Keywords
fetal drug exposure - acetaminophen - pregnancy - pharmacokinetics
Acetaminophen is taken by nearly two-thirds of pregnant women, making it the most
commonly utilized over-the-counter medication in pregnancy.[1] Despite the perception of safety, maternal acetaminophen use has been associated
with increased risks to the newborn of attention deficit hyperactivity disorder (ADHD),[2] drug-induced liver injury (DILI),[3] and asthma in childhood.[4] The extent of fetal exposure from a standard acetaminophen dose is not well understood.
Acetaminophen has been demonstrated to cross the placenta after maternal overdose[5] as well as after therapeutic doses.[6] Two case reports described fetal death after maternal overdose that resulted in
maternal liver injury; however, the cause of fetal death was not definitively determined
in either case.[3]
[5] Four other reports describe cases of toxic maternal levels of acetaminophen without
any documented fetal sequelae.[7]
[8]
[9]
[10] Fortunately, studies involving therapeutic doses of acetaminophen have failed to
demonstrate a risk to the fetus in any trimester[11] and is listed as a category B medication for use in pregnancy. In addition, a registry
of more than 88,000 first-trimester exposures to acetaminophen has not shown an increase
in congenital anomalies in the fetuses exposed.[12] However, the possibility of altered metabolism of the drug in the fetus raises the
possibility that it could accumulate to toxic levels with chronic use.
Acetaminophen is widely used in pregnancy,[13] as other pain relievers such as NSAIDs or narcotic medications carry the risk of
fetal harm, namely, premature closure of the ductus arteriosus and neonatal withdrawal,
respectively.[11] Surprisingly, search of the PubMed database for the terms “acetaminophen,” “paracetamol,”
and “pregnancy” revealed only one case report describing the levels of acetaminophen
in the neonate after a therapeutic maternal dose of acetaminophen.[6] This report suggests that the level attained in the neonate after a single maternal
dose of acetaminophen is similar to the levels obtained after an oral dose administered
directly to the neonate. An experimental study of normal pregnant women undergoing
scheduled cesarean delivery has also shown similar acetaminophen levels in mother
and neonate as soon as 30 minutes after maternal administration.[14] However, the rate of decline and duration of action of acetaminophen after placental
transfer has yet to be determined. In this study, we compare the maternal and fetal
pharmacokinetic (PK) profiles of acetaminophen after administration of a therapeutic
oral dose.
Study Design
Institutional Review Board approval was obtained for a prospective study of acetaminophen
PKs in term pregnant women. After obtaining written consent, women without medical
or obstetrical complications were given a single oral dose (1,000 mg) of acetaminophen
upon admission for scheduled cesarean delivery. At the time of delivery, 5 mL of maternal
peripheral venous blood and 15 mL of fetal cord blood were obtained at the time of
delivery. Acetaminophen and its deuterium labeled internal standard, acetaminophen
d4, were purchased from Cerilliant (Round Rock, TX). All solvents were high performance
liquid chromatography grade or better, and all chemicals were American Chemical Society
grade. Solid phase extraction was followed by derivatization using BSTFA 1% TMCS.
One microliter of prepared sample was injected onto an Agilent gas chromatography-mass
spectroscopy system (Agilent Technologies, Inc., Santa Clara, CA). Quantitation was
performed using selected ion monitoring and concentrations were calculated based on
a five-point calibration curve using a 1/x linear curve fit. The calibrators ranged from 0.50 to 15 µg/mL and were included
with each analytical run. Samples > 15 µg/mL were diluted with drug-free serum and
reanalyzed. Each maternal/child pair contributed one set of values to the analysis.
PK parameters were calculated by noncompartmental analysis using PK solver. PK parameters
assessed included maximum concentration (Cmax), area under the curve from time 0 to ∞ (AUC0–inf), apparent volume of distribution (Vd/F), and apparent clearance (Cl/F). AUC0–inf represents the total amount of drug available after administration. The Vd/F and Cl/F parameters illustrate the distribution of drug into body tissues and rate
of elimination of drug, respectively. A linear regression was performed to determine
how well maternal acetaminophen levels predicted fetal levels.
Results
In this study, 34 subjects were enrolled at a median age of 32 years (range, 25–39
years). Subjects were primarily Caucasian (31/34 or 91%), with the remainder Asian
(2/34 or 6%) or Hispanic (1/34 or 3%). The median maternal weight was 82 kg (range,
62–100 kg). Two women delivered at 38 weeks', 30 delivered at 39 weeks', and 2 women
delivered at 40 weeks' gestation. The median newborn birth weight was 3,590 g (interquartile
range, 3,403–3,848 g). Noncompartmental PK analysis described acetaminophen disposition
in the maternal compartment with a half-life of 84 minutes and Cl/F of 28.8 L/h. In
the fetal compartment, acetaminophen half-life was 82 minutes with a Cl/F of 31.2
L/h. Peak concentrations of acetaminophen (maternal 12.3 µg/mL; fetal 11.2 µg/mL)
and Vd/F (maternal 57.5 L; fetal 61.2 L) were similar. Linear regression analysis revealed
that maternal acetaminophen level was a significant predictor of fetal level (p > 0.0001) and that maternal and fetal levels were very highly correlated (r = 0.91). PK parameters and curves are provided in [Fig. 1].
Fig. 1 Acetaminophen PKs in maternal and fetal compartments. Maternal and fetal PK curves
are juxtaposed with key parameters listed later. Points on the graph are individual
acetaminophen levels with a line of best fit representing the PK curve for the study
population. AUC0–inf, area under the curve (time 0–∞); Cmax, maximum concentration; Cl/F, apparent clearance; PK, pharmacokinetic; Vd/F, apparent volume of distribution.
Conclusion
Acetaminophen PKs in maternal samples are consistent with values previously reported
in pregnant women (Vd/F, 57.5 L; Cl/F, 28.8 L/h), except for a shorter half-life (84
vs. 114 minutes).[15] They are also consistent with those described in healthy male volunteers in whom
serum levels peak between 7.7 and 17.6 µg/mL[12] and have a half-life of 1.5 to 2.5 hours.[16] These values are similar to the peak concentration of 12.3 µg/mL and a half-life
of 84 minutes seen in our PK model. Maternal and fetal acetaminophen levels are comparable
as early as 30 minutes after administration, indicating rapid placental transfer of
the drug. Notably, acetaminophen PKs in fetal samples closely parallels behavior of
the drug in the maternal system. The time to peak concentration and half-life are
similar, and the fetal AUC is nearly the same as maternal AUC (> 90%). The comparable
concentrations of acetaminophen in the maternal and fetal compartments suggest that
placental transfer is influenced primarily by rate of blood flow (“flow limited”)
and not by transporters in the placenta (“diffusion limited”).
Fetal acetaminophen exposure has been associated with ADHD,[2] DILI,[3] and childhood asthma,[4] though the threshold for these effects in the fetus is not known. An understanding
of placental transfer kinetics is necessary to correlate maternal drug intake to fetal
exposure and clinical outcomes. In this study, we have demonstrated that acetaminophen
levels in the fetal compartment are nearly identical to maternal levels. The very
high correlation between maternal and fetal levels suggests that maternal acetaminophen
levels can be used as a surrogate for the extent of fetal exposure.
The modest sample size and lack of information on acetaminophen metabolites are the
main weaknesses of the study. Although our findings do provide novel information on
the PKs of acetaminophen in pregnant women and their fetuses, acetaminophen levels
alone cannot provide precise estimations of fetal risk, as acetaminophen-mediated
injury occurs when a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), is formed.
Saturation of the metabolic enzymes that inactivate acetaminophen leads to accumulation
of NAPQI and subsequent adverse effects. Thus, future studies should assess NAPQI
along with acetaminophen levels and utilize a larger sample size to permit a formal
population PK analysis. In addition, our observation that transplacental passage of
acetaminophen is “flow limited” is based on features of the maternal and fetal PK
curves. Confirmation that acetaminophen does not interact with placental transporters
may be obtained through ex vivo placental perfusion studies.
Although the current study suggests that fetal exposure to acetaminophen can be predicted
using maternal drug levels, further study of acetaminophen metabolism to NAPQI in
the fetus is clearly needed to better understand the risk of fetal harm after maternal
acetaminophen use. However, our findings suggest that maternal use of acetaminophen
at the currently recommended dose is unlikely to lead to accumulation of potentially
toxic levels in the fetus.
