The data presented here demonstrates that shorter durations of exposure to intrapartum antibiotic prophylaxis are effective in attaining levels of penicillin G in the neonatal bloodstream significantly above the minimum inhibitory concentration for group B Streptococcus. Fetal serum penicillin levels peak within 1 hour of maternal intravenous administration of penicillin G. Levels recorded until 2 hours after initiation of chemoprophylaxis remain significantly above all later time intervals. In this cohort, individual samples were 10–179-fold above the MIC at all time points examined. The declining levels of penicillin G levels in the six patients who failed to receive the protocol-recommended 2.5 million units at the 4-hour time point supports the 4-hour dosing interval. Additionally, patients who received six additional doses of 2.5 million units every 4 hours had similar levels to those who received two additional doses. Fetal serum penicillin G levels do not build with time, rather they nadir at the end of each 4-hour interval. Therefore, adherence to dosing every 4 hours, independent of the duration of the intrapartum prophylaxis should be a priority.
Up until this point, little has been documented regarding the pharmacokinetic properties of penicillin G in the pregnant woman and her fetus. Similar studies on ampicillin have shown that ampicillin levels rise rapidly in the fetal serum following maternal intravenous administration.12
To date, studies on penicillin G pharmacokinetics have generally been performed on nonpregnant women or men or neonates themselves (dose given to the neonate after delivery).13-15
One recent study examined serum concentrations of penicillin G in pregnancy, but examined only the maternal circulation and not the fetal.9
Another study measured maternal and fetal penicillin G levels after one intramuscular dose of penicillin G benzathine. This study showed levels above the MIC at 30 days after injection.16
Our current investigation documents penicillin G levels in the fetus using the current intravascular CDC dosing regimen.
Several limitations in our study should be considered. Due to natural variability in duration of labor, we cannot control duration of prophylaxis in relation to timing of umbilical cord blood sampling. This investigation was therefore limited to observational study and a single sample per fetus at the time of birth. Traditional pharmacodynamic modeling, in which multiple serum samples are collected at designated time points after drug administration, is therefore not possible.
Furthermore, our methodology used umbilical blood samples retrieved from the blood bank. The focus of our investigation was rapidly progressing, less than 4-hour deliveries. The challenge of recruiting and consenting women in precipitous labor motivated us to evaluate the use of blood bank samples. We could therefore approach mothers after delivery and, if they consented, retrieve the blood bank sample. Our analysis of 18 fresh umbilical cord blood samples compared with their matched blood bank samples showed that this approach was legitimate. The blood bank samples represent a slight underestimation of the penicillin G levels contained in the cord blood at the time of delivery.
This study did not evaluate levels of penicillin G in amniotic fluid. Evaluating amniotic fluid would have required performing an invasive procedure, amniocentesis, in the setting of rapidly progressing deliveries or would have required limiting our cohort to women undergoing caesarean deliveries, which would have limited the generalizability of our findings. Because we did not examine the amniotic fluid, we are unable to document whether sufficiently high levels of penicillin G were obtained in the amniotic fluid to prevent transmission by that route. However, other studies on intrapartum ampicillin and cefazolin have shown that when adequate concentrations were achieved in the cord blood, they were also reported in the amniotic fluid.17,18
Ultimately, studies to assess the optimal duration of intrapartum prophylaxis will require correlation with clinical outcomes. However, early onset GBS sepsis is an infrequent event and even more rare in the setting of intrapartum prophylaxis. Only a well designed case—control or a large cohort study could examine this outcome. We must also consider that most cases of early onset GBS sepsis may represent fetal exposure to GBS in utero, in the setting of ruptured membranes, well before the initiation of intrapartum antibiotic prophylaxis. The fetal serum penicillin level and the duration of exposure to intrapartum antibiotic may be irrelevant in these cases.
Even with the most valiant of efforts, there will frequently be GBS-positive mothers who arrive at the labor floor and deliver in fewer than 4 hours. Obstetric providers have little control over the time patients arrive at the hospital to begin prophylaxis and likewise little control over the progression of labor and the ultimate timing of delivery. Providers may believe that 4 hours of prophylaxis are necessary to achieve adequate levels in the fetal bloodstream to prevent GBS transmission and therefore, may choose not to begin penicillin G dosing during precipitous labor. Likewise, providers may attempt to prolong labor to reach the 4-hour recommendation. Our data indicate that fetal serum levels far exceed the MIC at durations well under 1 hour, suggesting that antibiotic prophylaxis should be pursued even in the most precipitous of deliveries and that it is unnecessary to prolong labor to achieve adequate levels in fetal serum. Likewise, prolonging labor beyond 1 hour will not achieve higher penicillin levels in fetal serum.
Knowledge about the dosing regimen has implications beyond the labor and delivery floor. Preliminary studies as well as data from a large health maintenance organization demonstrate that 40–50% of GBS-colonized women do not receive antibiotics at least 4 hours before delivery due the rapidity of their labors.19
This is especially notable for multiparous women. According to the 2002 CDC guidelines, the newborns of all GBS-positive women who present to labor units and deliver before receiving 4 hours of intrapartum antibiotic prophylaxis are deemed as “at risk” and recommended to undergo blood cultures, complete blood count, and 48 hours of observation.3
At some institutions, these infants have been placed in designated observation units for up to 6 hours after delivery to monitor for signs of sepsis, often causing great angst for parents and care providers. These interventions have not been proven to reduce or detect more cases of GBS sepsis.20
Knowledge that fetal serum penicillin G levels are far above the MIC within 1 hour raise the possibility that these interventions and testing may be at best, superfluous, and at worst, expensive and deleterious.
This study shows that fetal serum penicillin G levels far exceed the MIC even for short durations of maternal intrapartum prophylaxis. However, studies that correlate duration of prophylaxis with clinical outcomes are needed. Much of the current literature has examined neonatal GBS colonization, but the usefulness of using this as a surrogate for risk of early onset GBS sepsis does not have much, if any, supporting evidence. Therefore, studies investigating duration of chemoprophylaxis in relation to incidence of early onset GBS sepsis are necessary. If those studies are in line with the evidence presented here, the results may alter GBS sepsis protocols, so that in appropriate circumstances, shorter durations of intrapartum prophylaxis may be considered adequate.