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doi:10.1111/jog.12102

J. Obstet. Gynaecol. Res. Vol. 39, No. 12: 15601568, December 2013

Optimal timing of prophylactic antibiotic for cesarean delivery: A randomized comparative study
Nabendu Bhattacharjee1, Shyama Prasad Saha2, Kajal Kumar Patra1, Udayan Mitra1 and Samir Chandra Ghoshroy2
1 Department of Obstetrics and Gynaecology, R.G. Kar Medical College, Kolkata, and 2Department of Obstetrics and Gynaecology, North Bengal Medical College, Darjeeling, West Bengal, India

Abstract
Aim: Cesarean delivery is associated with a signicantly higher postoperative infection rate than that following vaginal birth and other surgical procedures. This study compared whether antibiotic prophylaxis administered preoperatively was more effective in preventing infectious morbidity following cesarean delivery than administration at cord clamping. Material and Methods: In a randomized comparative trial, 953 women with a period of gestation of more than 34 weeks, scheduled to have cesarean section, were randomly assigned to the prophylactic single-dose antibiotic administration either preoperatively (study group) or at cord clamping (control group). Primary outcome measure was postoperative maternal infectious morbidity and secondary outcome measures were neonatal complications, and postoperative maternal hospital stay and stay of neonates in the neonatal intensive care unit. Results: Wound complications in the form of indurations, erythema and discharge, were signicantly fewer in the study group as compared to the control group (10/476 vs 25/477, P = 0.010, conditional maximum likelihood estimate of odds ratio = 0.388 and 95% condence interval = 0.1750.805). Women in the study group also had fewer incidents of endomyometritis when compared to the control group (1.47% vs 3.56%; P = 0.041; conditional maximum likelihood estimate of odds ratio = 0.404). There was no signicant difference in neonatal outcomes between the two groups. Mean postoperative stay of mothers in hospital was signicantly shorter in the study group (P = 0.009, 95% condence interval = -0.368 to -0.052) but neonatal intensive care unit stay of neonates was similar in both groups. Conclusion: Administration of prophylactic antibiotic at 3060 min before skin incision resulted in better maternal outcome when infectious morbidity and postoperative hospital stay were concerned, without inuencing the neonatal outcome. Key words: antibiotic prophylaxis, cesarean delivery, cord clamping, preoperative.

Introduction
Infectious complications following obstetric surgical procedures are a signicant source of maternal morbidity and potential mortality. The single most important risk factor for postpartum maternal infection is cesar-

ean delivery (CD).1,2 Compared with a vaginal birth, women undergoing cesarean delivery have a ve- to twentyfold greater risk for infection and infectious morbidity. Rising cesarean delivery rates are a global concern. Rates of cesarean section in many countries have

Received: July 29 2012. Accepted: February 12 2013. Reprint request to: Dr Nabendu Bhattacharjee, AD-289, Rabindrapally Krishnapur, PO Profullakanan, Kolkata-700101, West Bengal, India. Email: drnabendu@gmail.com; nuaab@indiatimes.com; drsps94@gmail.com

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increased beyond the World Health Organization (WHO) recommended level of 15%.3 A WHO survey of 122 facilities in nine Asian countries found that the overall rate of cesarean delivery was 27.3%.4 The WHO ofcially withdrew its previous recommendation of a 15% cesarean section rate in June 2010. Their ofcial statement read There is no empirical evidence for an optimum percentage. What matters most is that all women who need cesarean sections receive them.5 The US National Institutes of Health says that rises in rates of cesarean sections are not, in isolation, a cause for concern, but may reect changing reproductive patterns.6 The most important source of microorganisms responsible for post-cesarean section infection is the genital tract, particularly if the membranes are ruptured. Even in the presence of intact membranes, microbial invasion of the intrauterine cavity is common, especially with preterm labor.7 Infections are commonly polymicrobial (caused by many organisms). Wound infections caused by Staphylococcus aureus and coagulase negative staphylococci arise from contamination of the wound with the endogenous ora of the skin at the time of surgery.8 Much works have been done to study the effect of prophylactic antibiotics in reducing infectious morbidity. The purpose of antibiotic prophylaxis in surgical procedures is not to sterilize tissues but to reduce the colonization pressure of microorganisms introduced at the time of operation to a level that the patients immune system is able to overcome.9 Prophylaxis does not prevent infection caused by postoperative contamination. The agent must be administered in a way that ensures that serum and tissue levels are adequate before an incision is made and that therapeutic levels of the agent can be maintained in serum and tissues during surgery and for a few hours (at most) after the incision is closed.10 The majority of studies suggest that a single dose is effective, but for lengthy procedures (>3 h) the dose should be repeated at intervals 1 or 2 times of the half-life of the drug. It has also been suggested that with blood loss (>1500 mL), a second dose should be given.11 There has been debate about the benet of prophylactic antibiotics for a woman who has an elective cesarean section with intact membranes and without labor. A meta-analysis of four studies found that antibiotic prophylaxis resulted in a decrease in postoperative fever (relative risk [RR] 0.25; 95% condence interval [CI] 0.140.44) and endometritis (RR 0.05; 95%CI 0.010.38).12 Taken together, these data support

the recommendation to use prophylactic antibiotics for all women undergoing cesarean section. Cephalosporins are the most commonly used drugs for prophylaxis for their broad antibacterial spectrum.13 Antibiotic prophylaxis for cesarean delivery has traditionally been administered after clamping the umbilical cord due to apprehension of exposure of fetuses through placenta when given earlier.14,15 However, research in non-pregnant populations undergoing surgery and recent studies involving pregnant women have suggested that administration of antibiotics prior to incision (ideally 3060 min before, to allow for optimal concentration at the surgical site) may further reduce infection by about 50% compared to administration during surgery or after umbilical cord clamping.14,1619 Moreover, these studies have found no increase in adverse neonatal outcomes, including the need for sepsis workups and neonatal intensive care unit (NICU) admission.13,16,19 A review by the Cochrane Database found that there is an inconsistent and variable application of current recommendations in regard to appropriate timing, administration and choice of drug used for antibiotic prophylaxis at the time of cesarean delivery. From this perspective, a prospective, double-blinded, placebo-controlled, randomized clinical trial was performed to determine whether antibiotic prophylaxis administered preoperatively was more effective in preventing infectious morbidity following cesarean delivery than administration at cord clamping. The aim of the study was directed to: (i) assess the rates of maternal infectious morbidity following preoperative administration of antibiotics compared to antibiotic prophylaxis given at umbilical cord clamping; and (ii) weigh up the incidence of neonatal infectious morbidity (i.e. rates of sepsis workup, conrmed sepsis, and length of hospital stay) between the two procedures.

Methods
This was a prospective, double-blinded, placebocontrolled, randomized clinical trial. We conducted the study over a period of one and half years, from July 2010 to December 2011 simultaneously in two teaching institutions of West Bengal, India (R.G. Kar Medical College and Hospital, Kolkata and North Bengal Medical College and Hospital, Darjeeling). In total, 1060 pregnant women, who had more than 34 weeks of gestation, requiring cesarean sections for different indications were assessed for enrolment in

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the study. As premature delivery at or below 34 weeks is an independent risk factor for adverse perinatal outcome, women who underwent cesarean delivery at this stage were not considered for inclusion in the study. After going through exclusion criteria, a total of 953 women were ultimately included in the study. Exclusion criteria were: (i) patients with obstetric complications (such as pre-eclampsia and antepartum hemorrhage); (ii) patients with renal disease, heart disease, diabetes mellitus etc.; (iii) patients who are febrile during or prior to screening; (iv) patients who presented with ruptured membranes with or without antibiotic prophylaxis; (v) any exposure to antibiotic during past 1 week; (vi) obstetrical indication for emergency cesarean delivery during labor (e.g. obstructed labor, deep transverse arrest and severe fetal distress); and (vii) penicillin or cephalosporin allergy (all assessed women who did not give any history of penicillin allergy received a test dose of ceftriaxone before nal enrolment). There is no skin test that can reliably predict whether a patient will manifest an allergic reaction to cephalosporins.20 The correlation between the skin prick test responses and radioallergosorbent test (RAST) for allergen-specic serum IgE is fairly good21 but not 100%. RAST detects the serum level of IgE specic for a given antigen. The advantage of skin test is that it is relatively inexpensive and allows screening of a large number of allergens at one time. The disadvantage is that it sometimes sensitizes the allergic individuals to new allergens and in some rare cases may induce systemic anaphylactic shock. Sometime hypersensitivity may not be demonstrated by skin testing and ceftriaxone-specic IgE. Consequently life-threatening anaphylaxis may develop within minutes of the rst dose of intravenous injection of ceftriaxone. Failure of skin test to detect ceftriaxone-specic IgE and consequent untoward reaction has been observed.22 It is impractical to subject every individual to RAST before administration of a drug. Our institutional standard practice is to inject 100 mg ceftriaxone intravenously slowly over 10 min and wait for a further 30 min to recognize any immediate allergic reaction before giving the full dose of the drug, although the dose response correlation is usually not apparent for the provocation of allergic reactions. Such an intravenous test dose has become a standard practice in obstetrics in our state. In this study, all women who agreed to participate in the study and fullled the inclusion criteria but did not give any history of penicillin/

cephalosporin allergy received the test dose of ceftriaxone (100 mg) intravenously slowly over 10 min to recognize any immediate allergic reaction. This 100-mg test dose was in addition to the full prophylactic dose given later at the time of cesarean section. Those women who did not show any sign of hypersensitivity to the drug were subjected to randomization (n = 953). No further test dose was used before giving prophylactic antibiotic or placebo injection as per protocol. Decisions for emergency cesarean delivery were taken in some women after they went into labor but where maternal and fetal conditions were stable enough to delay the procedure for about 90120 min (e.g. cephalopelvic disproportion, malpresentation, intrauterine growth restriction with oligohydramnios, detected in early labor) and those women were included in the study. A total of 953 women with a gestation period of more than 34 weeks, scheduled to have cesarean section were included in the study. Patients were divided into two groups (A and B) using a computer-generated randomization protocol resulting in 476 women in group A (study group) and 477 women in group B (control group). After allocation, relevant history and patient particulars were recorded for each patient. In group A (study group) preoperative antibiotic (ceftriaxone 2 g intravenously) was administered to the mother 3060 min prior to skin incision and in group B (control group) the same antibiotic was administered at umbilical cord clamping. We used a computer-generated randomization sequence to assign participants into two treatment groups and the allocation was concealed in sealed, sequentially numbered, brown envelopes (opaque), which had been prepared by the statistician of each centre and handed over to the sister-in-charge of the operation theatre, Department of Obstetrics and Gynecology of the respective institutions. The researchers responsible for treating the pregnant women allocated the next available number on entry into the trial in the Department of Obstetrics and Gynecology and the operating surgeons collected the corresponding sealed envelope directly from the operation theatre sister-incharge. The envelope was opened just before performing caesarean section and the drug therapy was selected as per code. To make the study double-blinded the drugs were supplied in small sealed bags containing vial A (2 g ceftriaxone mixed with 10 mL water for injection, antibiotic was dissolved just before administration by an independent third person who ultimately

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did not participate in nal outcome) and Vial B (10 mL water for injection as placebo). Both vials were identical. Registration numbers of the patients were mentioned on the bag. While preparing the women for cesarean section, the on-duty resident doctor opened the supplied sealed bag and either vial A or vial B medicine was administered intravenously and slowly according to randomization. The exact time was recorded and the skin incision was made at least 30 min after the injection (not later than 60 min). Similarly vial B or vial A was administered at the time of cord clamping by the anesthetic staff in the same manner. Providers and patients were blinded to the contents of the bags. Cesarean sections were performed by resident medical ofcers and generally spinal anesthesia was given. The standard technique of cesarean section was modied by the Joel Cohen method for skin incision, two-layer closure of uterine lower segment and non-stitching of peritoneum. Postoperative follow-up was done by resident doctors who were blinded to the patients and babies identity. Infection morbidity, such as endometritis, was diagnosed if there was maternal fever greater than 38C on two separate occasions along with uterine fundal tenderness, tachycardia, or leukocytosis. Wound infection was diagnosed if there was purulent discharge, erythema, and indurations of the incision site. Hematoma, seromas, or wound breakdowns in the absence of previously discussed signs were not considered wound infections. Neonatal sepsis was diagnosed by clinical examination, blood picture, C-reactive protein estimation and positive blood culture as appropriate. Length of NICU stay, admission status and decision to undertake a sepsis workup were determined by the staff neonatologist who was blinded to group assignment. Primary outcome measure was postoperative maternal infectious morbidity and secondary outcome measures were neonatal complications, and postoperative hospital stay of mother and stay of neonates at NICU. From the hospital records of our institutions, we observed that the average incidence of post-cesarean infectious morbidity in mothers was 5.8% during the last 5 years when antibiotics were used only after clamping of umbilical cord. An incidence of 2% in mothers receiving pre-incision antibiotics was used to calculate the sample size having a power of 80 setting alpha error at 0.05. The minimum sample size thus calculated was 404 in each arm for power based on normal approximation and 455 in each arm for power based on normal approximation with continuity cor-

rection (Fleiss, Statistical Methods for Rates and Proportions, formulas 3.18 and 3.19). All data entries were visually double-checked by an independent second investigator. The data were analyzed using Open Source Epidemiologic Statistics for Public Health (Open Epi, version 2.3.1; updated on 2011/23/06) to compare the outcomes between the study group and the control group. A P-value less than 0.05 was considered statistically signicant. Statistical methods included the two samples independent t-tests, mid-p exact tests, maximum likelihood odds ratio estimate with condence limits produced by several methods. The study was approved by the Committee for Ethical Consideration and Approval for Human Research, R. G. Kar Medical College and Hospital, and the Medical Ethical Committee for Human Research, North Bengal Medical College and Hospital as required by Indian law. Before enrolments for the study entry, all women provided a written informed consent meeting all local institutional requirements.

Results
Initially 1060 women were assessed for eligibility criteria to include in this study; however, 107 women were excluded from the study due to either not meeting the inclusion criteria (n = 76) or refusal to participate (n = 31). In total, 953 women were thus randomized into two groups (A and B) resulting in 476 patients in the study group (group A) and 477 mothers in control group (group B). Prophylactic antibiotic was injected 3060 min before skin incision in group A and at cord clamping in group B. Subsequently, 18 women from group A and 21 from group B were lost to followup. Hence, 458 women in group A and 456 in group B completed the study. But all women in both groups who received allocation intervention were analyzed as we adopted the intention-to-treat protocol (Fig. 1). Demographic proles of the patients in both groups were comparable in relation to age, parity, gestational age and indication for cesarean sections (Table 1). From Table 2 it is evident that wound complications in the form of indurations, erythema and discharge were signicantly less in the study group as compared to the control group (10/476 vs 25/477, P = 0.010, conditional maximum likelihood estimate of odds ratio (CMLE OR) = 0.388 and 95%CI = 0.1750.805). Women in the study group also had fewer incidents of endomyometritis when compared to the control group (1.47% vs 3.56%; P = 0.041; CMLE OR = 0.404). None of the cases

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Assessed for eligibility (n = 1060)

Excluded (n = 107)

Enrollment

Not meeting inclusion criteria (n = 76) Refused to participate (n = 31)

Randomized (n = 953)

Allocated to prophylactic antibiotic administration before skin-incision group (n = 476) Received allocated intervention (n = 476) Did not receive allocated intervention (n = 0)

Allocated to prophylactic antibiotic administration at cord-clamping group (n = 477) Received allocated intervention (n = 477) Did not receive allocated intervention (n = 0)

Follow-up

Allocation

Lost to follow-up (n = 18)

Lost to follow-up (n = 21)

Mothers completed the study (n = 458)

Analyzed (n = 476) Excluded from analysis (n = 0)

Mothers completed the study (n = 456)

Analyzed (n = 477) Excluded from analysis (n = 0)

Figure 1 Patients ow through chart.

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Analysis

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Table 1 Demographic prole Characteristics Age in years (mean SD) BMI Gestational age in weeks (mean SD) Socioeconomic status APL BPL Indication for CS Emergency Elective Study group (n = 476) 23.08 3.48 24.19 2.61 38.60 1.55 183 (38.44%) 293 (61.46%) 107 (22.48%) 369 (77.52%) Control group (n = 477) 23.24 4.69 24.07 2.72 38.44 1.61 196 (41.09%) 281 (58.91%) 112 (23.48%) 365 (76.52%) P-value (95%CI) 0.550* (-0.685 to 0.365) 0.487* (-0.219 to 0.459) 0.118* (-0.041 to 0.361) 0.405** (-8.86% to 3.57%) 0.357** (-6.342% to 4.34%)

*P-value (two-tailed). **Mid-P exact. APL, above poverty line; BMI, body mass index; BPL, below poverty line (according to Indian standard); CI, condence interval; CS, cesarean section; SD, standard deviation.

Table 2 Post-cesarean infectious morbidity of mother Outcome Operative time Fever (2nd day onwards) Wound complications (indurations, erythema, discharge) Wound dehiscence Endomyometritis Study group (n = 476) 39.64 4.09 26 (5.46%) 10 (2.10%) 2 (0.42%) 7 (1.47%) Control group (n = 477) 40.05 3.96 33 (6.92%) 25 (5.24%) 5 (1.05%) 17 (3.56%) P-value (95%CI) 0.116* (-0.922 to 0.102) 0.355** (-5.519% to -0.761%) 0.010** (-1.711% to 0.455%) 0.288** (-4.077% to -0.109%) 0.041** (-4.077% to -0.109%) CMLE OR (95%CI)

0.778 (0.4531.323) 0.388 (0.1760.805) 0.398 (0.0532.032) 0.404 (0.1550.966)

*P-value (two-tailed). **Mid-P exact. CI, condence interval; CMLE OR, conditional maximum likelihood estimate of odds ratio.

Table 3 Neonatal morbidity Variable Sepsis Fever Poor feeding Perinatal asphyxia NICU admission Study group (n = 476) 15 8 9 5 39 (3.152%) (1.68%) (1.89%) (1.05%) (8.19%) Control group (n = 477) 19 12 12 6 42 (3.98%) (2.51%) (2.51%) (1.26%) (8.59%) P-value* (95%CI) 0.495 0.381 0.522 0.775 0.737 (-3.186% (-2.654% (-2.488% (-1.563% (-4.152% to to to to to 1.522%) 0.983%) 1.238%) 1.149%) 2.929%) CMLE OR (95%CI) 0.784 0.663 0.747 0.833 0.924 (0.386 to 1.570) (0.256 to 1.645) (0.30 to 1.807) (0.233 to 2.877) (0.584 to 1.461)

*Mid-P exact. CI, condence interval; CMLE OR, conditional maximum likelihood estimate of odds ratio; NICU, neonatal intensive care unit.

in both groups required lengthy procedures (>3 h). Mean operative times (standard deviation) were 39.64 (4.09) min and 40.05 (3.96) min in groups A and B, respectively. There was no signicant difference in neonatal outcomes between the two groups (Table 3). Mean postoperative stay of mothers in hospital was signicantly less in the study group (P = 0.009, 95%CI = -0.368 to -0.052) but NICU stay of neonates were similar in both groups (Table 4).

Discussion
Cesarean delivery is associated with a signicantly higher postoperative infection rate than that following

vaginal birth and other surgical procedures. With the increase in CD rates worldwide, such post-CD infections are likely to become a signicant health and economic burden. There is overwhelming evidence that antibiotic prophylaxis for CD is effective in preventing maternal infectious morbidity. These benets are true for both elective (scheduled) and non-elective (emergency or laboring) CD.23 Antibiotic prophylaxis for elective CD is also cost-effective.24,25 A single dose of antibiotics is as effective as multipledose regimens.23 The agent of choice for surgical prophylaxis should be long-acting, inexpensive and have a low incidence of side-effects.26 Most obstetricians use a single agent,

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Table 4 Postoperative hospital stay of mother & NICU stay of baby Study group (n = 476) Maternal stay in days (mean SD) NICU stay in days (mean SD) 4.36 1.15 5.65 3.61 Control group (n = 477) 4.57 1.33 5.77 3.86 P-value (two-tailed) 0.009 0.620 95%CI of difference -0.368 to -0.052 -0.595 to 0.355

CI, condence interval; NICU, neonatal intensive care unit.

commonly a cephalosporin, as the antibiotic of choice for prophylaxis. Various previous studies2733 already established ceftriaxone as an effective antibiotic for prophylaxis against postoperative infectious morbidities following cesarean section. The ceftriaxone concentrations in serum present at 24 h exceed the minimal bactericidal concentrations for common bacterial species.31 There is a lack of consensus regarding the timing of such prophylaxis in cesarean deliveries. The usual obstetric practice so far has been to give prophylactic antibiotics at cord clamping to avoid the unnecessary fetal exposure. Some have noticed a shift in early neonatal sepsis from group B streptococci to Escherichia coli and other Gram-negative organisms, with even change in the resistance patterns of these organisms.26,33,34 Moore et al.35 and Daley et al.36 explored potential associations between intra-partum antimicrobial prophylaxis use and changes in the causes of early onset sepsis and concluded that antibiotic prophylaxis declined the incidence of early onset infection due to group B streptococci. Daley et al. observed that there was also a trend to decreasing early onset E. Coli sepsis in all babies. In this study we had evaluated the effectiveness of prophylactic antibiotics when given preoperatively as compared to intraoperative administration of the same at cord clamping and whether the benets if any were at the cost of increasing neonatal morbidities. We had used a single dose of 2-g intravenous ceftriaxone as prophylaxis in our study. Maximum plasma concentration following intravenous infusion of ceftriaxone is achieved after 30 min of infusion. In a study by Patel et al.37 on Pharmacokinetics of Ceftriaxone in Humans using three different dose regimens, the authors showed that mean plasma concentrations observed at the end of the 30-min infusion were 82, 151, and 257 ug/mL after 0.5-, 1-, and 2-g doses, respectively. The plasma concentration-time curves of ceftriaxone in the post-infusion phase were biphasic, with a relatively short distribution phase (overall mean distribution half-life, 0.17 h) followed by a slow elimination phase (overall mean elimination half-life, 6.1 h). They had

also shown that ceftriaxone exhibited a relatively long elimination half-life and a relatively small volume of distribution (9.1 L) and plasma clearance (17.4 mL/min). In our study, although additional 100-mg intravenous test dose had been used to detect a hypersensitive reaction (used in both groups) and timings of which were variable in respect to timing of caesarean section (minimum time interval was 90 min), the tissue concentration achieved due to such a small dose was of little clinical signicance and was unlikely to affect the outcomes. In two double-blind placebo-controlled trials by Wax et al.38 and Thigpen et al.,39 the authors had observed that there was no difference in maternal infectious morbidity whether antibiotics were given before skin incision or at cord clamping. But in our present study, postoperative maternal infectious morbidities, such as incidence of wound infections and endomyometritis, were more in the control group (at cord clamping administration group) as compared to the study group (preoperative administration group) and this was statistically signicant. The studies done by Wax et al. and Thigpen et al. were on laboring women only and sample sizes were also small. But the majority of the women in our study underwent elective cesarean delivery before going into labor and the study was conducted using a larger sample size. These might be the probable reasons for difference in outcomes in our study when compared to those of the abovementioned studies. Our results were similar to the ndings observed by Sulivan et al.16 in their prospective, randomized, double-blind, placebocontrolled trial using prophylactic cefazolin prior to skin incision. They also observed that this dosing did not result in increased neonatal septic workups or complications which were similar to our observations. Bromberger et al.40 demonstrated that exposure to antibiotics during labor did not change the clinical spectrum of disease or the onset of clinical signs of infection within 24 h of birth for term infants with group B Streptococcus (GBS) infection and concluded that 48 h stay is not required to monitor asymptomatic

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term infants exposed to intrapartum antibiotics for onset of GBS infection. Smaill and Hofmeyr, in a Cochrane review in 2002, observed that hospital stay was reduced in patients who received prophylactic antibiotics by 0.47 days (95%CI 0.880.19) compared to patients without such prophylaxis.27 In our study, mean postoperative hospital stay of women in the pre-incision antibiotic group was signicantly less when compared to that of women who received antibiotic at cord clamping (P = 0.009, 95%CI = -0.368 to -0.052). But NICU stay of neonates did not vary with the timing of maternal antibiotic administration. In our study we could analyze a reasonably large sample size for assessment of fetomaternal outcome according to timing of prophylactic antibiotic administrations. In this study there was not a single case of discontinued intervention after randomization because of the nature of selection. Intention-to-treat principle was adopted for analyzing the results. The weakness of this study was that we could not compare the pharmacokinetics of antibiotics in individual patients. Non-estimation of blood loss during surgery (and in the immediate postoperative period) is another weakness of the study though signicant hemorrhage requiring blood transfusion was nil in both groups. Administration of prophylactic antibiotic at 3060 min before skin incision resulted in better maternal outcome when infectious morbidity and postoperative hospital stay were concerned, without inuencing the neonatal outcome. This is likely to be cost-effective also, considering the fact that incidence of cesarean section has progressively increased over the last 2 decades.

References
1. Declercq E, Barger M, Cabral HJ et al. Maternal outcomes associated with planned primary cesarean births compared with planned vaginal births. Obstet Gynecol 2007; 109: 669 677. 2. Gibbs RS. Clinical risk factors for puerperal infection. Obstet Gynecol 1980; 55: 178S183S. 3. World Health Organization. Appropriate technology for birth. Lancet 1985; 2: 436437. 4. Lumbiganon P, Laopaiboon M, Glmezoglu AM et al. Method of delivery and pregnancy outcomes in Asia: The WHO global survey on maternal and perinatal health 2007 08. Lancet 2010; 375: 490499. 5. Roxby P. Should there be a limit on Caesareans?. 2010. [Cited 11 March 2013.] Available from URL: http://www. bbc.co.uk/news/10448034 6. National Institutes of Health state-of-the-science conference statement: Cesarean delivery on maternal request March 2729, 2006. Obstet Gynecol 2006; 107: 13861397. 7. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult amniotic uid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 1992; 79: 351357. 8. Emmons SL, Krohn M, Jackson M, Eschenbach DA. Development of wound infections among women undergoing cesarean section. Obstet Gynecol 1988; 72: 559564. 9. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999; 27: 97134. 10. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992; 326: 281286. 11. van Schalkwyk J, Vancouver BC, Van Eyk N, Halifax NS. Quality standard for antimicrobial prophylaxis in surgical procedures. Infectious Diseases Society of America. Clin Infect Dis 1994; 18: 422427. 12. Chelmow D, Ruehli MS, Huang E. Prophylactic use of antibiotics for non laboring patients undergoing cesarean delivery with intact membranes: A meta-analysis. Am J Obstet Gynecol 2001; 184: 656661. 13. Kaiser AB. Overview of cephalosporin prophylaxis. Am J Surg 1988; 155 (5A): 5255. 14. Tita AT, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: A systematic review. Obstet Gynecol 2009; 113: 675682. 15. Hopkins L, Smail F. Antibiotic prophylaxis regimes and drugs for cesarean section. Cochrane Database Syst Rev 2000; (2): CD001136. 16. Sullivan SA, Smith T, Chang E, Hulsey T, Vandorsten JP, Soper D. Administration of cefazolin prior to skin incision is superior to cefazolin at cord clamping in preventing postcesarean infectious morbidity: A randomized, controlled trial. Am J Obstet Gynecol 2007; 196: 455.e1455.e5. 17. Kaimal AJ, Zlatnik MG, Cheng YW et al. Effect of a change in policy regarding the timing of prophylactic antibiotics on the

Acknowledgments
We would like to acknowledge the contribution of the staff of the Pharmacy Departments of R. G. Kar Medical College and North Bengal Medical College, West Bengal, India, who have been of immense help in conduction of the present study.

Disclosure
The authors have no commercial or other conicts of interest, that is, nancial or otherwise. The authors have no commercial afliations to disclose.

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18.

19.

20.

21. 22.

23.

24.

25.

26.

27. 28.

29.

rate of postcesarean delivery surgical-site infections. Am J Obstet Gynecol 2008; 199: 310.e1310.e5. Owens SM, Brozanski BS, Meyn LA, Wiesenfeld HC. Antimicrobial prophylaxis for cesarean delivery before skin incision. Obstet Gynecol 2009; 114: 573579. Costantine MM, Rahman M, Ghulmiyah L et al. Timing of perioperative antibiotics for cesarean delivery: A metaanalysis. Am J Obstet Gynecol 2008; 199: 301.e1301.e6. Novalbos A, Sastre J, Cuesta J et al. Lack of allergic crossreactivity to cephalosporin among patients allergic to penicillins. Clin Exp Allergy 2001; 31: 438443. Roitt IM. Essential Immunology, 6th edn. London: ELBS, 1988; 197. Ernst MR, Van Dijken PJ, Kabel PJ, Draaisma JM. Anaphylaxis after rst exposure to ceftriaxone. Acta Paediatr 2002; 91: 355356. Smaill FM, Gyte GM. Antibiotic prophylaxis versus no prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev 2010; (1): CD007482. Ehrenkranz NJ, Blackwelder WC, Pfaff SJ, Poppe D, Yerg DE, Kaslow RA. Infections complicating low-risk cesarean sections in community hospitals: Efcacy of antimicrobial prophylaxis. AmJ Obstet Gynecol 1990; 162: 337343. Chelmow D, Hennesy M, Evantash EG. Prophylactic antibiotics for d non-laboring patients with intact membranes undergoing cesarean delivery: An economic analysis. Am J Obstet Gynecol 2004; 191: 16611665. American College of Obstetricians and Gynecologists. ACOG practice bulletin number 47, October 2003. Prophylactic antibiotics in labor and delivery. Obstet Gynecol 2003; 102: 875 882. Smail F, Hofmeyr GJ. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev 2002; (3): CD000933. Alekwe LO, Kuti O, Orji EO, Ogunniyi SO. Comparison of ceftriaxone versus triple drug regimen in the prevention of cesarean section infectious morbidities. J Matern Fetal Neonatal Med 2008; 21: 638642. Ahmed ET, Mirghani OA, Gerais AS, Adam I. Ceftriaxone versus ampicillin/cloxacillin as antibiotic prophylaxis in elective caesarean section. East Mediterr Health J 2004; 10: 277288.

30. Adam I, Adam ES, Gerais AS. Randomized trial of ceftriaxone prophylaxis in elective cesarean section. Saudi Med J 2005; 26: 500501. 31. Scully BE, Fu KP, Neu HC. Pharmacokinetics of ceftriaxone after intravenous infusion and intramuscular injection. Am J Med 1984; 77: 112116. 32. Chalkiadakis EG, Gonianakis C, Tsatsakis A, Tsakalof A, Michalodimitrakis M. Preincisional single-dose ceftriaxone for the prophylaxis of surgical wound infection. Am J Surg 1995; 170: 353355. 33. Schuchat A, Zywicki SS, Dinsmoor MJ et al. Risk factors and opportunities for prevention of early-onset neonatal sepsis: A multicenter case control study. Pediatrics 2000; 105: 21 26. 34. Terrone DA, Rinehart BK, Einstein MH, Britt LB, Martin JN Jr, Perry KG. Neonatal sepsis and death caused by resistant Escherichia coli: Possible consequences of extended maternal ampicillin administration. Am J Obstet Gynecol 1999; 180: 13451348. 35. Moore MR, Schrag SJ, Schuchat A. Effects of intrapartum antimicrobial prophylaxis for prevention of group B streptococcal disease on the incidence and ecology of early-onset neonatal sepsis. Lancet Infect Dis 2003; 3: 201213. 36. Daley AJ, Isaacs D. Ten years study on the effect of intrapartum antibiotic prophylaxis on early onset group B streptococcal and Escherichia coli neonatal sepsis in Australasia. Pediatr Infect Dis J 2004; 23: 630634. 37. Patel IH, Chen S, Parsonnet M et al. Pharmacokinetics of ceftriaxone in humans. Antimicrob Agents Chemother 1981; 20: 634641. 38. Wax JR, Hersey K, Philput C et al. Single dose cefazolin prophylaxis for postcesarean infections: Before vs. after cord clamping. J Matern Fetal Med 1997; 6: 6165. 39. Thigpen BD, Hood WA, Chauhan S et al. Timing of prophylactic antibiotic administration in the uninfected laboring gravida: A randomized clinical trial. Am J Obstet Gynecol 2005; 192: 18641868. 40. Bromberger P, Lawrence JM, Braun D, Saunders B, Contreras R, Petitti DB. The inuence of intrapartum antibiotics on the clinical spectrum of early onset group B streptococcal infection in term infants. Pediatrics 2000; 106 (2 Pt 1): 244250.

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