Neonatal Sepsis after Chorioamnionitis, what to do about healthy appearing newborns

In 2007, when I was chair of the CPS Fetus and Newborn Committee, we published a guideline regarding the approach to term and late preterm infants with perinatal risk factors for sepsis. Obviously any infant with clinical signs consistent with sepsis needs immediate work up and antibiotics, but the management of infants with risk factors for sepsis and no clinical signs evident was the focus of that guideline.

This is what we said about chorioamnionitis, based on what we thought was the most reliable literature:

The risk of sepsis (which may be due to a variety of different organisms, including GBS, E coli and other Gram-negative organisms) in an infant whose mother had definite chorioamnionitis is approximately 8%, and is approximately 3% to 4% if ‘possible’ and ‘definite’ chorioamnionitis are considered together [31][32] (evidence level 2b); among all mothers with fever, the incidence is 2% to 6% depending on the height of the fever [31] (evidence level 2b). Infants who do not have signs at birth are unlikely to develop sepsis, the odds ratio for sepsis among infants who are well at birth is 0.26 (95% CI 0.11 to 0.63) [31]. The incidence of invasive infection in the present study in an initially well-appearing infant with a maternal history of fever or chorioamnionitis was less than 2%, and this is confirmed by other data [33] (evidence level 2b). Therefore, it seems reasonable to perform a CBC and closely observe such an infant, and to only perform a full diagnostic evaluation and treat with antibiotics if the CBC is strongly suggestive of infection (low total WBC count) or if clinical signs develop. A requirement for extensive resuscitation at birth should be considered a sign of possible infection in such infants [32][33].

At that time the CDC guidelines recommended cultures and empiric antibiotics for all such infants, the CDC guidelines were updated in 2010, and continue to recommend the same thing, with the clarification that you should talk to the obstetricians (always a good idea!)

Well-appearing newborns whose mothers had suspected chorioamnionitis should undergo a limited evaluation and receive antibiotic therapy pending culture results (AII). The evaluation should include a blood culture and a CBC including white blood cell differential and platelet count; no chest radiograph or lumbar puncture is needed. Consultation with obstetric providers to assess whether chorioamnionitis was suspected is important to determine neonatal management (CIII).

Is there anything new recently? I think you all know the answer to that question.

Braun D, et al. Low Rate of Perinatal Sepsis in Term Infants of Mothers with Chorioamnionitis. Amer J Perinatol. 2016;33(02):143-50. This database analysis from Kaiser Permanent Southern California found an incidence of maternal fever in labour (38 degrees or more) at or after 35 weeks to be 9% and chorioamnionitis (based on ICD-9 codes from discharge data) to be 4%, chorioamnionitis based on a fever of 38 degrees followed by antibiotic treatment was 5%. There were around 30,000 deliveries in this cohort and in total there were 19 babies with culture positive early onset sepsis, 14 were symptomatic and 5 had bacteremia without clinical signs. That gives an overall incidence of culture positive symptomatic sepsis of 0.45 per 1000, and of culture positive bacteremia without clinical signs of 0.16 per 1000. Among mothers without fever the rate of sepsis was 0.5 per 1000, if they had fever without chorioamnionitis it was 0.6 per 1000, and if they had chorioamnionitis it was 4 per 1000.

One interesting thing in this study is that many physicians do not follow the CDC guidelines, the rate of neonatal treatment with antibiotics after maternal chorio, which should be close to 100%, ranged from 7 to 76% in different hospitals.

The authors don’t say how many of the babies without clinical signs were from the maternal chorio group, there were 5 babies who did not have clinical signs, if all of them were from mothers with chorioamnionitis (which I think is unlikely) then you would have to treat 250 clinically well infants after maternal chorioamnionitis with antibiotics to be sure to cover 1 baby with bacteremia. Of course if some of those babies were symptomatic, then you would have to treat many more without clinical signs for each baby infected, for example if the proportion of asymptomatic babies is the same as in the next study (about 1/3) then you would have to treat over 700 asymptomatic babies to cover that 1 with bacteremia.

The authors also calculated that if the CDC guidelines had been followed (for chorioamnionitis, but also for other indications for neonatal antibiotic treatment) then 8% of all the term and late preterm babies would have received 48 hours of antibiotics.

Another very large study Wortham JM, et al. Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections. Pediatrics. 2016;137(1). instituted prospective surveillance for early onset sepsis among nearly 400,000 deliveries. In contrast to the other study they did not collect data from mothers whose babies did not get septic, so we don’t know overall incidence of chorioamnionitis in this study, and you can’t make some of the same calculations.
They found 389 cases of early onset, culture positive, infections, in the cohort which included both preterm and term babies. Eighty-one of those infections were in term babies (37 weeks and more; from 350,000 term deliveries) 58 of which had clinical signs at birth. Which leaves 23 term infants who had no signs at birth but had culture positive sepsis, from mothers with chorioamnionitis, and 6 preterm babies with the same combination. The authors include some babies, 1 at  term and 4 preterm, who only had histological evidence of chorioamnionitis, which doesn’t help our decision-making as you don’t know about those unless you did placental pathology and got the results back.

If the prevalence of chorioamnionitis is 4 to 5% (as in the first study), then there would have been about 16,000 cases of chorio among the term deliveries, which gives the incidence of early neonatal sepsis (81/16,000) of 5 per 1000 which is very similar to the Kaiser Permanent data. We know 23 were without signs at birth (but one of those would not have had a diagnosis of chorio) so to ensure that 22 those asymptomatic babies with sepsis received early treatment, you would have to screen, culture and treat 16,000 babies, which is a number needed to treat of over 700.

I think that is too many. NICE in the UK seems to have a similar opinion in their guideline from 2012, their guidance is a little more complicated, but goes like this (the links should work to take you to the tables):

Use the following framework based on risk factors and clinical indicators, including red flags (see tables 1 and 2), to direct antibiotic management decisions:

  • In babies with any red flags, or with two or more ‘non-red flag’ risk factors or clinical indicators (see tables 1 and 2), perform investigations (see recommendations 1.5.1.1–1.5.1.3) and start antibiotic treatment. Do not delay starting antibiotics pending the test results (see recommendations 1.6.1.1–1.6.1.3).
  • In babies without red flags and only one risk factor or one clinical indicator, using clinical judgement, consider:
    • whether it is safe to withhold antibiotics, and
    • whether it is necessary to monitor the baby’s vital signs and clinical condition – if monitoring is required continue it for at least 12 hours (at 0, 1 and 2 hours and then 2-hourly for 10 hours).

     

In their scheme chorioamnionitis is a risk factor, but not a “red flag”, so if the baby does not have any of the clinical indicators they would be observed, but not treated.

As I said I think that an NNT of over 700 is too many, but others may not agree, specifically the parents may not agree. Shouldn’t they be involved in that decision? A decision aid may help them to decide, with the medical team, between one or multiple IV installations, antibiotics for 36 hours (you can stop them before the 48 hour dose if cultures are negative) and hospitalisation for at least that long. Depending on how your hospital is organized term newborns on antibiotics may also not be in the room with the mother. The contrasting choice is close observation with the option of starting antibiotics later if clinical signs appear (which happened in 18 of the 23 initially asymptomatic term babies with positive cultures). Also there is no difference in mortality (there was one death in the Wortham study, a baby who died soon after cultures and never had antibiotics, 2 deaths in the Braun study both of whom were symptomatic) shown in these recent studies.

Very frequent use of antibiotics of course affects colonization and resistance patterns in an environment, and will affect the development of the infant’s microbiome, perhaps for many months or years.

I think in these days of shared decision-making and family centered care, when a term baby is born after maternal chorioamnionitis but is clinically well, we should inform the parents that the baby has a very small risk of having an infection, (1 in several hundreds) and that there are 2 options. We should also organize our care so that both close repeated observation, and/or antibiotic administration, can be performed in a mother and infant room, without interfering with breastfeeding and the evolution of the new family, and then give the parents a big place in that decision.

 

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Clinical Practice Guidelines, Neonatal Research and tagged , , . Bookmark the permalink.

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