVIDENCE: II

An update on the controversies of tocolytic therapy for the prevention of preterm birth

Acta Obstet Gynecol Scand 2003; 82: 1–9.

Timing of planned cesarean delivery by racial group.

OBJECTIVE: To estimate the incidence of newborn respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN) in relation to gestational age and planned cesarean delivery in white, South Asian, and black women. METHODS: Included in this study were 442,596 white, South Asian, and black women who delivered single live infants at 28 of weeks gestation onwards between 1988 and 2000. Using multiple logistic regression, the gestation-specific patterns of RDS for all deliveries and RDS plus TTN for deliveries by planned cesarean delivery were analyzed by racial group. The predictors of RDS from 37 weeks of gestation onwards were determined. RESULTS: More South Asians (28.2%, 95% confidence interval [CI] 27.8–28.6) and blacks (24.6%, 95% CI 24.0–25.1) delivered spontaneously before 39 weeks than whites (16.9%, 95% CI 16.8–17.1). Respiratory distress syndrome patterns by gestation differed significantly (P<.001). Compared with whites, the gestation-specific crude RDS rate was lower in South Asians up until 40 weeks and after adjusting for confounders; South Asians were most protected against RDS (odds ratio [OR] 0.6, 95% CI 0.5–0.9). The gestation-specific patterns of RDS plus TTN after planned cesarean delivery also differed significantly (P<.001) between racial groups. The lowest rate of TTN plus RDS was at 40 weeks for whites, but in South Asians and blacks, it was lowest at 38 weeks. CONCLUSION: The gestation-specific patterns of RDS differed significantly by racial group from 32 weeks of gestation onwards. Preterm black infants had a lower rate of RDS when compared with whites; also, South Asians had the lowest rate of transient tachypnea until 38 weeks and the lowest rate of RDS until 40 weeks of gestation. The advantages of waiting until 39 weeks to perform planned cesarean delivery for white women are not seen in South Asians or blacks. LEVEL OF EVIDENCE: II

The development and introduction of anti‐oxytocic tocolytics

The perfect tocolytic agent, which is completely safe for both the mother and fetus and, which will inhibit uterine contractions and stop preterm labour in every case does not exist and the search continues. Recently, research into a new group of tocolytic agents (the oxytocic antagonists) has led to the introduction of a new licensed drug, atosiban. Since the early 1950s, modifications of the oxytocin molecule have resulted in many analogues and antagonists, though initially none emerged as potentially useful drugs. Further modifications resulted in full uterotonic antagonism in animal models before an analogue was found that inhibited vasopressin‐stimulated uterine contractions in non‐pregnant healthy women. In vitro and animal models suggested the molecule was fully antagonistic, although it was found to be only partially agonistic in women. Further developments led to two modified oxytocin molecules with higher receptor affinity for human myometrium, both of which lacked agonism in humans. The analogue, atosiban, was found to be more potent and so was chosen for clinical evaluation in dysmenorrhoea and preterm labour. The first clinical reports were open label, observational pilot studies. Randomised, double‐blind, phase II placebo‐controlled studies followed showing that atosiban was significantly more effective than placebo with very few side effects. Dose‐response studies and phase III studies in which study or placebo groups could use alternative tocolytic agents also suggested that atosiban was an effective tocolytic agent with very few adverse events. The recent worldwide comparative study of atosiban versus different beta‐agonists represents the largest and most strictly controlled study of tocolytics ever published. Atosiban was found to be at least as effective as the beta‐agonists as a tocolytic agent, but significantly less likely to result in maternal cardiovascular side effects or the need to discontinue therapy as a result of unacceptable side effects.

Comparison of Gram-stained smears prepared from blind vaginal swabs with those obtained at speculum examination for the assessment of vaginal flora

Objective To determine whether Gram‐stained smears obtained from blind vaginal swabs could be used reliably for the assessment of the vaginal flora.

Review of the accuracy of various diagnostic tests for bacterial vaginosis to predict preterm birth (Honest et al., BJOG, May 2004)

Sir, We struggle to understand the complexities of the methods used by Honest et al. in their review of the accuracy of various diagnostic tests for bacterial vaginosis (BV) used to predict preterm birth (PTB). We are in awe of the statistical analyses, applaud the comprehensive nature of the research and respect the standing of the authors in their fields of data gathering, extraction, reviews and dissemination. However, we feel that the impact of the authors’ review suffers from their apparent lack of understanding of the diagnosis of BV and of the use of screening for BV in an attempt to predict and prevent PTB. We would like to make a number of points: Current practice does not consider the diagnosis of BV to be clinically helpful in the prediction of PTB in women with threatened spontaneous preterm labour (SPTL) and this is reflected by the diagnostic criteria used in those outdated studies. The diagnosis of BV in an attempt to prevent PTB should be limited to early pregnancy when antibiotic prophylaxis is most effective and tocolytics and steroids are not a consideration. Gas–liquid chromatography for diagnosing BV was a research tool used only once, 20 years ago, for women in threatened SPTL. In this circumstance, the delayed result would be entirely unhelpful as a means of managing SPTL. Two important factors were not considered as part of the analysis. (a) The composite clinical criteria of Amsel for the diagnosis of BV undoubtedly have been of value but they are subjective, clumsy, unpleasant and irreproducible. On the other hand, a Gram stain of an air-dried smear of vaginal secretions provides a permanent, quick, simple, cheap, reproducible and objective method which corresponds with and has largely replaced the composite clinical criteria as the gold standard of measurement for the diagnosis of BV. The Gram stain approach was described first by Spiegel et al. and a more detailed modification by Nugent et al. eight years later. A further simplified modification is one currently used by many investigators. Most importantly, the Gram stain approach, but not the composite clinical criteria, also identifies a less florid but nevertheless abnormal vaginal flora which is genuinely intermediate in character. In addition, changing patterns of microbial colonisation are identifiable with different Gram stain scores or readings. We suggest that if the review of Honest et al. is to reflect current practice, as opposed to historical evolution through different diagnostic methods, the focus should be on the Gram stain where, in their assessment, the likelihood ratios of a positive or negative Nugent test result for the prediction of PTB were statistically significant. (b) Attempting to predict PTB by screening for BV is more likely to be gestational age specific than method specific. The earlier in pregnancy at which BV is diagnosed, the greater is the risk of an adverse outcome. Screening between 26 and 32 weeks of gestation is associated with a 1.4to 1.9-fold statistically significant increased risk of PTB. In contrast, an abnormal screening result in the second trimester is associated with a 2.6to 6.9-fold increased risk of PTB. Finally, with respect to the use of antibiotics for the prevention of SPTL and PTB in women with BV in early pregnancy, Honest et al. fail to refer to the 1998 Food and Drug Administration Guidelines for studies evaluating the treatment of BV which is prescriptive with respect to the diagnosis of BV before intervention. In addition, they do not mention two recent studies in which a statistically significant reduction in the incidence of PTB was shown in low risk unselected women with BV treated with clindamycin in early pregnancy (<20 weeks). These results contrast with those of most studies carried out later in pregnancy (>20 weeks) where no benefit was shown.

Reply to article by King et al.

I was fascinated to read the case report by SenguptaGiridharan et al. on a patient with a long-term eating disorder, Bartter’s syndrome and pregnancy, particularly as I care for a young woman with Gitelman’s syndrome who is planning a pregnancy in the near future. I did, however, have two concerns related to their paper. The first related to their reliance on urinary sodium values to make the diagnosis of Bartter’s syndrome as the cause of hypokalaemic alkalosis with hyperreninaemic hyperaldosteronism without hypertension. I would be grateful if they would consider answering the following queries: 1 Was urinary chloride excretion measured to differentiate between hypokalaemic alkalosis due to vomiting (low urine chloride) and Bartter’s syndrome (high urine chloride)? 2 Was 24 h urine calcium excretion measured to differentiate between the more common Gitelman’s (low urine calcium) and Bartter’s syndromes (high urine calcium)? This would need to take into consideration the approximate 30% rise in calcium excretion in pregnancy. 3 Was genetic testing performed to confirm the diagnosis and determine the subtype of potassium tubulopathy? My second concern related to their attributing a cervical spine fracture solely to underlying osteoporosis. Conventional teaching has been that osteoporosis alone is not associated with fractures above the level of the fourth thoracic vertebra. Was there any history of neck trauma in their patient, and was computed axial tomography or magnetic resonance imaging performed to exclude other pathology such as tumour or infection?

Oxytocin receptor antagonists for inhibiting preterm labour.

To the Editor: The Cochrane Collaboration is a respected organization with a justifiable reputation for publishing evidencebased systematic reviews that influence clinical practice. Maintaining impartiality and independence, something for which Cochrane is famous, requires balanced opinions from authors of systematic reviews. Many opinion leaders feel this is not the case with the Cochrane review of oxytocin antagonists recently reviewed.1 Concerns have been expressed that an unintentional bias exists in favor of calcium channel blockers due to poor choice of outcomes reported in the abstract better qualified in the text, there was a different choice of reported outcomes compared with a previous calcium channel blocker review by the same authors, there was poor objective and subjective judgment of trial quality, and there was poor choice of language showing a favorable opinion of calcium channel blockers.2 Other concerns were that the review’s methodology did not enable the outcomes to be evaluated,3 undue importance was attached to the rate of infant deaths in one study that was unbalanced at baseline,3 and the claim that calcium channel blockers were associated with better neonatal outcome was not qualified.3 Akerlund4 criticized the review for lacking rationale behind which trials were selected to evaluate safety and efficacy, making conclusions about calcium channel blockers and -agonists when calcium channel blockers were not the subject of the review, and exemplifying the drawbacks of meta-analysis with respect to the risk of selection bias and absence of quality weighting. Goodwin,5 much of whose published research occupied the review, was concerned that acknowledgment of his assistance implied concurrence with their conclusions. He felt the analysis was “flawed” and “not up to the high standards of Cochrane reviews.” Others recorded that the review contained a worrying degree of subjectivism involving study inclusions and interpretation focusing on data out of context and lacking reference to subject profiles.6,7 The authors of the review were self-appointed and the principal author has published widely on and is a strong advocate of nifedipine. None of the coauthors appear to have publication experience on using oxytocin antagonists. In a review by the same authors8 on calcium channel blockers versus -agonists, no mention is made of atosiban, yet somewhat unaccountably in the review of atosiban compared with -agonists,1 nifedipine is mentioned as having benefits over -agonists. This probably reflects the authors’ clinical preference but raises further questions of partiality and bias. A more detailed critique of the Cochrane review1 can be found elsewhere.9

Comparison of Gram-stained smears prepared from vaginal swabs taken blindly with those obtained at speculum examination for the assessment of vaginal flora

D John Morgan MBBS, Catherine J Aboud RGN SCM, I Mary B McCaffrey MRCOG, Supriya A Bhide MRCOG, Ronald F Lamont MD FRCOG and David Taylor-Robinson FRCPath 1Department of Obstetrics and Gynaecology, Northwick Park and St Mark’s NHS Trust, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3AU, and 2MRC Sexually Transmitted Diseases Research Group, Jefferiss Wing, St Mary’s Hospital, Paddington, London W2 1NY, UK