receiving epidural. As women with epidural analgesia had longer labors, it would be expected that they would have, on average, more vaginal examinations than women who did not receive epidural analgesia. However, when the number of vaginal exam-inations is added to the logistic regression model, epidural use remains strongly associated with intrapartum fever, sepsis evalu-ation, and antibiotic use. The most plausible mechanism by which an increased number of vaginal examinations would cause fever would be an increase in infections. As noted in our article, it is difficult during labor to determine whether intrapartum fever is of infectious origin because traditional markers are not useful. Al-though there was no evidence of an increase in sepsis among the neonates of women receiving epidural, our study cannot abso-lutely rule out the possibility that women receiving epidural did develop more infections during labor (perhaps related to their longer labors) and that an increase in neonatal sepsis was averted by treatment of the mother with antibiotics during labor.
Gambling et al suggest that opiod analgesics may also impair thermoregulation. We found no evidence for this in our data. Women receiving opiod analgesics had the same risk of fever as women not receiving such analgesics in both the epidural and no-epidural groups. They also suggest that our findings could some-how be related to diurnal variation in temperature. To evaluate these factors, we performed a logistic regression controlling for time of admission and the use of opiod analgesia (in addition to factors controlled in the original model). The adjusted odds ratio for the association of epidural with fever, sepsis evaluation, and antibiotic use were essentially unchanged from those we reported. The question of the role of environmental temperature was also raised (Dolak and Brown, Gambling et al). Given the prospective studies in the anesthesia literature demonstrating a rise in tem-perature with epidural administration, we do not believe that differences in environmental temperature caused the epidural-related temperature increase we observed. One of those prospec-tive studies5was conducted at the same institution as the current study and describes the environmental conditions in labor and delivery as follows:
“All labor rooms at Brigham and Women’s Hospital are be-low ground without windows or direct exposure to the ex-ternal environment. A partially recirculating ventilation and air conditioning system supplies approximately 8 fresh air exchanges and 30 total air exchanges per hour. Ambient room temperature is maintained at 20°C to 22°C.”
The other factors noted to be unstudied in our report, the use of fans and tepid sponging (Gambling et al), are not potential causes of the temperature increase but rather approaches to limiting the temperature rise. As noted in our article, we also believe that it would be useful to study these approaches as means of limiting epidural-related temperature elevations.
The alternative explanations for our findings raised by the correspondents allude to the issue more directly raised by Tarshis et al, ie, is it likely that the fevers we observed can be fairly attributed to the use of epidural analgesia? As noted above, a number of prospective studies have documented an increase in maternal temperature with epidural use1,2,5and in our study the association remained stable even after controlling for multiple confounding factors. We know of no other factor that could be responsible for the magnitude of the association we reported. We therefore believe that the association of epidural with fever we observed is most likely causal. As neither this study nor others in the literature to date support an increase in infection, we postulate that the most likely explanation is thermoregulatory changes ac-companying epidural use.
The correspondents also reiterate that a large number of sepsis evaluations were performed in the infants of women whose tem-perature did not exceed 100.4°F (Tarshis et al, Lewis and Con-nelly). In the article, we discussed possible reasons for the in-creased rate of sepsis evaluation in that group. As we noted, it is likely that these women had other factors (such as a fever not reaching 100.4°F and long rupture of membranes) that met the objective criteria used by neonatologists at our institution to de-termine which infants are evaluated for sepsis. As stated in the article, more detailed analyses were not presented as we did not have specific temperature information available at that time. How-ever, as we have since re-reviewed all of the medical records of study women who had the spontaneous onset of labor, we will be able to analyze more precisely the reasons for that increase in evaluations.
The potential benefits of epidural use were raised. Dolak and Brown note the potential increase in noninfectious morbidity in the no-epidural group, specifically neonatal depression secondary to the use of opioid analgesics. In our study population, naloxone use was rare (only one infant in the epidural group). Overall, 4.8% of infants whose mothers had an epidural compared with 2.8% of infants of mothers without an epidural required bag and mask or more serious resuscitation measures.
We agree that the criteria for neonatal sepsis workup should be re-evaluated, a suggestion we made in the article. We also agree that epidural analgesia is the most effective means of pain relief currently available and that women should be free to choose epidural analgesia for pain relief during labor. We also believe, however, that women should be fully informed about the risks and benefits of epidural analgesia before making their decision. The informed consent should include information about the asso-ciation of epidural use with rise in maternal temperature (which has been amply demonstrated in the anesthesia literature) as well as information related to the possible need for general anesthesia in the event of an emergent delivery (noted by Tarshis et al to be an additional advantage of epidural use). Although in our popu-lation general anesthesia was used somewhat less often in the presence of an epidural, its use was rare with or without an epidural in place (1.5% without epidural, 0.4% with epidural; rate difference51.1%).
We believe that women should be free to choose epidural analgesia for pain relief during labor. Because epidural is an elective procedure, the decision about its use will differ for indi-vidual women. Only when women are fully informed about the procedure can they intelligently weigh the potential risks and benefits to make the decision that is right for them.
Ellice Lieberman, MD, DrPH Janet Lang, PhD, ScD Fredric Frigoletto, MD
Douglas Richardson, MD, MBA Steven A. Ringer, MD, PhD Amy Cohen, BA
Brigham and Women’s Hospital
Department of Obstetrics and Gynecology Boston, MA 02115
REFERENCES
1. Fusi L, Maresh MJA, Steer PJ, Beard RW. Maternal pyrexia associated with the use of epidural analgesia in labour.Lancet.1989;i:1250 –1252 2. Vinson DC, Thomas R, Kiser T. Association between epidural analgesia
during labor and fever.J Fam Pract.1993;36:617– 622
3. Lieberman E, Lang JM, Cohen A, D’Agostino R, Frigoletto FD. Associ-ation of epidural analgesia with cesarean section in nulliparous women.
Obstet Gynecol.1996;88:993–1000
4. Thorp JA, Hu DH, Albin RM, et al. The effect of intrapartum epidural analgesia on nulliparous labor: a randomized controlled prospective trial.Am J Obstet Gynecol.1993;169:851– 858
5. Camann WR, Hortvet LA, Hughes N, Bader AM, Datta S. Maternal temperature regulation during extradural analgesia for labour. Br J Anaesth.1991;67:565–568
The Neonatal Group B Streptococcal Debate
To the Editor.—
We are indebted to Drs Gotoff and Boyer1for their insights regarding prevention of early-onset neonatal group B streptococ-cal (GBS EOD) infection. In their commentary, they make three points that merit emphasis and comment. First, the strategy re-cently recommended by the Centers for Disease Control and Pre-vention (CDC)2may not be the most efficient or cost-effective way of dealing with this problem, and “there is no current agreement on the approach to chemoprophylaxis of GBS EOD.” It should be clear that the CDC recommendations, even with endorsements by the American College of Obstetricians and Gynecologists (ACOG)3and the American Academy of Pediatrics (AAP)4do not establish a national standard of care for management of this problem. Second, there is a danger that failure to explicitly include chorioamnionitis as an indication for treatment in the CDC’s “screening-based approach” could result in failure to treat women
with chorioamnionitis, because the recommendations indicate that “no intrapartum prophylaxis [is] needed” for febrile women with negative antepartum screening cultures. As Gotoff and Boyer have stated, chorioamnionitis should indeed be “an unquestioned indi-cation for antibiotic treatment.” Third, they present a cogent ar-gument for use of ampicillin rather than penicillin for prophylaxis in labor, and suggest that either agent might be appropriate for prophylaxis of healthy GBS-exposed newborns. Because new-borns born to women with prolonged rupture of membranes or intrapartum fever are at increased risk for infection with Gram-negative enteric organisms as well as GBS, ampicillin would also be more appropriate for prophylaxis of sepsis in these infants. Infants born to women with frank chorioamnionitis, like their mothers, deserve treatment (rather than just prophylaxis) with broad-spectrum antibiotics.
Neither Gotoff and Boyer nor Mohle-Boetani et al,5 whose analysis provided the basis for estimates of efficacy and cost, provide sufficient details to permit replication of their calcula-tions. However, Mohle-Boetani et al assumed that all cases of early-onset GBS disease are prevented in infants born to women who receive intrapartum prophylaxis, and Gotoff and Boyer as-sume that postpartum prophylaxis reduces the attack rate by 80%. These are probably overestimates of efficacy. Although postpar-tum prophylaxis reduced the attack rate by nearly 80% in the clinical trial reported by Siegel et al,6it was less effective (68% reduction in attack rate) in their subsequent experience with nearly 200 000 infants born at Parkland Hospital.7 Intrapartum prophylaxis alone reduces the attack rate by 80%,8 –12and com-bined use of intrapartum and postpartum prophylaxis, as de-scribed by Boyer and Gotoff13and by Garland and Fleigner,14 reduces the attack rate by nearly 95%. In addition, the sensitivity of screening rectovaginal cultures at 35 to 37 weeks gestation for colonization status at delivery is only about 90%, not 100% as assumed for Gotoff and Boyer’s analysis, and about 10% of women deliver before such screening. Taking these factors into account, the strategy proposed by Gotoff and Boyer would require treatment of approximately 480 000 women and 800 000 neonates in the United States each year, but would prevent only 75% of the expected early-onset GBS cases. The “screening-based approach” of the CDC would be equally effective but would require treat-ment of 1.2 million women and is therefore substantially more costly, as indicated by their analysis. The AAP and ACOG strat-egies are substantially less effective.
More importantly, however, we should not disregard the most serious shortcoming of postpartum penicillin prophylaxis: a sig-nificant increase in mortality attributable to bacterial infection in prophylaxis recipients. In the data reported by Siegel and Cush-ion,7the odds ratios for mortality due to bacterial infection were 1.5 for the clinical trial cohorts and 1.4 in subsequent deliveries. The 95% confidence interval for the pooled odds ratio (Mantel-Haenszel method) is 0.99 to 2.0, which excludes the 2.5% proba-bility that the true odds ratio is greater than the upper confidence limit. There is a 97% probability that the odds ratio exceeds 1. Surely this provides sufficient reason to conclude that postpartum penicillin prophylaxis is best avoided. It is not clear whether this risk could be eliminated if postpartum ampicillin prophylaxis were used instead, nor is it certain that other approaches are superior, because reports of trials of other preventive interven-tions have not included mortality statistics nor have sample sizes been sufficient to detect such effects. In any case, exposure of 800 000 infants a year to this hazard cannot be justified.
Gotoff and Boyer call for “prospective monitoring of GBS EOD, late-onset GBS infections, and antibiotic resistance” as new strat-egies for prevention of early-onset GBS disease are implemented.1 The Parkland experience should teach us that solving part of the problem (GBS EOD) may not improve more global results (neo-natal mortality), and that data from a large numbers of deliveries may be required to demonstrate such failures. Because the pur-pose of these interventions is to have more healthy, surviving neonates, we must also comprehensively monitor the overall mor-tality rate and that attributable to all bacterial infections so that we can ascertain, at least in retrospect, whether this has been achieved.
William E. Benitz, MD
Division of Neonatal and Developmental Medicine Stanford University School of Medicine
Palo Alto, CA 94304
REFERENCES
1. Gotoff S, Boyer K. Prevention of early-onset group B streptococcal disease.Pediatrics.1997;99:866 – 869
2. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR.
1996;45(No. RR-7):1–24
3. Committee on Obstetric Practice. Prevention of early-onset group B streptococcal disease in newborns.ACOG Committee Opinion.1996;173: 1– 8
4. American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised guidelines for preven-tion of early-onset group B streptococcal (GBS) infecpreven-tion. Pediatrics.
1997;99:489 – 496
5. Mohle-Boetani JC, Schuchat A, Plikaytis BD, Smith JD, Broome CV. Comparison of prevention strategies for neonatal group B streptococcal infection. A population-based economic analysis. JAMA. 1993;270: 1442–1448
6. Siegel JD, McCracken GH Jr, Threlkeld N, DePasse BM, Rosenfeld CR. Single-dose penicillin prophylaxis of neonatal group-B-streptococcal disease.Lancet.1982;1:1426 –1430
7. Siegel JD, Cushion NB. Prevention of early-onset group B streptococcal disease: another look at single-dose penicillin at birth.Obstet Gynecol.
1996;87:692– 698
8. Allardice JG, Baskett TF, Seshia MM, Bowman N, Malazdrewicz R. Perinatal group B streptococcal colonization and infection.Am J Obstet Gynecol.1982;142:617– 620
9. Morales WJ, Lim DV, Walsh AF. Prevention of neonatal group B strep-tococcal sepsis by the use of a rapid screening test and selective intra-partum chemoprophylaxis.Am J Obstet Gynecol.1986;155:979 –983 10. Tuppurainen N, Hallman M. Prevention of neonatal group B
strepto-coccal disease: intrapartum detection and chemoprophylaxis of heavily colonized parturients.Obstet Gynecol.1989;73:583–587
11. Matorras R, Garcia-Perea A, Omenaca F, Diez-Enciso M, Madero R, Usandizaga JA. Intrapartum chemoprophylaxis of early-onset group B streptococcal disease.Eur J Obstet Gynecol Reprod Biol.1991;40:57– 62 12. Pylipow M, Gaddis M, Kinney JS. Selective intrapartum prophylaxis for
group B streptococcus colonization: management and outcome of new-borns.Pediatrics.1994;93:631– 635
13. Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B strep-tococcal disease with selective intrapartum chemoprophylaxis.N Engl J Med.1986;314:1665–1669
14. Garland S, Fliegner J. Group B streptococcus (GBS) and neonatal infections: the case for intrapartum chemoprophylaxis.Aust N Z J Obstet Gynaecol.1991;31:119 –122
In Reply.—
Dr Benitz agrees with our commentary1on the lack of a national consensus on the prevention of GBS EOD, the management of chorioamnionitis, and the use of ampicillin for selective intrapar-tum chemoprophylaxis (SIC). However, he questions our analysis of efficacy and raises a concern about the risk of penicillin-resis-tant bacterial infections in newborns receiving penicillin prophy-laxis (NC). We may differ with regard to actual costs, but Mohle-Boetani et al2 provide sufficient details on costs to compare strategies. With regard to efficacy, there are published data on NC, combined SIC-NC, and SIC.
The only controlled study of NC reported a reduction in the attack rate of 82%.3The subsequent experience at Parkland was with the sequential use of NC for 5 years followed by no prophy-laxis for 8 years.4 These two periods are not comparable. An increase in the attack rate of neonatal invasive bacterial disease from 1986 –1994, the “no prophylaxis” period, might be attribut-able to no prophylaxis, an increase in the number of very low birth weight/high-risk infants, more invasive procedures, etc. How-ever, the authors didnotreport an increase in neonatal mortality during the periods of penicillin prophylaxis, but they did find a higher proportion of penicillin-resistant bacterial infections com-pared with penicillin-susceptible cases during periods of prophy-laxis, as expected. NC has had no reported side effects to date and should not be considered “hazardous.”
The two reports on combined SIC-NC reported no failures of chemoprophylaxis.5,6The studies of SIC cited by Benitz7–11total “three failures of prophylaxis” in 371 women given SIC. Each of these women had chorioamnionitis and was given a single dose of ampicillin. These cases of GBS EOD might more appropriately be considered partially treated intrauterine infections with a
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able outcome. Although the strategy of combined SIC-NC that we proposed in our commentary has not been studied, we predict
.95% efficacy based on the literature and our knowledge of the pathogenesis of GBS EOD.
With regard to the predictive value of screening for GBS at 35 to 36 weeks gestation, the most extensive study showed a positive predictive value of 87%.12More importantly, the negative predic-tive value was 96%. The 10% of women who deliver without screening, most of whom have premature labor, should be given SIC; and chorioamnionitis should be treated as a maternal infec-tion, not prophylaxis. Most of the neonatal infections acquired in utero will be adequately prevented with SIC, but there will still be occasional cases of GBS EOD attributable to unrecognized or recognized in utero infection or failure to implement the protocol. The question is whether to treat prophylactically all GBS colo-nized women with penicillin or ampicillin according to the “screening-based” approach of the CDC13and revised AAP guide-lines,14or to restrict SIC to a high-risk group of colonized women and treat all GBS-exposed newborns, whose mothers do not have risk factors, with penicillin. We advocate the latter.
Samuel P. Gotoff, MD Kenneth M. Boyer, MD
Rush Medical College Chicago, IL 60612-3833
REFERENCES
1. Gotoff SP, Boyer KM. Prevention of early-onset group B streptococcal disease.Pediatrics.1997;99:866 – 869
2. Mohle-Boetani J, Schuchat A, Plikaytis BD, Smith D, Broome CV. Com-parison of prevention strategies for neonatal group B streptococcal infection: a population-based economic analysis. JAMA. 1993;270: 1442–1448
3. Siegel JD, McCracken GH Jr, Threlkeld N, DePasse BM, Rosenfeld CR. Single-dose penicillin prophylaxis of neonatal group B streptococcal disease.Lancet.1982;i:1426 –1430
4. Siegel JD, Cushion NB. Prevention of early-onset group B streptococcal disease: another look at single-dose penicillin at birth.Obstet Gynecol.
1966;87:692– 698
5. Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B strep-tococcal disease with selective intrapartum chemoprophylaxis.N Engl J Med.1986;314:1665–1669
6. Garland SM, Fliegner JR. Group B streptococcus and neonatal infections: the case for intrapartum chemoprophylaxis.Aust N Z J Obstet Gynaecol.1991;31:119 –122
7. Allardice JG, Baskett TF, Seshia MMK, Bowman N, Malazdrewicz R. Perinatal group B streptococcal colonization and infection.Am J Obstet Gynecol.1982;142:617– 620
8. Morales WJ, Lim D. Reduction of group B streptococcal maternal and neonatal infections in preterm pregnancies with premature rupture of membranes through a rapid identification test.Am J Obstet Gynecol.
1987;157:13–16
9. Tuppurainen N, Hallman M. Prevention of neonatal group B strepto-coccal disease: intrapartum detection and chemoprophylaxis of heavily colonized parturients.Obstet Gynecol.1989;73:583–587
10. Matorras R, Garcia-Perea A, Omenaca F, Diez-Enciso M, Madero R, Usandizaga JA. Intrapartum chemoprophylaxis of early onset group B
streptococcal disease.Eur J Obstet Gynecol Reprod Biol.1991;40:57– 62 11. Pylipow M, Gaddis M, Kinney JS. Selective intrapartum prophylaxis for
group B streptococcus colonization: management and outcome of new-borns.Pediatrics.1994;93:631– 635
12. Yancey MK, Schuchat A, Brown LK, Ventura VL, Markenson GR. The accuracy of late antenatal screening cultures in predicting genital group B streptococcal colonization at delivery.Obstet Gynecol.1996;88:811– 815 13. Centers for Disease Control. Prevention of perinatal group B strepto-coccal disease: a public health perspective.MMWR.1996;45(RR-7):1–24 14. American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised guidelines for preven-tion of early-onset group B streptococcal (GBS) infecpreven-tion. Pediatrics.
1997;99:489 – 496
Loxitane Overdose
To the Editor.—
Loxitane, loxapine hydrochloride, is a new subclass tricyclic antipsychotic agent. The oral solution contains 25 mg of loxapine per mL.
Overdosage can result in depression of the central nervous and cardiovascular systems with hypotension, respiratory depression, extrapyramidal symptoms, and seizures.
Our review of the literature has found a single reported case of loxapine overdose in a pediatric patient. This was a 20-month-old child who ingested an unknown amount of loxapine.1
We are reporting a case of an 8-year-old boy who accidentally was given 15 mL (375 mg) of loxapine instead of his prescribed dose of 0.6 mL (15 mg) loxapine. Within minutes after the acci-dental ingestion of loxapine, the parents noticed the mistake and he was brought to the local emergency room.
Within 30 minutes, the child was given 50 g of activated char-coal, which he freely ingested. By 45 minutes after the loxapine ingestion the patient was drowsy and by 1 hour past the loxapine ingestion, the patient was asleep but arousable, and when aroused he was oriented to time, place, and person. His pupils were constricted and remained so over the next 7 hours.
Over the next several hours, the patient was monitored closely. His highest heart rate was 101 beats per minute at approximately 150 minutes postingestion and the lowest blood pressure was 97/54 at approximately 4 hours post-loxapine ingestion.
The patient became increasingly more difficult to arouse over the first 4 hours post-loxapine ingestion and this seemed to peak at approximately 3 hours, 45 minutes postingestion. By 4 hours postingestion, the patient was more easily arousable and in fact was able to stand with help and voided.
The patient did well from that time on and maintained stable vitals. He was subsequently discharged from the hospital at ap-proximately 20 hours postingestion.
Nicholas W. Tarricone, MD
Child and Adolescent Health Care of Oneonta, PC Oneonta, NY 13820
REFERENCE
1. Helper BR, Solano R, Weber TR, Sunshine I. Acute loxapine intoxication in a child.J Anal Toxicol.1982;(Sept/Oct):258 –259
DOI: 10.1542/peds.101.3.494
1998;101;494
Pediatrics
William E. Benitz
The Neonatal Group B Streptococcal Debate
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