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									     Effect of early oral clindamycin on late
miscarriage and preterm delivery in asymptomatic
women with abnormal vaginal flora and bacterial
      vaginosis: a randomised control trial

 Authors: Austin Ugwumadu, Isaac Manyonda, Fiona
                  Reid, Phillip Hay


           Journal club presentation by
              Cynthia Salinas, M.D.
                  May 28, 2003
Prematurity Statistics

• In 2000, 467,201 babies were born preterm, representing
  12% of the 4,058,814 births in the United States.

• In an average week in the U.S. 8,985 babies are born
  preterm.

• The rate of preterm birth is highest for African Americans
  (17.4%), followed by Native Americans (12.6%) , Whites
  (10.6%) and Asians (10.2%).

Source
• National Health Statistics, final natality data, 2000.
Prematurity Statistics

• Prematurity is the second leading cause of
  neonatal mortality in the United States, and is the
  leading cause of death among non-Hispanic black
  infants.

• Babies who are born preterm are at higher risk of
  illness, disability, and death, compared to infants
  born at full term.
Source
• National Health Statistics, final natality data, 2000.
Question

 Does antibiotic treatment early in the second
  trimester reduce miscarriage and spontaneous
  preterm delivery?
Study Design

 Randomized placebo-controlled trial

 Double blinded
Target Population
 Pregnant women seeking antenatal care between
  November 1996 and February 1999 at St. George’s
  Hospital in London and St. Helier Hospital in
  Surrey, UK
Methods
 Each participant self-screened with vaginal swab

 Gram stains assigned a Nugent Score

  • Quantifies the presence of Lactobacillus species,
  Gardnerella/Prevotella and Mobiluncus
    Score
    0-3       Normal flora
    4-6       Intermediate abnormal flora
    7-10      Bacterial vaginosis

    Inter-observer variation negligible
Methods
 Inclusion criteria:
      Nugent score > 4
      Women with GA > 12 wks but < 22 wks
 Exclusion criteria:
      Multiple pregnancy
      History of cone biopsy
      Uterine, cervical or fetal anomaly
      Diabetes, HTN, renal or collagen disease
      Lupus or antiphospholipid syndrome
      Age <16yrs
      Women with vaginal discharge
Methods
 Women were then randomly assigned to receive a
  five day course of twice daily clindamycin or
  placebo

 Treatment initiated at randomization with a mean
  gestation of 15.6wks

 76% of study population received treatment or
  placebo by 17 weeks gestation

 Both groups received follow up at 2-4 weeks
Trial Profile
   11,189 total antenatal
        population

                             5,069 declined screening
                            or were over cutoff for GA

   6120 women screened


                             5,380 had normal vaginal
                            flora or inadequate smears
  740 with BV or abnormal
       vaginal flora


                                  246 excluded


  494 randomly allocated
                   494 randomly allocated




   249 Clindamycin                          245 Placebo


   4 lost to follow up                 1 lost to follow up
 1 elective termination              3 elective termination



244 analyzed for primary            241 analyzed for primary
        outcome                             outcome
Statistical Analysis

• Analysis was by intention to treat
• Categorical variables compared with Fisher’s
  exact test
• Continuous variables compared with Student’s
  t-test
• Kaplan-Meier survival curve for time to delivery
  or miscarriage
Primary endpoints
 Spontaneous preterm birth
     delivery of neonate at or beyond 24 wks but
     before 37 completed weeks

 Miscarriage
     spontaneous expulsion of products before 13
     completed wks of gestation or between 13 but
     before 24 weeks
Primary endpoints

 Spontaneous preterm birth
     Birth at >24 weeks but <37 weeks

 Miscarriage
     Pregnancy loss at >13 weeks but <24weeks
Secondary endpoints

 Side Effects
 Gestational age at delivery
 Birth-weight
 Admission to NICU
Baseline characteristics
Groups                        Clinda          Placebo
                              n =244          n = 241

Age (years, mean [SD])        28.8 (5.6)      28.5 (5.4)
Parity (mean, [SD])           0.8 (1.1)       0.8 (1.0)
GA                            15.6 (2.6)      15.7 (2.6)
Ethnicity
   White                      155/241 (64%)   144/237 (61%)
   Black African              25/241 (10%)    24/237 (10%)
   Black Caribbean            36/241 (15%)    42/237 (18%)
   Asian                      16/241 (7%)     20/237 (8%)
   Other                      9/241 (4%)      7/237 (3%)
Nugent Score
   Intermediate flora (4-6)   37 (15%)        38 (16%)
   BV (7-10)                  207 (85%)       203 (84%)
Baseline characteristics
Groups                                    Clinda                          Placebo
                                          n =244                          n = 241
Previous miscarriage
   Any                                    63/240 (26%)                    80/234 (34%)
   2nd Trimester, any                     15/240 (6%)                     20/234 (9%)
   1st Trimester, only                    48/240 (20%)                    60/234 (26%)

Previous spontaneous                      24/235 (10%)                    22/233 (9%)
Preterm delivery


•   Data are missing for some patient’s characteristics.
•   Three participants randomized below 12 wks’ gestation were instructed to commence
    treatment at 12 weeks.
Primary pregnancy outcomes
                   Clinda      Placebo
                   n=244       n=241       p value

PTD                11 (5%)     28 (12%)     .007
Late miscarriage   2 (1%)      10 (4%)      .039
Elective PTD       8 (3%)      3 (1%)       .230
IUFD               1 (<1%)     1 (<1%)      .484
Term delivery      222 (91%)   199 (83%)    .005
      Primary pregnancy outcomes
100
 90
 80
 70
 60
 50                             Clinda
 40                             Placebo
 30
 20
 10
  0
      PTD   LM    IUFD   Term
Pregnancy Outcome: Preterm delivery

                                            95% CI
 Relative risk reduction (RRR) = 0.612   [0.238-0.802]

 Absolute risk reduction (ARR) = 0.071   [0.023-0.119]

 Number need to treat (NNT)   = 14
Pregnancy Outcome: Late miscarriage

                                       95% CI
 Relative risk reduction = 0.802   [0.108, 0.956]

 Absolute risk reduction = 0.033   [0.006, 0.061]

 Number needed to treat = 30
Difference in percentage of spontaneous PTD and miscarriages
between groups that might affect outcomes
                             Clindamycin          Placebo
                             n = 244              n = 241
Nugent Score
5                            9%                   33%
6                            4%                   14%
7                            3%                   14%
8                            6%                   7%
9                            6%                   15%
10                           5%                   36%
Previous preterm delivery
or late miscarriage
 Yes                         19%                  42%
 No                          3%                   11%
Ethnicity
 White                       3%                   14 %
 Black Caribbean             8%                   33 %
 Black African               12%                  8%
 Asian                       6%                   10 %
Secondary endpoints
                               Clinda             Placebo
                               n=244              n=241          p value

Admission to NICU              18/238 (8%)        23/228 (10%)    0.41
Side-effects reported          17/239 (7%)        8/239 (3%)      0.10
Birthweight 
    Low (<2500g)               20/240 (8%)        23/227 (10%)    0.53
    Very low (<1500)           10/240 (4%)        4/227 (2%)      0.18
Gestation at delivery 
    (weeks, mean [SD])         38.8 (3.6)         38.0 (5.0)      0.05
Birthweight
    (g, mean [SD])             3227 (668)         3239 (637)      0.84

 Excludes 14 miscarriages and deaths in utero.
 Includes 14 miscarriages and deaths in utero
Discussion
 First of its kind to assess the role of antibiotic treatment in
  reduction of risk of late miscarriage in women with
  abnormal vaginal flora

 Contradicts the findings of two previous RCT’s that failed
  to show a benefit from treatment with systemic
  metronidazole on preterm delivery

 Women with previous spontaneous preterm delivery or
  mid-trimester miscarriage had worse overall outcomes but
  also benefited from treatment
Limitations

 Data on the occurrence of preterm prelabor rupture of
  membranes was not systematically gathered

 Randomization did not perfectly balance the baseline
  history of previous miscarriage between groups

 Outcome data were not available for nine women who
  were lost after randomization
Interpretation

 Great internal validity
  • Randomized
  • Randomization concealed (double blind)
  • Intention to treat analysis
  • xcept for history of any previous miscarriage treatment
     and control similar with respect to baseline
     characteristics
  • Follow up complete
Interpretation
 Good external validity
  • Urban inner city population similar to ours
  • High concentration of Caucasian women

 Clinically important outcome was considered

 Relatively cheap form of treatment compared to the costs of
  miscarriage and preterm delivery

 Side effects were not significant making the treatment
  benefits worth the potential harm and costs
                              References
Ugwumadu, A, et al. Effect of early oral clindamycin on late miscarriage and
   preterm delivery in asymptomatic women with abnormal vaginal flora and
   bacterial vaginosis: a randomised control trial. Lancet 2003; 361:983-988.
Users’ guides to the medical literature: essentials of evidence-based clinical
   practice.

								
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