Pharmacokinetics and Target Attainment of Antimicrobial Drugs Throughout Pregnancy. Part II: Cephalosporins

Abstract

Background and Objectives

Understanding the pharmacokinetics (PK) of antibiotics in pregnant women is essential for safe and effective treatment. This review is part of a series that evaluates the PK, exposure, and target attainment of antibiotics during pregnancy. Part II focuses on cephalosporins and investigates if evidence-based dosing regimens are developed.

Methods

A systematic literature search was conducted using PubMed on 24 July 2025. Articles containing PK data on pregnant women treated with any of the 35 selected cephalosporins were classified as relevant. Extracted PK and target attainment parameters included volume of distribution (Vd), clearance (CL), drug concentrations, area under the curve, elimination half-life (t_1/2), probability of target attainment, and proposed dosing regimens.

Results

Of 219 articles identified, 44 met the inclusion criteria, covering 14 out of 35 cephalosporins. During second (T2) and third (T3) trimesters of pregnancy, Vd (9.2–18.4%) and CL (30.8–100%) were higher compared with nonpregnant, first trimester, or postpartum women. Consequently, reduced target attainment was reported in T2 and T3 pregnant women. Evidence-based dosing regimens were proposed for pregnant women receiving cefazolin, cefuroxime, cefoxitin, ceftazidime, cephradine, cefatrizine, and ceftizoxime.

Conclusions

During pregnancy, an increase in Vd and CL was observed, indicating a potential need for higher or additional dosages, or shorter dosing intervals to achieve target attainment. However, evidence-based dosing adjustments were identified for only seven cephalosporins. These findings highlight significant gaps in knowledge and underscore the need for further research to characterize PK profiles and establish dosing recommendations for the remaining cephalosporins in pregnant women.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s40262-026-01696-4.

Key Points

During the second and third trimesters of pregnancy, cephalosporins exhibit increased clearance and volume of distribution compared with nonpregnant women, resulting in reduced systemic exposure and target attainment.

Evidence-based dosing adjustments have been proposed for only seven cephalosporins, highlighting substantial gaps in current knowledge regarding optimal dosing in pregnant women.

Further pharmacokinetic and pharmacodynamic studies are required to establish robust dosing recommendations to ensure therapeutic efficacy and safety across the full spectrum of cephalosporins used in pregnancy.

Introduction

During pregnancy, the female body undergoes various anatomical and physiological changes that may affect drug absorption, distribution, metabolism, and elimination (ADME) [1]. Pregnancy-related changes such as decreased gastrointestinal motility and increased gastric pH may alter drug absorption, while increased total body volume and glomerular filtration rate can affect drug distribution and elimination [1]. These physiological changes can influence the pharmacokinetics (PK) of drugs, potentially resulting in subtherapeutic or toxic concentrations in the mother and/or fetus [2]. Owing to ethical, legal, and logistical considerations, pregnant women are typically excluded from clinical research. As a result, the effects of pregnancy on PK and pharmacodynamics (PD) are often not well defined for most drugs [1]. However, prescribing drugs to pregnant women is sometimes unavoidable. For example, antibiotics are prescribed to approximately 25% of pregnant women, accounting for nearly 80% of all prescription drugs use in this population [1]. Antibiotics are often used during pregnancy, as they are usually the first-line treatment for bacterial infections in pregnant women [3]. Cephalosporins, a broad class of $\beta$-lactam antibiotics, are reserved for patients who are allergic or intolerant to penicillins [3]. In many countries, first-generation cephalosporins are recommended as the primary prophylactic agents for caesarean sections [4]. Whether changes in PK lead to nontarget attainment of cephalosporins in pregnant women also depends on the PD interaction between the specific cephalosporin and microorganism. The two main parameters in this interaction are the microorganism’s susceptibility, defined by the minimum inhibitory concentration (MIC) and the time-dependent bactericidal activity of the cephalosporin, expressed as the fraction of time the free (unbound) drug concentration remains above the MIC (fT > MIC) [5]. Understanding changes in PK parameters and identifying optimal PD targets are essential for developing evidence-based dosing regimens for pregnant women.

This literature review aims to provide an overview of the PK and exposure as well as target attainment of cephalosporins throughout pregnancy. Furthermore, this review evaluates current dosing regimens, on the basis of altered PK and PD parameters, to achieve adequate target attainment. Our study may help to identify knowledge gaps, guiding further research toward development of evidence-based dosing regimens for cephalosporins in pregnant women.

Materials and Methods

Search Strategy

This literature review was performed in accordance with the PRISMA guidelines of 2020 [6]. The PRISMA checklist is provided in the Online Supplementary Materials (Supplementary File 1). A search was conducted using PubMed on 30 April 2022 and updated on 24 July 2025. This review described the following 35 cephalosporin species from five generations; 1st generation: cefadroxil, cefatrizine, cefazolin, ceftezole, cephalexin, cephaloridine, cephalothin, cephapirin, cephradine; 2nd generation: cefaclor, cefamandole, cefmetazole, cefonicid, ceforanide, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuroxime axetil; 3rd generation: cefdinir, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone; 4th generation: cefclidin, cefepime, cefpirome, cefquinome, cefuprenam; 5th generation: ceftaroline fosamil, ceftobiprole. A separate search was performed for each cephalosporin to find studies on the PK/exposure and target attainment in pregnant women. The medical subject headings (MeSH) and title/abstract terms used for each search are shown in the Online Supplementary Materials (Supplementary File 2). In addition, studies were identified through reference checks of the included studies. Search results were stored in Microsoft Excel (version 16.59).

Inclusion Criteria

We included studies comparing PK and/or exposure of cephalosporins in pregnant women with that of nonpregnant or postpartum women, to accurately determine the potential influence of pregnancy. Only data obtained from nonpregnant and/or postpartum women, if reported within the context of a study with pregnant women, were eligible for this literature review. No fetal PK, exposure, or safety data were included. Comparison of PK and exposure parameters between nonpregnant and/or postpartum and pregnant women were made as follows: the percental changes were calculated between those two groups and reported in the results section. When multiple studies reported PK data, the lowest and highest percentage changes between nonpregnant and pregnant women within all those studies were reported in the results section. Eligible study designs included randomized controlled trials, prospective or retrospective cohort studies, case-control studies, and case series. No restrictions on the year of publication were placed on the search, and only studies written in English were included. All dosage forms (intravenous (i.v.), intramuscular (i.m.), and oral) were included in this study. Furthermore, studies were included if at least one PK or exposure parameter was reported in pregnant women. This systematic review only focusses on PK-related end points and does not include efficacy studies. However, for cephalosporins, efficacy is known to correlate with achieving the PK/PD target of time during which the free (unbound) drug concentration exceeds the MIC (fT > MIC) [5], a relationship that we also evaluated in our results section.

Study Selection

Titles and abstracts were independently screened for relevance by two investigators (F.M., P.M.). After this initial selection, the full texts of the articles were obtained. Studies not meeting the study aim and inclusion criteria were excluded. In case of disagreement, a third author (D.T.) was consulted.

Data Extraction

Data extraction was performed independently by two investigators (F.M., P.M.) and, in case of disagreement, discussed with a third author (D.T.). The extracted study and population characteristics of interest included study design, population number, age, weight (and body mass index (BMI) if reported), height, conditions, gestational age, dosage form, and dose. The collected PK parameters of interest were volume of distribution (Vd), and clearance (CL). In addition, exposure parameters including trough (C_min) and peak (C_max) drug concentrations, time of maximum concentration (T_max), area under the curve (AUC), and half-life (t_1/2) were collected. PD parameters collected included the probability of target attainment (PTA) and the MIC. Furthermore, the studies were evaluated to determine whether, on the basis of potentially altered PK/PD, adapted dosages were recommended to achieve adequate target attainment. All data extracted from the included studies were stored in Microsoft Excel (version 16.59).

Results

Study Selection and Data Extraction

A total of 327 articles were identified using the search criteria described. Of these articles, four articles were obtained through reference checking. First, the duplicate articles (n = 108) were removed and subsequently the titles and abstracts of the remaining articles (n = 219) were screened. Of the 65 selected articles based on title and abstract, the full texts were assessed, and 21 articles were excluded. The most important reasons for exclusion were no PK/exposure parameters reported, physiologically based pharmacokinetic modelling studies or only inclusion of postpartum women. Finally, 44 articles were included in this literature overview, providing data for 14 of the 35 originally selected cephalosporins. Overall, 22 studies were identified for cefazolin, followed by 7 for cefuroxime, 4 for ceftriaxone, 3 for both cefoxitin and ceftazidime, 2 for each of cephalothin, cefoperazone, and cefotaxime, and 1 study each for cefatrizine, ceftezole, cephradine, cefamandole, ceftizoxime, and cefepime. In Fig. 1 the PRISMA flow diagram is shown. An overview of the PK and exposure of the cephalosporins is presented for the five generations in alphabetic order. Subsequently, cephalosporins are discussed according to the ADME (absorption, distribution, metabolism, and elimination) and, if available, the obtained target, PTA and evidence-based dosages of the individual cephalosporine are discussed.

Fig. 1.

PRISMA flow diagram

First Generation Cephalosporins

No studies were identified that investigated the PK or exposure of cefadroxil, cephalexin, cephaloridine, and cephapirin. Table 1 presents the study characteristics and the PK/exposure parameters of pregnant women (with comparisons to nonpregnant and/or postpartum women when available) from studies on cefatrizine, cefazolin, ceftezole, cephalothin, and cephradine.

Table 1.

Study and patient characteristics, PK and exposure parameters, probability of target attainment, and dose advice of the included first-generation cephalosporin studies, in alphabetical order by cephalosporin followed by author

Author (year) (citation)	Study design	Patient population number	Age (years)	Weight (kg)	Condition	Trimester (T0–T5) / GA (weeks)	Dose and administration route	PK/exposure parameters	PTA	Dosing advice
Cefatrizine
Papantoniou et al. (2007) [7]	Prospective study	Ntotal: 40 T0: 20 T2: 20	T0: 29.0 ± 6.3 T2: 26.7 ± 8.5	T0: 61.1 ± 4.7 T2: 76.2 ± 21.1	Women with affected fetuses, undergoing termination of gestation between 19 and 24 weeks Healthy nonpregnant women	T2: 22.8 ± 1.6	1 g oral every 12 h 3 g total	Cmax (mg/l) T0: 9.6 ± 2.1 (2.2 ± 0.67 h after administration) T2: 5.3 ± 1.2 (2.6 ± 0.78 h after administration) AUC0-12h (mg*h/l) T0: 31.9 ± 5.6 T2: 18.2 ± 4.7 Ke (h-1) T0: 0.46 ± 0.07 T2: 0.28 ± 0.08 t1/2 (h) T0: 1.5 ± 0.21 T2: 2.5 ± 0.34	–	Increased frequency of administration could result in optimal coverage for both mother and fetus (i.e., 0.5 g every 6 h as opposed to 1 g every 12 h)
Cefazolin
Allegaert et al. (2009) [17]	Prospective study	49	–	72 (54–95)	Women ndergoing in utero surgery during pregnancy	T2: 25 (17–34)	I.v. infusion, 2 g every 8 h for2 days First dose 1–2 h before surgery	Estimate (%SE) CL (l/h): 7.4 (4.4) Vc (l): 8.0 (12.0) Vp (l): 4.1 (6.1) Teq (h): 4.4 (25.1)	− (≥ 0.5–4.0 mg/l)	An additional dose hours before surgery might provide an alternative prophylactic dosing during in utero surgery
Bernard et al. (1977) [21]	Prospective study	40	–	68.8 (35–102)	Healthy women scheduled for elective therapeutic abortion and sterilization by hysterectomy	T2: 14 ± 3.7* (8–20)	I.m. 14 mg/kg (interval between administration of cefazolin and procedure ranged from 0.25– 68.5 h)	Cmean,serum (mg/l)* 2 h: 39.2 4 h: 16.1 8 h: 3.9 (Cmean at other time points are not defined) t1/2 in maternal serum: 1.5 h	–	–
Brown et al. (1990) [18]	Prospective study	7	–	72.4 ± 12.6* (160 ± 27.7 lb)	Pregnant women receiving intravascular intrauterine transfusions	T3: 27 ± 3.4*	I.v. 2g administered in addition to the sedative directly before the procedure	Concentration (mg/l)* : 121 ± 50	(≥ 2–8 mg/l)	–
Dotters-Katz et al. (2019) [29]	Prospective observational study	20 High QBL: 5 Lower 75% QBL: 15	Lower 75% QBL: 32.6 [27.3–35.1] High QBL: 32.9 [32.8–34.1]	BMI (kg/m2) Lower 75% QBL: 31.9 [25.6–35.2] High QBL: 38.1 [34.5–50.3]	Women undergoing caesarean delivery	T4: 34–41	I.v. 2g for women weighing < 100kg, 3g for women weighing ≥ 100 kg within 60 min of skin incision	AT sample 1 (µg/g): Lower 75% QBL: 7.2 [4.1–11] High QBL: 4.5 [3.6–9.7] AT sample 2 (µg/g): Lower 75% QBL: 3.5 [1.9–5.0] High QBL: 3.9 [3.0–5.5]	(≥ 4 µg/g)	Dose is too low, as more than half of subjects had an adipose cefazolin level of below MIC post-fascial closure
Dotters-Katz et al. (continued) [29]	–	–	–	–	–	–	–	Maternal blood sample 1 (mg/l)* : Lower 75% QBL: 136 [104–164] High QBL: 134 [128–205] Maternal blood sample 2 (mg/l)* : Lower 75% QBL: 96.2 [90.4–115] High QBL: 82.3 [75.6–93.6] Maternal blood sample 3 (mg/l)* : Lower 75% QBL: 77.7 [68.9–91.9] High QBL: 65.3 [56–78.8] Maternal blood sample 4 (mg/l)* : Lower 75% QBL: 61.1 [54.4–74.8] High QBL: 50.9 [44.4–71.5] t1/2 (h)* Lower 75% QBL: 0.9 [0.8–1.2] High QBL: 0.8 [0.7–1.0]	–	–
Dotters-Katz et al. (continued) [29]	–	–	–	–	–	–	–	AUC (mg*h/l)* Lower 75% QBL: 710.5 [623.2–766.7] High QBL: 622.1 [481.6–880.8] Plasma CL rate (mg/(mg/l)/h)* Lower 75% QBL: 0.10 [0.09–0.12] High QBL: 0.15 [0.08–0.17] Cmax (mg/l)* Lower 75% QBL: 140 [112–172] High QBL: 134 [128–205]	–	–
Eley et al. (2020) [14]	Prospective study	12	23.8 ± 4.8	119.1 ± 18.8 BMI (kg/m2): 41.5 [39.7–46.6]	Women with obesity (BMI > 35 kg/m2) undergoing caesarean delivery	T4: ≥ 37	I.v. bolus, 2 g within 30 min of skin incision	Total plasma concentrations (mg/l): 0.17 h: 118.1 [93.5–142.8] 0.5 h: 81.9 [66.7–96.7] 1 h: 59.9 [48.8–70.9] 1.5 h: 49.8 [43.0–56.9] 3 h: 35.9 [31.8–39.8]	–	Administering two 2 g boluses 2 h apart when surgery continues could provide an approach to practice change. Using two boluses of 3 g requires more research
Eley et al. (continued) [14]	–	–	–	–	–	–	–	Unbound (free) plasma concentrations (mg/l): 0.17 h: 46.2 [33.4–59.4] 0.5 h: 29.0 [23.9–34.3] 1 h: 19.3 [15.1–23.4] 1.5 h: 12.8 [9.7–16.6] 3 h: 9.8 [7.6–11.7] Interstitial fluid concentrations (mg/l): 0.25 h: 5.8 [1.3–11.2] 0.5 h: 11.7 [4.4–20.0] 0.75 h: 8.3 [1.3–15.7] 1 h: 7.5 [3.9–12.0] 1.5 h: 7.1 [4.9–8.1] 2 h: 5.7 [4.2–8.1] 2.5 h: 3.7 [0.32–7.8] Values are estimates: CL (l/h): 25.0 ± 7.0 Vc (l): 10.5 ± 2.1 Vp (l): 25.0 ± 12.1	–	–
Elkayal et al. (2021) [24]	Prospective study	24	30 [26–32.3]	80.5 [70.5- –89.7]	Women colonized with GBS undergoing vaginal delivery	T4: 39 [39, 40]	I.v. infusion, 2 g (n = 24) + 1 g if no delivery after 8h of initial infusion (n = 8)	Plasma concentration (mg/l): 61 [23.3–99.4] Values in estimate (%RSE) CL (l/h): 7.2 (10) Vc (l): 6.2 (19) Vp (l): 7.0 (23)	– (≥ 1 mg/l)	Standard predelivery cefazolin dosing showed to be adequate
Elkomy et al. (2014) [26]	Prospective study	20	32.5 ± 5.3	79.3 ± 8.3	Women undergoing caesarean delivery	T4: 39.1 ± 0.86	I.v. bolus, 1 g within 1 h of skin incision	Values given as: point estimates (%SE) CL during pregnancy (l/h): 7.2 (7.8) CL postpregnancy (l/h): 4.1 (7.7) Vd during pregnancy: 9.4 (7.1)	> 70% for MIC 8 mg/l When dose is less than 2 g or administered less than 1 h before delivery	Larger doses or shorter dosing intervals are recommended for surgical prophylaxis in pregnant women
Fiore Mitchell et al. (2001) [19]	Prospective study	26	31 ± 5	–	Undergoing caesarean delivery with intact membranes	T4: 39 ± 1	I.v. 1 ginfusion 0.5 h (n = 5), 1 h (n = 5), 2 h (n = 6), 4 h (n = 5), 6 h (n = 5)	Concentration–time profile shown in Fig. 4	96%* (MIC90 ≥ 0.5 mg/l)	According to the MIC90 used in this article, almost all plasma concentrations are above the desired MIC. However, if other aims are used (> 4 or 8
Fiore Mitchell et al. (continued) [19]							prior to incision			mg/l) then the drawn conclusions should be reconsidered
Fouks et al. (2020) [20]	Prospective study	Ntotal: 42 T0: 17 1 g group: n = 21 2 g group: n = 21	T0: 53 ± 15.8 1 g group: 34 ± 1.1 2 g group: 34.6 ± 7.1	T0: 61.8 ± 6.1 1 g group: 67.3 ± 6.1 2 g group: 92.4 ± 8.2	Undergoing caesarean delivery	T4 1 g group: 38 ± 2 2 g group: 38 ± 0	I.v. infusion, 1 g group 30 min prior to skin incision to women weighing < 80 kg; 2 g group 30 min prior to skin incision to women weighing ≥ 80kg	Concentrations (mg/l)* T0: At incision: 112.7 ± 32.2 30 min post-incision: 75.2 ±20.3 1 g group: At incision: 91.0 ± 30.8 30 min post-incision: 55.4 ± 16.6 2 g group: At incision: 128.6 ± 41.8 30 min post-incision: 87.0 ± 26.0 t1/2 (h) T0: 1.7 ± 1.1 1 g group: 1.2 ± 0.6 2 g group: 2.6 ± 2.1	(≥ 8 mg/l)	A single-dose 1 g (< 80 kg) or 2 g (> 80 kg) provides cefazolin serum concentrations above MIC for susceptible pathogens in most women undergoing scheduled caesarean delivery
Groff et al. (2017) [8]	Prospective study	Ntotal: 8 Obese group (BMI ≥ 30 kg/m2): 4 Nonobese group (BMI < 25 kg/m2): 4	≥ 18	Values given as mean (SEM) BMI (kg/m2) obese: 35.2 ± 2.7 BMI (kg/m2) nonobese: 22.4 ± 2.5	Obese (BMI ≥ 30 kg/m2) and nonobese (BMI < 25 kg/m2) women undergoing caesarean delivery	T4: ≥ 37	I.v.-bolus, 2 g, average time (min) between administration and delivery: 30 (18–37)	Total mean blood cefazolin (mg/l)* First maternal blood sample (within 10 min after cefazolin infusion): Obese: 144 Nonobese: 135.4 Second maternal blood sample (within 10 min after delivery): Obese: 91.2 Nonobese: 84 Total and free plasma concentrations were > MIC90 for GBS (0.5 mg/l), S. aureus (0.12 mg/l), and E. coli (16 mg/l) No correlation between maternal BMI and total and free cefazolin was observed	100%* (≥ 16 mg/l)	Routine prophylaxis with 2 g cefazolin for pregnant women undergoing planned caesarean section seems adequate in both patients without and with obesity 2 g provides in all women with and without obesity cefazolin serum concentrations above MIC90 for susceptible pathogens
Grujić et al. (2010) [27]	Prospective study	Ntotal: 49 T0: 4 T4: 45	28.9 ± 6.1	80.0 ± 11.9	Undergoing caesarean delivery or undergoing gynecological surgery	T0/T4	I.v., 2 g 10 min before surgery	Cefazolin plasma concentration (mg/l)* T0: Immediately after operation: 30.1 ± 13.7 6 h after operation: 17.2 ± 8.1 T4: Immediately after operation: 44.8 ± 22.0 6 h after operation: 24.8 ± 9.2 T0: Ke (h-1): 0.11 ± 0.01 t1/2 (h): 6.3 ± 0.97 Vd (l): 66.8 ± 23.1 CL (l/h): 7.5 ± 3.0 T4: Ke (h-1): 0.10 ± 0.05 t1/2 (h): 8.3 ± 6.3 Vd (l): 48.3 ± 19.8 CL (l/h): 4.9 ± 2.3	– Susceptible: ≤ 8mg/l; intermediate: 16 mg/l; resistant: ≥ 32 mg/l	It is recommended to monitor the concentrations of cefazolin individually after caesarean section
Grupper et al. (2017) [15]	Population PK analysis	67	30.9 ± 6	102.6 ± 24 BMI (kg/m2): 38.7 ± 7.5	Overweight and women with obesity undergoing caesarean section	T4 ≥ 37	I.v. bolus, 2 g or 3 g Described in Swank et al.	Values are estimates CL (l/h): 7.4 ± 5.3 Vc (l): 11.8 ± 9.4 Vat (l): 80.1 ± 55.5	T = 1 h 1 g: 93.7% 2 g: 96.5% 3 g: 97.6%	Cefazolin in doses of 2 g or 3 g likely yields concentrations above 2 mg/l for 1.5 h and 2 h, respectively
Grupper et al. (2017) [15]	–	–	–	–	Delivery	–	[13], Maggio et al. [10] and Pevzner et al. [12]	–	T = 1.5 h 1 g: 84.4% 2 g: 94.5% 3 g: 95.2% T = 2 h 1 g: 74.5% 2 g: 91.5% 3 g: 93.3%	However, the aimed MIC in this study (2 mg/l) is significantly lower than the other MIC aims found in other studies (previously 4 mg/l and later 8 mg/l)
van Hasselt et al. (2014) [25]	Population PK modelling by pooling one prospective clinical study (Allegaert et al. [17] and two other studies (Fiore Mitchell et al. [19] and Brown et al. [18])	94	Values given as median (range): 31 (20–42)	Values given as median (range): 72 (54–99)	Described in Allegaert et al. [17] and two other studies (Fiore Mitchell et al. [19] and Brown et al. [18])	Values given as median (range): T2–3: 33 (17–40)	I.v., described in Allegaert et al. [17], Fiore Mitchell et al. [19] and Brown et al. [18])	Values given as estimate (%RSE) CL (l/h)* : 8.5 (44) Vc (l): 14.1 (25) Vp (l): 17.1 (7)	–(≥ 4 mg/l)	Simulation of free and total cefazolin concentration–time profiles suggested that administering 2 g cefazolin every 6 h, rather than every 8 h, prolonged therapeutic concentrations while remaining feasible for implementation in routine clinical practice
Kram et al. (2017) [9]	Prospective observational study	Ntotal: 84 2 g group: 65 3 g group: 19	Values given as mean (95% CI) Overall: 29.5 (28.2–30.7) 2 g group: 29.6 (28.1–31.1) 3 g group: 29.9 (26.6–31.2)	Values given as mean (95% CI) Overall: 107 (103–111) 2 g group: 99.8 (97.1- 103) 3 g group: 132 (126- 138) BMI (kg/m2): Overall: 40.6 (39.3–41.9) 2 g group: 38.3 (37.3– 39.3) 3 g group: 48.4 (46.5– 50.4)	Women with obesity (BMI > 30 kg/m2) undergoing caesarean delivery	T4: ≥ 36	I.v., 2 g for body weight < 120 kg and 3 g for body weight ≥ 120 kg administered 30–60 min before anticipated time of skin incision	Closure (µg/g): Overall: 4.7 [2.8–7.6] 2 g group: 4.5 [2.8–7.3] 3 g group: 6.9 [2.–10.6] Maternal blood sample (mg/l)* drawn following skin closure: Overall: 43.7 [30.6–60.2] 2 g group: 41.6 [26.3–57.0] 3 g group: 45.3 [36.7–68.3]	(≥ 1–8 mg/l)	A cefazolin dose of 2 g (BW < 120 kg) or 3 g (BW ≥ 120 kg) achieves adequate concentrations to cover a MIC of 8 mg/l in 91.7% of women
Maggio et al. (2015) [10]	Double-blind randomized controlled trial	Ntotal: 57 2 g group: 28 3 g group: 29	2 g group: 30 [25.5–34.0] 3 g group: 32 [22–44]	BMI (kg/m2) at delivery in: 2 g group: 38.9 [35.4–45.6] 3 g group: 39.3 [36.7–44.8]	Women undergoing caesarean delivery	T4: ≥ 37	I.v.-bolus, 2 or 3 g < 60 min before the start of the surgery	Serum cefazolin concentrations (µg/g) Initial: 2 g group: 113.1 [104.5–142.3] 3 g group: 208.7 [193.3–244.9] P = 0.004 Opening: 2 g group: 100.7 [90.4–134.2]	(≥ 2–8 mg/l)	The recommended use of 3 g cefazolin in women with obesity is not supported by this study A dose of 2 g or 3 g provided for all samples cefazolin adipose tissue concentrations above the 2 µg/g MIC for Enterobacteriaceae
Maggio et al. (continued) [10]								3 g group: 153.7 [123.7–166.0] P = 0.06 Closing: 2 g group: 75.1 [68.9–78.4] 3 g group: 83.8 [61.7–115.3] P = 0.47 AT cefazolin concentrations (µg/g) Opening: 2 g group: 9.4 [5.1–13.4] 3 g group: 11.7 [7.0–18.3] P = 0.12 Closing: 2 g group: 8.4 [4.4–13.2] 3 g group: 8.7 [6.7–18.8] P = 0.31 AT cefazolin concentrations (µg/g) stratified by BMI: BMI 30–39.9 kg/m2:
Maggio et al. (continued) [10]								Opening: 2 g group: 10.7 [7.2–21.2] 3 g group: 13.0 [10.1–24.2] P = 0.17 Closing: 2 g group: 11.4 [7.6–18.5] 3 g group: 15.2 [8.5–21.2] P = 0.40 BMI ≥ 40 kg/m2: Opening: 2 g group: 8.9 [5.0–10.6] 3 g group: 7.0 [6.2–13.1] P = 0.44 Closing: 2 g group: 5.6 [4.1–9.0] 3 g group: 7.5 [5.4–8.5] P = 0.64
Pevzner et al. (2011) [12]	Prospective study	Ntotal: 29 Lean group (BMI < 30 kg/m2): 10	Lean: 28.3 ± 5.6 Obese: 32.8 ± 7.1	Lean: 65.7 ± 4.8 Obese: 90.0 ± 10.8	Lean (BMI < 30 kg/m2), obese (BMI ≥30 kg/m2), and extremely	T4: ≥ 37	I.v., 2 g cefazolin 30–60 min before skin incision	AT sample 1 (µg/g): Lean: 9.4 ± 2.7 Obese: 6.4 ± 2.3 Extremely obese: 4.4 ± 1.2	– (≥ 4 µg/g)	–
Pevzner et al. (continued) [12]		Obese group (BMI 30–39.9 kg/m2): 10 Extremely obese group (BMI ≥ 40 kg/m2): 9	Extremely obese: 28.1 ± 4.6	Extremely obese: 121.8 ± 16.1 BMI (kg/m2): Lean: 26.7 ± 1.3 Obese: 34.1 ± 2.6 Extremely obese: 44.5 ± 4.5	obese (BMI ≥ 40 kg/m2) women undergoing caesarean delivery			AT sample 2 (µg/g): Lean: 9.1 ± 6.4 Obese: 6.6 ± 3.5 Extremely obese: 4.7 ± 1.5 Maternal blood sample (mg/l)*: Lean: 65.2 ± 30.0 Obese: 54.9 ± 41.3 Extremely obese: 49.9 ± 20.7
Philipson et al. (1987) [28]	Prospective study	6	–	T2: 67.9 ± 6.9 T0: 62.3 ± 6.3	Pregnant women with asympto matic lower urinary tract infections	T2: 24.5 ± 4.2* (19–33)	I.v., 2 times 0.5 g: one at T2 and one at T0	Concentration–time profile shown in Fig. 4 T2: t1/2 (h): 1.1 ± 0.11 AUC (mg*h/l): 75.7 ± 27.6 CL (l/h): 7.3 ± 3.0 CL/BW (l/h/kg): 0.11 ± 0.034 Vdarea (l): 11.7 ± 4.6 Vdarea/BW (l/kg): 0.17 ± 0.050 T0: t1/2 (h): 1.7 ± 0.26	–	Total dosage and dosage per kg bodyweight should be increased in pregnant women. A dosage increase of about 40–60% is reasonable
Philipson et al. (continued) [28]								AUC (mg/l*h): 110.0 ± 20.7 CL (l/h): 4.7 ± 0.74 CL/BW (l/h/kg): 0.075 ± 0.012 Vdarea (l): 11.6 ± 2.8 Vdarea/BW (l/kg): 0.19 ± 0.045
Popović et al. (2007) [23]	Prospective study	Ntotal: 22 T0: 4 T4: 18	–	T0: 70 ± 8 T4: 74 ± 10	Undergoing caesarean delivery or undergoing gynecological surgery	T4	I.v.-bolus, 2 g 10 min before surgery	Cefazolin plasma concentration (mg/l) T0: Immediately after operation: 30.1 ± 13.8 6 h after cefazolin application: 17.4 ± 8.1 T4: Immediately after operation: 44.8 ± 22.0 6 h after cefazolin application: 24.9 ± 9.2 T0: Ke (h-1): 0.11 ± 0.017 t1/2 (h): 6.3 ± 0.97		A single dose of cefazolin may well be the optimal preoperative prophylactic treatment for obstetrical and gynecological surgical procedures
Popović et al. (continued) [23]								Vd (l): 66.8 ± 23.1 CL (l/h): 7.5 ± 3.0 T4: Ke (h-1): 0.11 ± 0.052 t1/2 (h): 8.3 ± 6.3 Vd (l): 48.3 ± 19.81 CL (l/h): 4.9 ± 2.3
Stitely et al. (2013) [11]	Randomized controlled trial	Ntotal: 20 2 g group: 11 4 g group: 9	2 g group: 31.1 ± 6.5 4 g group: 30.3 ± 4.6	2 g group: 117.8 ± 23.4 4 g group: 107.8 ± 28.3 BMI (kg/m2): 2 g group: 46.0 ± 6.0 4 g group: 43.2 ± 8.4	Obese women undergoing caesarean delivery	T4 GA (weeks): 2 g group: 38.8 ± 1.3 4 g group: 36.9 ± 3.4	I.v. 2 g or 4 g	Cefazolin plasma concentration (mg/l) At incision: 2 g group: 155.5 ± 51.0 4 g group: 346.2 ± 166.0 At closure: 2 g group: 83.5 ± 35.0 4 g group: 150.1 ± 55.5 Cefazolin subcutaneous concentration (µg/g) At incision: 2 g group: 18.4 ± 6.7		–
Stitely et al. (continued) [11]								4 g group: 40.1 ± 24.1 At closure: 2 g group: 21.7 ± 16.0 4 g group: 34.9 ± 17.4
Swank et al. (2015) [13]	Prospective study	Ntotal: 28 Obese group (BMI 30–40 kg/m2): 14 Extremely obese group (BMI > 40 kg/m2): 14	31.5 [26.5–36.5]	105.6 [87.2–120.0] BMI (kg/m2): Obese: 33.82 ± 2.92 Extremely obese: 45.03 ± 3.77	Obese women undergoing caesarean delivery	T4: ≥ 37	I.v. bolus, 3 g 30–60 min before incision	AT cefazolin concentration (µg/g) Initial: Obese group: 22.4 [20.3–34.4] Extremely obese group: 9.6 [7.6–15.8] Closure: Obese group: 24.8 [18.9–34.1] Extremely obese group: 7.1 [6.2–9.8] Serum concentration (mg/l): Obese group: 166.7 [143.8–185.7] Extremely obese group: 176.5 [127.9–192.6]	8 mg/l	The weight breakpoint that would allow most of with obesity patients to achieve concentrations above the recommended MIC with a dosing of 3 g would be 80 kg or a BMI of 30 kg/m2
Yamada et al. (1982) [22]	Prospective study	31	–	61.5 ± 6.5	Women undergoing vaginal delivery	T4: full term	I.v. injection, 2 g 0.25–9.5 h before vaginal delivery	Concentration–time profile shown in Fig. 4		–
Young et al. (2015) [16]	Double-blinded randomized controlled trial	Ntotal: 26 2 g group: 13 3 g group: 13	2 g group: 29.0 [23.5–34.0] 3 g group: 31 [30.0–35.0]	BMI (kg/m2): 2 g group: 42.9 [39.1–46.2] 3 g group: 41.8 [37.3–44.6]	Obese women (BMI > 30 kg/m2) undergoing caesarean delivery	T4: ≥ 37	I.v., 2 g or 3 g within 30 min of incision	Concentration–time profile shown in Fig. 4 AT concentrations (µg/g): Pre-fascial entry: 2 g group: 7.4 [5.4–9.4] t (min): 4 (2–6) 3 g group: 12.0 [5.4–16.0] t (min): 3 (1–10) Closure of hysterotomy: 2 g group: 12.4 [10–14] t (min): 25 [22–38] 3 g group: 16.8 [13.0–23.0] t (min): 28 [22–37]		Women with obesity administered either a 2 g or 3 g dose of cefazolin appears to achieve appropriate maternal AT levels above the MIC of causative organisms of SSIs. Therefore, alterations in currently accepted standards of practice is not recommended
Young et al. (continued) [16]								Post-fascial closure: 2 g group: 11.8 [9.2–16.2] t (h)*: 0.69 [0.58–.91] 3 g group: 14.6 [10.8–20.8] t (h)*: 0.85 [0.62–1.1] Values given as median ± SE AUC versus time curve (mg*h/l)*: 2 g group: 843,480 ± 80,568 3 g group: 1,632,240 ± 141,948 t1/2 (h)*: 2 g group: 1.8 ± 0.10 3 g group: 2.1 ± 0.14 Plasma CL rate (l/h)*: 2 g group: 8.4 ± 0.6 3 g group: 6.6 ± 0.6 Plasma Vd (l/kg): 2 g group: 13.4 ± 1.1
Young et al. (continued) [16]								3 g group: 13.5 ± 1.5 Umbilical cord blood CL cate (mg/l): 2 g group: 21.4 ± 1.5 3 g group: 34.5 ± 5.8 Plasma Vdss (l/kg): 2 g group: 19.8 ± 1.2 3 g group: 18.6 ± 1.4 Umbilical cord plasma concentration to maternal plasma concentration ratio: 2 g group: 0.18 ± 0.02 3 g group: 0.22 ± 0.06 Maternal renal CL (l/h)*: 2 g group: 1.3 ± 0.29 3 g group: 1.4 ± 0.17
Ceftezole
Spreafico et al. (1987) [31]	Prospective randomized trial	11	–	–	Pregnant women undergoing caesarean section	T4	I.v. 2 g 30 min before surgery	Mean Concentration (mg/l* or µg/g) Maternal serum (n = 9): 68.5 ± 22.6 Myometrium (n = 11): 85.4 ± 31.5 Endometrium (n = 8): 61.7 ± 27.5 Placenta (n = 11): 27.6 ± 15.0	–	–
Cephalothin
Duff et al. (1982) [32]	Prospective study	10	24.2 ± 5.8 (n = 30)	–	Pregnant women undergoing caesarean section	T4: at term	2 g intraoperative irrigation	Serum concentrations (mg/l) 15 min: 0.79 ± 0.3 (n = 8) 60 min: 0.19 ± 0.13 (n = 2) 120 min: 0.03 ± 0.03 (n = 1)	–	–
Nöschel et al. (1980) [33]	Prospective study	Ntotal: 27 T0: 10 T3: 10 T4: 7	–	–	–	T0, T3, and T4	–	t1/2 (h)* T0: 0.92 ± 0.26 T3: 0.85 ± 0.17 T4: 0.91 ± 0.33	–	–
Cephradine
Philipson et al. (1987) [28]	Prospective study	12	NR	T2: 62.9 ± 9.1 T5: 61.0 ± 8.0	NR	T2: 10–29 (17.7 ± 6.0*)	2 times 0.5 g: one at T2 and one at T5 (after pregnancy, when breastfeeding had ceased and normal menstruation had returned	T2 t1/2 (h): 0.50 ± 0.098 AUC (mg*h/l): 24.3 ± 8.0 CL (l/h): 22.4 ± 6.5 CL/BW (l/h/kg): 0.36 ± 0.97 Vdarea (l): 15.6 ± 3.8 Vdarea/BW (l/kg): 0.25 ± 0.057 T5 t1/2 (h): 0.68 ± 0.20 AUC (mg/l*h): 38.9 ± 12.9 CL (l/h): 14.1 ± 4.1 CL/BW (l/h/kg): 0.23 ± 0.069 Vdarea (l): 13.2 ± 3.5 Vdarea/BW (l/kg): 0.22 ± 0.064	NR	A dosage increase of 40–60%

Values are given as mean ± SD or median [interquartile range] or mean (range), unless otherwise specified

AT adipose tissue, AUC area under the curve, BMI body mass index, BW body weight, CI confidence interval, CL clearance, C_max maximum observed concentration, C_mean mean concentration, GA gestational age, GBS Group B Streptococcus, GNR gram-negative rod, h hours, i.m. intramuscular, i.v. intravenous, Ke elimination rate constant, MIC minimal inhibitory concentration, min minutes, n number of determinants, NR not reported, N_total total number of participants of the study, PK pharmacokinetics, PTA probability of target attainment, QBL quantitative blood loss, RSE root squared error, SE standard error, SEM standard error of means, ss steady-state, SSI surgical site infections, t time, T0 nonpregnant, t_1/2 half-life, T1, 2, 3 first, second and third trimester, T4 intrapartum, T5 postpartum, T_eq equilibration half-time, Vat adipose tissue volume, Vc central volume of distribution, Vd volume of distribution, Vp peripheral volume of distribution

*Values calculated manually from the available data

Cefatrizine

Only one study on cefatrizine was included, which compared the PK and exposure of oral cefatrizine administration (1 g every 12 h, 3 g total) in second trimester pregnant women relative with nonpregnant women [7]. Study characteristics and PK/exposure parameters are presented in Table 1.

No information on absorption-related parameters was reported. When focusing on the distribution-related parameter, C_max was significantly lower (P < 0.05) in second trimester pregnant women compared with nonpregnant women, with a decrease of 44.5%. Considering the clearance-related parameters, a significant reduction (P < 0.05) of 42.8% in AUC_0–12h was observed, while t_1/2 significantly increased (P <0.05) with 63.2% during the second trimester compared with the nonpregnant state [7].

Although Papantoniou et al. [7] did not report a target concentration or PTA, the authors concluded that shortening the dosing interval may provide more optimal cefatrizine exposure than increasing the dose. However, this conclusion appears contradictory when considering the reported t_1/2. Moreover, no evidence-based dosing regimens for cefatrizine has been established for pregnant women, underscoring the need for further research.

In summary, based on limited data, it is plausible that PK and exposure of cefatrizine during pregnancy are altered, as a trend toward decreased AUC driven with increased CL was observed. Notably, these findings are not consistent with an increased t_1/2, which would not align with the observed increase in CL. However, more robust studies are required to confirm these findings. To achieve adequate cefatrizine exposure, shortening the dosing interval, rather than increasing the dose, is suggested.

Cefazolin

Cefazolin is the most extensively studied cephalosporin throughout pregnancy. This review included 22 studies on cefazolin [8–29], comprising 17 prospective studies, 3 randomized controlled trials, and 2 population PK studies. Cefazolin was administered i.v. at doses ranging from 0.5 to 3 g and was investigated in both pregnant women who were lean (64.0% of studies) and pregnant women with obesity (BMI ≥ 30 kg/m²) (36.0% of studies). The majority of studies focused on pregnant women at time of delivery (77.3%), followed by those in third trimester (16.3%) and second trimester (9.1%). Study characteristics and PK/exposure parameters are presented in Table 1.

Obese

Out of the 22 studies, 10 examined the use of cefazolin in women with obesity undergoing caesarean section. The number of subjects in the different studies ranged from 8 to 84. The mean age ranged from 23.8 to 32.8 years. Groff et al. included only participants aged over 18 years but did not specify their mean age [8]. Mean BMI values ranged from 34.1 to 48.4 kg/m². The mean gestational age ranged from 36.9 to 39.3 weeks. In all studies, cefazolin was administered i.v. within 30–60 min prior to the caesarean section.

The PK and exposure parameters of pregnant women with obesity (if possible, in comparison with nonpregnant and/or women without obesity) of the included studies are presented in Table 1. Seven studies examined cefazolin serum concentrations at the start of caesarean section and at incision closure in pregnant women with obesity. When 2 g of cefazolin was administered as an i.v. bolus, mean maternal serum concentrations ranged from 39.7 to 155.5 mg/l at 15–60 min before the start of caesarean section [10, 11, 13], and from 19.5 to 91.2 mg/l, measured 28.0–77.1 min after delivery [8–12]. Following a dose of 3 g, concentrations ranged from 153.7 to 176.5 mg/l preincision [10, 13], and from 27.9 to 83.8 mg/l postdelivery [9, 10]. The highest concentrations were observed after administration of a 4 g dose, 346.2 mg/l at the start and 150.1 mg/l after delivery [11]. Across studies comparing women with obesity (BMI ≥ 30 kg/m²) and women without obesity, cefazolin concentrations were 6.4–36.8% lower in the obese group, though these differences were not statistically significant [8, 10, 12, 13]. Comparisons between pregnant women with obesity and extreme obesity (BMI ≥ 40 kg/m²) showed nonsignificantly lower cefazolin concentrations ranging from 9 to 30% in the extremely obese group, relative to women with obesity [12]. Despite these lower levels, increasing the cefazolin dose from 2 g to 3 or 4 g in women with higher body weight or BMI was associated with 8–122% higher serum concentrations compared with those receiving 2 g [9, 13].

Six studies examined cefazolin adipose tissue concentrations at the start of caesarean section and at incision closure in pregnant women with obesity [9–13, 29]. When 2 g of cefazolin was administered, mean adipose tissue concentrations ranged from 4.4 to 18.4 µg/g at the start of caesarean section [9–13], and from 4.3 to 21.7 µg/g after delivery [9–13]. Following a dose of 3 g, concentrations ranged from 6.4 to 22.4 µg/g preincision and from 6.9 to 24.8 µg/g postdelivery [9, 10, 13]. The highest concentrations were observed after administration of a 4 g dose, with 40.1 µg/g at the start and 34.9 µg/g after delivery in pregnant women with obesity (BMI > 35 kg/m²) [11]. Across studies comparing pregnant women without obesity (BMI < 30 kg/m²), pregnant women with obesity (BMI 30–40 kg/m²), and pregnant women with extreme obesity (BMI ≥ 40 kg/m²), cefazolin adipose tissue concentrations were consistently lower in the obese and extremely obese groups. Pevzner et al. reported a statistically significant 32% (P = 0.009) and 53% (P < 0.001) lower concentration at the start of caesarean section in women with obesity and extreme obesity, respectively, and a nonsignificant 27% (P = 0.360) and 48% (P = 0.070) lower concentration at incision closure compared with women without obesity [12]. Swank et al. observed 25% and 45% lower concentrations at the start and 32% and 42% lower concentrations at closure in women with obesity and extreme obesity, respectively, following a 2 g dose (P < 0.05) [13]. Maggio et al. reported nonsignificant 16% and 50% lower adipose tissue concentrations in women with extreme obesity at start and closure, respectively, after a 2 g dose [10]. Pevzner et al. also compared women with obesity and extreme obesity and found 31% and 28% lower concentrations at start and closure, respectively, in the extremely obese group [12]. Kram et al. compared cefazolin adipose concentrations between women receiving 2 g (< 120 kg body weight) and 3 g (≥ 120 kg body weight) and reported nonsignificant 19% and 55% lower concentrations in the 2 g group [9]. Stitely et al. compared cefazolin subcutaneous concentrations at the start of caesarean section and closure of incision after administration of a 2 g or 4 g cefazolin dose in pregnant women obesity (BMI > 35 kg/m²). Increasing the cefazolin dose from 2 to 4 g in pregnant women with obesity (BMI > 35 kg/m²) was associated with 118% and 60% higher adipose tissue concentrations at the start of caesarean section [11].

Young et al. reported the median AUC from time 0 to 8 h (AUC_0–8h), as well as the median area under the cefazolin adipose tissue concentration versus time curve from the beginning to the end of the caesarean delivery (AUC_{0–fascial closure}). Both the AUC_0–8h and AUC_{0–fascial closure} in pregnant women with obesity (BMI > 30 kg/m²) were greater after use of 3 g cefazolin dose compared with a 2 g dose (P = 0.002 and P = 0.0022, respectively) [16].

When focusing on the distribution and elimination phase, three studies reported on the CL and Vd of cefazolin in pregnant women with obesity [14–16] (Figs. 2A, 3A). No comparison with nonpregnant women was made. Grupper et al. used cefazolin serum and adipose tissue concentrations from three previous studies to create a two-compartment population PK model [15]. Using this model, the study reported a mean CL of 7.38 l/h, which is similar to estimates of CL in pregnant patients without obesity reported by previous studies. The study reported a mean volume of the central compartment (Vc) of 11.8 l [15]. Young et al. reported no significant difference of the CL and Vd in pregnant women with obesity (BMI > 30 kg/m²) after a 2 g cefazolin dose compared with a 3 g cefazolin dose [16]. Eley et al. created a PK model using cefazolin serum concentrations from pregnant women with obesity (BMI > 35 kg/m²) and reported a mean CL of 25.0 l/h and a mean Vc of 10.5 l [14]. In addition to total plasma concentrations, Eley et al. also reported free (unbound) plasma concentrations. Unbound plasma concentrations declined from 46.2 mg/l at 10 min after administration to 9.8 mg/l at 3 h, remaining above the commonly reported MIC range (2–16 mg/l) throughout the perioperative period [14].

Fig. 2.

Graphical representation of the described clearance (CL) values per cephalosporin from the included articles. The corresponding articles are described by the first author for each bar. A) Cefazolin, B) Cephradine, C) Cefoxitin, D) Cefuroxime, E) Ceftazidime, and F) Ceftriaxone. T0 nonpregnant, T1 first trimester, T2 second trimester, T3 third trimester, T4 intrapartum, T5 postpartum

Fig. 3.

Graphical representation of the described volume of distribution (Vd) values per cephalosporin from the included articles. The corresponding articles are described by the first author for each bar. A) Cefazolin, B) Cephradine, C) Cefoxitin, D) Cefuroxime, and E) Ceftriaxone. T0 nonpregnant, T1 first trimester, T2 second trimester, T3 third trimester, T4 intrapartum, T5 postpartum

Five studies reported on cefazolin target attainment in pregnant women with obesity [8, 13–16]. Groff et al. reported that there was no correlation between maternal BMI and maternal total or free (unbound) cefazolin concentration after delivery [8]. Furthermore, both total and free cefazolin concentrations exceeded the MIC90 values for common pathogens, including group B Streptococcus, S. aureus, and E. coli, in all participants [8]. Grupper et al. reported that, on the basis of the PTA, a 2 g dose provides 92.4% likelihood of the concentration reaching the MIC of 2 mg/l during average caesarean delivery [15]. Young et al. demonstrated that a 2 g dose of cefazolin achieves tissue concentrations exceeding the MIC of 1 µg/g for gram-positive cocci and 4 µg/g for gram-negative rods [16]. Thus, results from the three aforementioned studies do not support a dose alteration for obese women undergoing caesarean delivery. However, Swank et al. reported that only 20% of initial adipose samples from obese women (BMI = 30–40 kg/m²) reached appropriate concentrations after a 2 g cefazolin dose, where 100% of the women reached appropriate concentrations after a 3 g cefazolin dose [13]. Therefore, this study suggested that a 3 g cefazolin dose would be necessary to achieve appropriate concentrations in patients with a BMI > 30 kg/m², or body weight > 80 kg [13]. The results of the study by Eley et al. support the suggested dose alteration, as the calculated mean fractional target attainment (FTA) of obese patients (body weight > 90 kg) was 77.8% [14]. To improve the FTA in women between 90 and 150 kg, the study suggested a 3 g bolus initially, followed by a 3 g bolus at 2 h [14].

In summary, the cefazolin serum concentrations, as well as the cefazolin adipose tissue concentrations, seem to be decreased in pregnant women with obesity compared with pregnant women without obesity. However, there is a large variety within the values, and the difference is not always significant. Furthermore, comparison with nonpregnant women was limited. A dose of 2 g cefazolin one h before caesarean delivery results in adequate antimicrobial target attainment in pregnant women with obesity. An additional dose may be required in patients with obesity if caesarean section is delayed or if the wound is not closed within 1.5–2 h. Swank et al. recommended a 3 g cefazolin dose in patients with obesity to achieve appropriate concentrations [13]. Eley et al. supported this dose alteration and recommended shortening the dosing interval to every 2 h [14]. Young et al. confirmed that i.v. cefazolin doses of 2 or 3 g are appropriate for patients with obesity, as both regimens achieved adipose tissue concentrations exceeding the MIC [16]. Limited data suggest adequate free cefazolin exposure throughout the perioperative period, with no evidence that obesity reduces free cefazolin concentrations.

Nonobese

Of the 22 studies, 12 focused on the use of cefazolin in pregnant women without obesity at different time points throughout pregnancy. The number of subjects in the different studies ranged from 6 to 94. The mean age ranged from 28.9 to 34.0 years. Six studies only included participants above 18 years old but did not report the age of the participants [17, 18, 23–25, 30]. The mean body weight ranged from 61.5 to 80.5 kg. The mean gestational age ranged from 24.5 to 39.1 weeks. Seven studies focused on cefazolin use at the time of delivery [19, 20, 22–24, 26, 27], four studies focused on cefazolin use during the second and third trimester [17, 18, 25, 28]. Only one study focused on cefazolin use during the first and second trimester [21].

The PK and exposure parameters of pregnant women without obesity (if possible, in comparison with nonpregnant women) of the included studies are presented in Table 1. Three studies reported on cefazolin serum concentrations during caesarean section in pregnant women without obesity. Fouks et al. reported a mean maternal serum concentration of 91.0 mg/l at the start of caesarean section and 55.4 mg/l 30 min later, where cefazolin was dosed as 1 g [20]. When cefazolin was dosed as 2 g 10 min before surgery, mean maternal serum concentrations in pregnant and nonpregnant women were 44.8 and 30.1 mg/l, respectively, immediately after a 30-min surgery [27]. Brown et al. reported a mean maternal cefazolin serum concentration of pregnant women, during their second and third trimester of 121 mg/l [18]. The samples were taken on average 30 min after administration of a 2 g cefazolin dose, during intrauterine transfusion [18]. Bernard et al. measured the mean maternal cefazolin serum concentrations of pregnant women, during their first and second trimester, at 2, 4, and 8 h after administration of a 14 mg/kg i.m. cefazolin dose [21]. The study reported mean concentrations of 39.2, 16.1 and 3.9 mg/l, respectively [21]. None of the studies reported on cefazolin adipose tissue concentrations in pregnant women without obesity.

When focusing on the distribution and elimination phase, four studies reported on the CL and Vd of cefazolin in pregnant women without obesity at time of delivery [23, 24, 26, 27]. The reported CL ranged from 4.9 to 7.2 l/h. The reported Vd ranged from 6.2 to 48.3 l, which represents a remarkably broad range. Elkomy et al. reported a 74% increase in cefazolin clearance during pregnancy [26]. Three studies reported on the t_1/2 of cefazolin in pregnant women without obesity at the time of delivery, ranging from 1.2 to 8.3 h, indicating substantial variability [20, 23, 27]. Grujić et al. compared the PK parameters with those of nonpregnant participants and concluded that pregnancy did not affect cefazolin PK [27].

Three studies reported on the CL and Vd of cefazolin in pregnant women without obesity during the second and third trimester [17, 25, 28] (Fig. 2A, 3A). The CL ranged from 7.3 to 8.5 l/h and Vd varied between 8.0 and 14.1 l. Philipson et al. reported a nonsignificant higher CL of 57% in pregnant women during the second trimester compared with nonpregnant women [28]. In the same study, the t_1/2 of cefazolin was 1.1 h in pregnant women and 1.7 h in nonpregnant women, representing a significant 35% decrease (P < 0.005) [28]. Bernard et al. reported a t_1/2 of 1.5 h in pregnant women without obesity during the first and second trimester [21].

Eight studies reported target attainment of prophylactic cefazolin therapy in pregnant women without obesity [17–20, 23, 24, 26, 27]. Five studies reported 100% attainment of the therapeutic target (MIC 2-16 mg/l) in all participants and therefore concluded that the cefazolin dose was adequate. Fiore Mitchell et al. reported that 96% of participants had cefazolin serum concentrations above therapeutic target of MIC₉₀ ≥ 0.5 mg/l at the time of delivery [19]. Elkayal et al. reported that 95.8% of participants had cefazolin serum concentrations above the therapeutic target of ≥ 1 mg/l at the time of delivery [24]. Therefore, both studies also concluded that the cefazolin dose was adequate. Philipson et al. used a 0.5 g cefazolin dose and recommended increasing the dose because cefazolin CL increases during pregnancy [28]. Elkomy et al. advised an initial 2 g cefazolin dose less than 1 h prior to surgery, where redosing every 2 h would be necessary to reach a target attainment rate above 50% in maternal blood [26].

In summary, data on cefazolin absorption and distribution in pregnant women without obesity remain limited. No comparison was made of cefazolin absorption and distribution parameters between pregnant and nonpregnant women and none of the studies report the cefazolin AUC or adipose tissue concentrations. Only two studies compared elimination parameters between pregnant and nonpregnant women, where it was concluded that the t_1/2 decreases and the CL increases during pregnancy [27, 28]. No comparison of PK parameters was made between the pregnancy trimesters and only one study included pregnant women during their first trimester. Out of eight studies that investigated cefazolin target attainment, seven studies reported that no dosing adjustments for cefazolin are necessary. However, one study suggested shortening the dosing interval to reach the target attainment rate in both maternal and cord blood [26]. Information on unbound cefazolin exposure was limited. However, Van Hasselt et al. incorporated both free and total cefazolin concentration–time profiles in population PK simulations and suggested that administering 2 g cefazolin every 6 h, rather than every 8 h, may prolong therapeutic concentrations while remaining feasible in routine clinical practice [25].

Ceftezole

The exposure of ceftezole was investigated in one randomized controlled trial. In this study, 11 pregnant women undergoing caesarean section received an i.v. dose of 2 g ceftezole as prophylaxis, administered 30 min prior to surgery (Table 1) [31].

No PK-related parameters, other than ceftezole concentrations, were assessed in this study. Despite the concentration data being reported, the study did not provide any statements regarding target attainment or recommendations for dose adjustments [31].

Cephalothin

Two studies investigating the PK and exposure of cephalothin were included (Table 1) [32, 33]. Duff et al. [32] examined ten term pregnant women undergoing caesarean section, where cephalothin was administered intraoperatively as an irrigation solution at approximately 2 g/l. Nöschel et al. [33] evaluated cephalothin PK across nonpregnant, term pregnant, and intrapartum women; however, both the cephalothin dose and study conditions were not reported.

Focusing on PK and exposure parameters, no absorption or distribution parameters were reported. Regarding elimination, the t_1/2 in term pregnant women was 7.9% and 6.9% lower, respectively, compared with nonpregnant and intrapartum women. However, these reductions were not statistically significant [32, 33].

In summary, available data on cephalothin PK and exposure during pregnancy remain limited. Consequently, no definitive conclusions can be drawn regarding changes in PK and exposure parameters between pregnant and nonpregnant women. A nonsignificant trend toward reduced t_1/2 during pregnancy was observed. Despite reported exposure data, no statements on target attainment or recommendations for dose adjustments were reported.

Cephradine

Only one study on the PK and exposure of cephradine was included [28] (Table 1), which evaluated differences between women in the second trimester and the postpartum period.

Absorption-related parameters were not reported. In terms of distribution and elimination, the Vd and CL values increased during the second trimester compared with postpartum, with 18.2% (P < 0.05) and 58.9% (P < 0.001), respectively (Figs. 2B, 3B). As a result of the increased CL, AUC was significantly lower (37.0%, P < 0.001) in pregnant women relative to postpartum women [28]. To achieve similar cephradine exposure, Philipson et al. [28] recommended increasing the total dose and dose per kg bodyweight by 40–60% during pregnancy.

In summary, while only one study has investigated cephradine PK and exposure during pregnancy, the findings suggest a trend toward increased Vd and CL in the second trimester. Although the study proposed adjusted dosing strategies, no data on target concentrations or probability of target attainment were reported.

Fig. 4.

Pooled mean A) serum and B–C) adipose tissue cefazolin concentration–time profiles from the included studies.

Second Generation Cephalosporins

No studies were identified that investigated the PK or exposure of cefaclor, cefmetazole, cefonicid, ceforanide, cefotetan, cefprozil, and cefuroxime axetil. Table 2 presents the study characteristics and the PK/exposure parameters of pregnant women (with comparisons to nonpregnant and/or postpartum women when available) from studies on cefamandole, cefoxitin, and cefuroxime.

Table 2.

Study and patient characteristics, PK and exposure parameters, probability of target attainment, and dose advice of the included second-generation cephalosporin studies, in alphabetical order by cephalosporin followed by author

Author (year) (citation)	Study design	Patient population number	Age (years)	Weight (kg)	Condition	Trimester (T0–T5) / GA (weeks)	Dose and administration route	PK/exposure parameters	PTA	Dosing advice
Cefamandole
Duff et al. (1982) [32]	Prospective study	10	24.2 ± 5.8 (n = 30)	NR	Pregnant women undergoing caesarean section	T4: At term	2 g intraoperative irrigation	Serum concentrations (mg/l) 15 min: 1.6 ± 0.49 (n = 10) 60 min: 0.78 ± 0.38 (n = 6) 120 min: 0.35 ± 0.22 (n = 3)	NR	NR
Cefoxitin
Flaherty et al. (1983) [34]	Prospective study	Ntotal: 14 I.v. group: 5 Uterine and peritoneal lavage group: 5 Peritoneal lavage group: 2	NR	NR	Pregnant women undergoing caesarean section	T4: At term	2 g i.v. or lavage solution	Vd (l): 18.8 t1/2 (h): 0.53 CL (l/h): 20.4 Concentration-time profile shown in Fig. 5A	NR	NR
Giamarellou et al. (1983) [35]	Prospective study	9	22.9 ± 5.0	NR	Pregnant women with termination of gestation	T2: 19–21	I.v. 2 g, three times a day	Serum concentrations (mg/l)* 1h: 26.7 ± 4.9 2h: 19.2 ± 1.5 4h: 0.6 ± 0.3 6h: 0 ± 0 8h: 0 ± 0 (Fig. 5A)	NR	NR
Roex et al. (1988) [36]	Prospective study	8	NR	NR	Pregnant women undergoing caesarean section	T4: 36–42 weeks	I.v. 4 g, given as 2 g, 1 g, and 1 g in 6 h intervals	After first administration (2 g): t1/2 (h): 0.99 ± 0.29 Vdss (l): 17.1 ± 3.2 CL (l/h): 19.4 ± 4.4 AUC (mg*h/l): 108.5 ± 27.4 After third administration (1 g): t1/2 (h): 1.0 ± 0.36 Vdss (l): 18.6 ± 7.0 CL (l/h): 22.7 ± 6.2 AUC (mg*h/l): 47.8 ± 16.0	16 mg/l	Using an i.v. infusion with an infusion rate of 310 mg cefoxitin per hour the required antibiotic level of 16 mg/l can be maintained during the infusion period after the initial bolusinjection of approximately 300 mg cefoxitin. No change in dosage needed
Cefuroxime
Bousfield et al. (1981) [37]	Prospective study	Ntotal: 20 Induced labor group: 10 Caesarean section group: 10	Induced labor group: 25 (16–32) Caesarean section group: 29 (17–36)	Induced labor group: 74.7 (63.0–85.8) Caesarean section group: 70.3 (52.3–88.7)	Undergoing Induced vaginal or elective caesarean delivery	T4: At term	I.v., induced labor group: 1.5 g every 4 h until delivery caesarean section group: 1.5 g at	Cefuroxime concentrations in maternal blood (mg/l) Induced labor group: concentration-time profile shown in Fig. 5B	NR	NR
Bousfield et al. (continued) [37]							Varying times before delivery (48 min, 5 h, and 37 min)	Caesarean section group: concentration-time profile shown in Fig. 5B
Craft et al. (1981)	Prospective study	Ntotal: 22 Induced labor group: 10 Caesarean section group: 12	NR	Induced labor group: 66.1 (53.0–83.0) Caesarean section group: 73.9 (58.2–85.0)	Pregnant women undergoing induced vaginal or elective caesarean delivery	T4: At term	I.m., Induced labor group: 0.75 g at time of amniotomy Caesarean section group: 0.75 g at varying times before delivery	Induced labor group: concentration-time profile shown in Fig. 5B for both induced labor group as Caesarean section group	NR	NR
Holt et al. (1994) [39]	Prospective study	Ntotal: 39 0.75 g group: 26 1.5 g group: 13	NR	Values given as median and range 0.75 g group: 71.5 (56–105)	Pregnant women undergoing vaginal or caesarean delivery	T4 Values given as median and range 0.75 g group:	I.v., 0.75 g or 1.5 g	0.75 g group: concentration-time profile shown in Fig. 5B	MIC is generally, < 1 mg/l. However, in 20% of E. coli strains	A dose of 1.5 g i.v. is required at parturition
Holt et al. (continued) [39]				1.5 g group: 74 (62–101)		38.5 (35–41) 1.5 g group: 39 (38–41)		1.5 g group: concentration-time profile shown in Fig. 5B Values given as mean and 95% CI 0.75 g group: 14.9 (10.5–21.1) 1.5 g group: 51.9 (33.4–80.9)	MIC is 4–16 mg/l and in 50% of Klebsiella MIC is > 3.1 mg/l
Lalic-Popovic et al. (2016) [40]	Prospective study	Ntotal: 53 Healthy group: 18 Hypertension group: 21 Gestational diabetes group: 14	Healthy group: 30.3 ± 4.4 Hypertension group: 35.0 ± 5.0 Gestational diabetes group: 32.1 ± 5.8	Healthy group: 78.9 ± 11.3 Hypertension group: 90.8 ± 20.1 Gestational diabetes group: 87.0 ± 21.5 BMI (kg/m2): Healthy group: 39.6 ± 4.9 Hypertension group: 33.4 ± 7.2	Pregnant women undergoing caesarean section	T4 Healthy group: 39.6 ± 0.7* (276.9 ± 4.6 days) Hypertension group: 37.7 ± 2.5* (263.9 ± 17.5 days) Gestational diabetes group: 38.3 ± 0.7* (267.9 ±	I.v., 1.5 g	Vd (l)* Healthy group: 66.5 ± 29.7 Hypertension group: 45.7 ± 21.8 Gestational diabetes group: 47.5 ± 14.0 CL (l/h)* Healthy group: 36.8 ± 14.7 Hypertension group: 36.8 ± 17.9 Gestational diabetes group: 25.7 ± 12.1	MIC is < 1 mg/l but 20% of E. coli strains MIC is 4–16 mg/l and in 50% of Klebsiella MIC is > 3,1 mg/l	With 1.5 g i.v. cefuroxime prophylactic concentrations can be reached if cefuroxime is dosed not less than 30 min and not more than 2 h before parturition
Lalic-Popovic et al. (continued) [40]				Gestational diabetes group: 31.8 ± 7.5		5.1 days)		t1/2 (h)* Healthy group: 1.3 ± 0.37 Hypertension group: 0.93 ± 0.38 Gestational diabetes group: 1.5 ± 0.55 ${\mathit{AUC}}_{0-\infty }$ (mg*h/l)* Healthy group: 50.8 ± 22.2 Hypertension group: 67.0 ± 41.3 Gestational diabetes group: 58.0 ± 14.7
De Leeuw et al. (1993) [41]	Prospective study	9	31 (median)	70.9 (median)	Pregnant women with premature rupture of membranes	T3: 27–33	I.v., 1.5 g every 8 h	Values given as median with range Maternal plasma concentration (mg/l)* After 1 h (n = 33): 35.0 (13.1–58.7) After 8 h (n = 28): 1.2 (0.4−22.7)	Breakpoint for intermediate bacterial susceptibility to cefuroxime is 16.0 mg/l	NR
Philipson et al. (1982) [30]	Prospective study	7	NR	T1-3: 64.4 ± 8.5 T4: 74.0 ± 9.9 T0/5: 61.7 ± 8.7	Pregnant women with asymptomatic UTI	T2: 19 (11–35) 18.6 ± 8.7* T4: 40 (37–42)	I.v., 0.75 g at three times points 1. start of UTI treatment during pregnancy; 2. upon admission of the patient for delivery; 3. after delivery (when normal menstruation had returned and breast feeding ceased)	t1/2 (h)* T2: 0.73 ± 0.083 T4: 0.87 ± 0.17 T0: 0.97 ± 0.13 Vd (l) T2: 17.8 ± 1.9 T4: 19.3 ± 3.1 T0: 16.3 ± 2.1 AUC (cm2 (arbitrary unit for mg*h/l) T2: 42.0 ± 5.2 T4: 46.7 ± 8.4 T0: 60.8 ± 8.6 CLplasma (l/h)* T2: 16.9 ± 2.0 T4: 15.5 ± 2.1 T0: 11.9 ± 1.6 CLrenal (l/h)* T2: 15.1 ± 2.2 T0: 9.5 ± 1.9
Roumen et al. (1990) [42]	Prospective study	6	30.7 ± 7.5	NR	Pregnant women with preterm premature membrane rupture	T3: 27–33	I.v., 1.5 g every 8 h	Maternal plasma concentration (mg/l)* After 1 h (n = 11): 28.7 ± 6.2 After 8 h (n=8): 1.2 ± 0.43	16 mg/l is the breakpoint for susceptibility	NR

Values are given as mean ± SD or median [interquartile range] or mean (range), unless otherwise specified

AUC area under the curve, BMI Body Mass Index, CI confidence interval, CL clearance, GA gestational age, h hours, i.v. intravenous, MIC minimal inhibitory concentration, min minutes, n number of determinations, NR not reported, N_total total number of participants of the study, PK pharmacokinetics, PTA probability of target attainment, ss steady-state, T0 nonpregnant, t_1/2 half-life, T1, 2, 3 first, second and third trimester, T4 intrapartum, T5 postpartum, UTI urinary tract infection, Vd volume of distribution

*Values calculated manually from the available data

Cefamandole

Duff et al. [32] administered 2 g of cefamandole to ten term pregnant women undergoing caesarean delivery (Table 2). Cefamandole was administered as intraoperative irrigation.

The study by Duff et al. [32] did not evaluate PK or exposure-related parameters. Serum concentrations were measured at various time points following cefamandole administration. However, no details regarding target concentrations, PTA, or dosing recommendations were provided.

In summary, no conclusions can be drawn about changes in PK or cefamandole exposure in pregnant women.

Cefoxitin

Three prospective studies have investigated PK and exposure of cefoxitin in pregnant women. A total of 49 women in their third trimester or at term were included. All women received cefoxitin either i.v. (2–4 g) or as a lavage solution [34–36]. Study characteristics and PK/exposure parameters are presented in Table 2.

Only Flaherty et al. [34] and Roex et al. [36] reported detailed PK and exposure parameters. Absorption data were not provided in both studies. The Vd and CL reported by Flaherty et al. were 18.8 l and 20.4 l/h, respectively [34]. These PK parameters were consistent with those observed by Roex et al. [36], as shown in Figs. 2C and 3C. By contrast, Giamarellou et al. [35] focused only on serum concentrations following cefoxitin administration (Fig. 5A).

Fig. 5.

Pooled mean serum concentration–time profiles from the included studies for A) Cefoxitin, B) Cefuroxime, C) Cefoperazole, D) Cefotaxime, E) Ceftazidime, and F) Ceftriaxone. T0 nonpregnant, T1 first trimester, T2 second trimester, T3 third trimester, T4 intrapartum, T5 postpartum

Of the three studies, only one study evaluated the PTA. Roex et al. [36] reported that 0.31 g cefoxitin per hour is sufficient to reach a plasma concentration of 16 mg/l, which is considered adequate for therapeutic exposure [36].

Although PK and exposure data for cefoxitin during caesarean section are available, none of the studies included a comparison with nonpregnant women. Therefore, it remains unclear whether pregnancy alters the PK of cefoxitin. However, based on the findings by Roex et al. [36], no dose adjustment is necessary, as i.v. infusion of cefoxitin with an infusion rate of 0.31 g per hour achieves the target plasma concentration of 16 mg/l.

Cefuroxime

Seven prospective studies have examined PK and exposure of cefuroxime in pregnant women, with study populations ranging from 6 to 53 participants. Four studies examined women at delivery [37–40], two in the third trimester [41, 42], and one in the second trimester [30]. All studies administered cefuroxime either i.v. or i.m. at doses of 0.75 g or 1.5 g, although the dosing frequency varied across studies. Notably, Lalic-Popovic et al. [40] included comparisons between healthy pregnant women and those with hypertension or diabetes. Study characteristics and PK/exposure parameters are presented in Table 2.

Two studies reported PK and exposure parameters [30, 40], while five studies measured only serum concentrations following cefuroxime administration [37–39, 41, 42]. As shown in Fig. 5B, most serum concentrations exceeded the MIC of 16 mg/l during the first 2 h after administration, followed by a gradual decline below the MIC [37–39, 41, 42]. Bousfield et al. [37] concluded that cefuroxime serum levels in women during induced labor were comparable with those in healthy nonpregnant volunteers [43]. Among the studies reporting PK and exposure parameters, Vd, CL, and t_1/2 were evaluated [30, 38, 40]. According to Philipson et al. [30], Vd was increased with 9.2% during the second trimester and with 18.4% at delivery compared with nonpregnant women. By contrast, when comparing healthy pregnant women with those with comorbidities, Vd decreased with 28.6% (P ≤ 0.05) in pregnant women with diabetes and with 31.3% (P > 0.05) in pregnant women with hypertension [40] (Fig. 3D). Craft et al. [38] reported that t_1/2 was similar between pregnant women at delivery and nonpregnant women [44, 45]. This was supported by the study of Philipson et al. [30], which reported that t_1/2 was only 10.3% lower in pregnant women at delivery compared with nonpregnant women. In addition,, this study showed that CL was increased with 42.4% during the second trimester and 30.8% at delivery compared with nonpregnant women [30]. In pregnant women with diabetes, t_1/2 increased with 19.3% (P > 0.05), whereas it decreased with 26.4% (P ≤ 0.05) in those with hypertension [40]. In addition, CL decreased by 30.2% (P ≤ 0.05) in the diabetes group, whereas it remained unchanged in the hypertension group (P > 0.05) [40]. Fig. 2D shows an overview of CL values reported by Lalic-Popovic et al. [40] and Philipson et al. [30].

Although limited data are available on the PK and exposure of cefuroxime in pregnant women, several studies have evaluated target attainment and dosing strategies during pregnancy. To achieve adequate exposure, with maintaining serum concentrations above MIC of 16 mg/l during the first hour postadministration, an i.v. dose of 1.5 g cefuroxime is considered sufficient in women at term [40]. Cefuroxime should be administered prophylactically between 2 h and 30 min prior to delivery [40]. For women in the second trimester, an increased dose may be necessary to match exposure levels measured in nonpregnant women [30]. However, no specific dose adjustment can be recommended [30]. Furthermore, altered Vd and CL in pregnant women with hypertension or diabetes should be considered when determining cefuroxime dosing [40].

Third Generation Cephalosporins

No studies were identified that investigated PK or exposure of cefdinir, cefixime, cefpodoxime, and ceftibuten. Table 3 presents the study characteristics and the PK/exposure parameters of pregnant women (with comparisons to nonpregnant and/or postpartum women when available) from studies on cefoperazone, cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone.

Table 3.

Study and patient characteristics, PK and exposure parameters, probability of target attainment, and dose advice of the included third generation cephalosporin studies, in alphabetical order by cephalosporin followed by author

Author (year) (citation)	Study design	Patient population number	Age (years)	Weight (kg)	Condition	Trimester (T0–T5) / GA (weeks)	Dose and administration route	PK/exposure parameters	PTA	Dosing advice
Cefoperazone
Ogita et al. (1988) [46]	Prospective study	Ntotal: 64 Patients are divided in 0.1 g and 0.5 g groups. Number of patients in each group is not defined	NR	NR	Pregnant women undergoing induction of labor	T4: At term	Infusion of 0.1 or 0.5 g into the amniotic cavity or 1 g i.v.	Cmax, serum (mg/l): 0.1 g group: 0.75 ± 0.02 0.5 g group: 4.6 ± 1.6 Concentration−time profile shown in Fig. 5C	≥ 10 mg/l	A daily dose of 100 mg or more is most likely sufficient to reach an effective exposure. In case of an intrauterine infection the dose may be increased to 500 mg or more. Besides, transplacental administration may further increase the efficacy of cefuroxime in case of intrauterine infections
Ozyuncu et al. (2010) [47]	Prospective study	10	27.6 ± 5.5	71.3 ± 9.7	Pregnant women undergoing caesarean delivery	T4: 38.4 ± 0.61*(269.0 ± 4.2 days)	I.v., 1 g	Serum concentration (mg/l): 68.0 ± 12.3	NR	It is not possible to achieve the required exposure to cefoperazone, because the common practice is to clamp the cord before administering cefoperazone
Cefotaxime
Kafetzis et al. (1980) [48]	Prospective study	Ntotal: 14 Single dose group: 10 Multiple dose group: 4	NR	NR	Pregnant women scheduled for abortion	T2: 15–24	I.v., 1 g single or multiple doses	Serum concentration (mg/l): Single dose group: 1 h: 8.2 ± 2.9 2 h: 2.2 ± 0.43	NR	NR
Kafetzis et al. (continued) [48]								3 h: 0.89 ± 0.14 Multiple dose group: 1 h: 14.3 ± 6.3 2 h: 3.8 ± 0.9 t1/2, serum (h): Single dose group: 0.68 ± 0.18 Multiple dose group: 0.69 ± 0.17 (Fig. 5D)
Ogita et al. (1988) [46]	Prospective study	Ntotal: 64 Patients are divided in 0.1 g and 0.5 g groups. Number of patients in each group is not defined	NR	NR	Pregnant women undergoing induction of labor	T4: At term	Infusion of 0.1 or 0.5 g into the amniotic cavity	Cmax, serum (mg/l): 0.1 g group: 0.28 ± 0.4 0.5 g group: 3.9 ± 2.39 (Fig. 5D)	≥ 10 mg/l	A daily single dose of 0.1 g cefotaxime is considered to be an effective prophylaxis in cases of PROM. The dose may be increased to 0.5 g in case of intrauterine infection. To reach an effective exposure in the fetus the dose of cefotaxime needs to be further increased.
Ceftazidime
Dallmann et al. (2019) [51]	Prospective study	10	≥ 18	NR	Pregnant women with suspected or proven intrauterine infections in	T2–3: 25.6–33.6	I.v., 1 g every 6 h	Blood concentration per individual patient (mg/l) (t(min)): 43.9 (10);23.8 (75);	NR	NR
Dallmann et al. (continued) [51]					the late second and early third trimester			18.2 (120); 16.9 (130); 12.7 (175); 11.4 (210); 9.2 (235); 8.1 (255); 6.0 (280); 5.0 (330) (Fig. 5E) CL (l/h): 9.0 Vc (l): 23.1 Vp (l): 6.8 Vd (l): 29.9*
Giamarellou et al. (1983) [35]	Prospective study	9	25.7 ± 4.3	NR	Pregnant women with termination of gestation	T2: 20–21	I.m., 1 g three times per day	Concentration–time profile shown in Fig. 5E	NR	NR
Nathorst-Böös et al. (1995) [50]	Prospective study	Ntotal: 12 T1: 8 T3: 8 T5: 8	NR	NR	Pregnant women with asymptomatic bacteriuria (UTI)	T1, T3, and T5	I.v. 0.4 g bolus followed by a constant 4 mg/min infusion for 4 h (total 1.36 g)	Serum concentrations (mg/l) T1: 32.8 ± 4.4 T3: 28.6 ± 5.3 T5: 41.1 ± 7.7 CL (l/h)* T1: 8.6 ± 2.1 T3: 10.2 ± 3.7 T5: 6.2 ± 1.3	NR	Owing to an increased GFR the dosage in pregnant women should be increased by approximately 40%
Cefoperazone
Ogita et al. (1988) [46]	Prospective study	Ntotal: 64 Patients are divided in 0.1 g and 0.5 g groups. Number of patients in each group is not defined	NR	NR	Pregnant women undergoing induction of labor	T4: At term	Infusion of 0.1 or 0.5 g into the amniotic cavity or 1 g i.v.	Cmax, serum (mg/l): 0.1 g group: 0.75 ± 0.02 0.5 g group: 4.7 ± 1.6 Concentration–time profile shown in Fig. 5C	≥ 10 mg/l	A daily dose of 100 mg or more is most likely sufficient to reach an effective exposure. In case of an intrauterine infection the dose may be increased to 500 mg or more. Besides, transplacental administration may further increase the efficacy of cefuroxime in case of intrauterine infections
Cefotaxime
Fortunato et al. (1988) [52]	Prospective study	NR	NR	NR	Pregnant women with premature membrane rupture	T3: 26–37	I.v., 2 g every 8 h	Serum concentration (mg/l): 1 h (n = 1): 72.9 ± - 2 h (n = 3): 17 ± 4.4 3 h (n = 1): 13.9 ± - 4 h (n = 4): 23.3 ± 6.9 5 h (n = 4): 8.4 ± 2.7 6 h (n = 2): 10.1 ± 5.5 7 h (n = 1): 3.0 ± - 8 h (n = 4): 3.1 ± 0.55 (Fig. 5D)	The MIC for 90% of the Gram negative bacteria is < 1 mg/l and < 16 mg/l for sensitive ante-robes	2 g every 8 h is sufficient to reach effective concentrations in the cord and amniotic fluid
Ceftriaxone
Bourget et al. (1993, A) [53]	Prospective study	Ntotal: 17 Pregnant women: 9 Healthy nonpregnant women: 8	29.0 ± 4.1	69.0 ± 10.8	Pregnant woman with fever and signs of infection	T3: 28.6– 40.7	I.v., 2 g per day (25.6 mg/kg)	Total ceftriaxone Pregnant women: Cmax (mg/l)* Day 1: 224.3 ± 31.3 Day 7: 214.8 ± 35.6 Cmin (mg/l)* Day 1: 12.9 ± 3.5 Day 7: 12.5 ± 2.3 ${\mathit{AUC}}_{0-\infty }$ (mg*h/l) Day 1: 1588 ± 225 Day 7: 1713 ± 201 CLserum (l/h)* Day 1: 1.3 ± 0.18 Day 7: 1.2 ± 0.14 Vd (l) Day 1: 12.5 ± 2.7 Day 7: 10.5 ± 1.6 t1/2 (h) Day 1: 6.8 ± 1.1 Day 7: 6.5 ± 0.66 Healthy nonpregnant women: Cmax (mg/l)* Day 1: 239 Day 4: 260 Cmin (mg/l)* Day 1: 13 Day 4: 15	NR	No dosage adjustments are required during the final three months of pregnancy.
Bourget et al. (continued) [53]								CL (l/h)* Day 1: 1.3 Day 4: 1.4 Vd (l) Day 1: 11.7 Day 4: 12.3 t1/2 (h) Day 1: 6.2 Day 4: 6.2 Unbound ceftriaxone Pregnant women: Cmax (mg/l)* Day 1: 33.2 ± 10.3 Cmin (mg/l)* Day 1: 0.17 ± 0.31 ${\mathit{AUC}}_{0-\infty }$ (mg*h/l) Day 1: 107.6 ± 55.5 CLserum (l/h)* Day 1: 15.0 ± 6.3 Vd (l) Day 1: 152.0 ± 58.0 t1/2 (h) Day 1: 7.0 ± 1.2
Bourget et al. (1993, B) [54]	Case report	1	26	78	Pregnant woman with fever and signs of infection	T3: 40	I.v., 2 g per day (25.6 mg/kg)	Total ceftriaxone Cmax (mg/l)* Day 1: 234.2 Day 7: 245.1	NR	NR
Bourget et al. (continued) [54]								Cmin (mg/l)* Day 1: 12.7 Day 7: 19.7 AUC0-24h (mg*h/l) Day 1: 1610 Day 7: 1982 CLserum (l/h)* Day 1: 1.3 Day 7: 0.98 Vd (l)* Day 1: 11.7 Day 7: 10.9 t1/2 (h) Day 1: 6.4 Day 7: 6.6 Unbound ceftriaxone Cmax (mg/l)* Day 1: 35.6 Cmin (mg/l)* Day 1: 1.2 AUC0-24h (mg*h/l) Day 1: 146.0 CLserum (l/h)* Day 1: 13.7 t1/2 (h) Day 1: 7.0
Grujić et al. (2010)	Prospective study	Ntotal: 49 T0: 4 T4: 45	30.8 ± 5.7	83.0 ± 12.6	Pregnant women undergoing caesarean delivery or gyneco- logical surgery	T0/T4	I.v., 2 g 10 min before surgery	Concentration in plasma (mg/l) T0: Immediately after operation: 12.0 ± 9.8 6 h after operation: 5.7 ± 5.0 T4: Immediately after operation: 22.7 ± 20.4 6 h after operation: 13.2 ± 11.2 T0: Ke (h-1): 0.18 ± 0.05 t1/2 (h): 4.0 ± 1.0 Vd (l): 234.4 ± 167.0 CL (l/h): 48.2 ± 41.5 T4: Ke (h-1): 0.11 ± 0.04 t1/2 (h): 7.3 ± 3.3 Vd (l): 189.8 ± 197.7 CL (l/h): 24.4 ± 34.4	NR	NR
Popović et al. (continued) [23]	Prospective study	Ntotal: 22 T0: 4 T4: 18	NR	T0: 65 ± 7 T4: 85 ± 14	Pregnant women undergoing caesarean delivery or gynecological surgery	T0/T4	I.v., 2 g 10 min before surgery	Concentrations in plasma (mg/l) T0: Immediately after operation: 12.0 ± 9.9 6 h after application: 5.7 ± 5.1 T4: Immediately after operation: 22.8 ± 20.4 6 h after application: 13.2 ± 11.2 T0: Ke (h-1): 0.18 ± 0.045 t1/2 (h): 4.0 ± 1.0 Vd (l): 234.4 ± 167.0 CL (l/h): 48.2 ± 41.5 T4: Ke (h-1): 0.11 ± 0.042 t1/2 (h): 7.3 ± 3.3 Vd (l): 189.8 ± 197.7 CL (l/h): 24.4 ± 34.4	NR	A dose increase for ceftriaxone is not recommended, because exposure to ceftriaxone in nonpregnant women were lower compared with pregnant women, despite a lower relative dose in pregnant women

Values are given as mean ± SD or median [interquartile range] or mean (range), unless otherwise specified

AUC area under the curve, CL clearance, C_max maximum observed concentration, C_min minimum observed concentration, GA gestational age, GFR glomerular filtration rate, h hours, i.m. intramuscular, i.v. intravenous, Ke elimination rate constant, MIC minimal inhibitory concentration, min minutes, n number of determinations, NR not reported, N_total total number of participants of the study, PK pharmacokinetics, PROM premature rupture of membranes, PTA probability of target attainment, t time, T0 nonpregnant, t_1/2 half-life, T1, 2, 3 first, second and third trimester, T4 intrapartum, T5 postpartum, UTI urinary tract infection, Vc central volume of distribution, Vd volume of distribution, Vp peripheral volume of distribution

*Values calculated manually from the available data

Cefoperazone

Two prospective studies investigated the PK and exposure of cefoperazone in pregnant women at delivery (Table 3). However, both studies did not provide detailed PK or exposure parameters following cefoperazone administration but instead focused on measuring serum concentrations [46, 47]. Ogita et al. [46] reported a serum concentration of 0.75 mg/l after a 0.1 g cefoperazone infusion into the amniotic cavity, which increased to 4.7 mg/l when the dose was raised to 0.5 g. Additionally, following i.v. administration of 1 g cefoperazone, maternal serum concentrations were 53.9 mg/l, 30.7 mg/l, and 12.3 mg/l after 0.5, 1, and 2 h, respectively, whereas amniotic fluid concentrations were 0.34 mg/l, 0.38 mg/l, and 0.96 mg/l, respectively [46] (Fig. 5C). These results demonstrate the transfer of cefoperazone from maternal blood to the amniotic fluid, indicating placental passage and subsequent fetal renal excretion into the amniotic cavity. Furthermore, Ozyuncu et al. [47] observed an average maternal serum concentration of 68.0 mg/l after i.v. administration of 1 g cefoperazone. Regarding target concentration attainment, Ogita et al. concluded that a daily amniotic infusion of 0.1 g cefoperazone is sufficient to maintain serum levels above the MIC of 10 mg/l [46].

In summary, owing to the limited data on PK, exposure parameters, and target attainment for cefoperazone in pregnant women, no recommendations for adjusting dosing regimens can be made. Nevertheless, based on available evidence, a daily 0.1 g amniotic infusion of cefoperazone might be adequate for prophylaxis [46].

Cefotaxime

Two prospective studies have investigated PK and exposure of cefotaxime in pregnant women (Table 3). A total of 78 women in their second trimester, scheduled for abortion, or term delivery were included [46, 48]. In the study by Kafetzis et al. [48], cefotaxime was administered as 1 g i.v., either as a single dose or in multiple doses prior to abortion, whereas in the study by Ogita et al. [46], it was given as a single 0.1 g or 0.5 g infusion into the amniotic cavity.

Kafetzis et al. [48] reported higher maternal serum concentrations of cefotaxime following multiple 1 g i.v. doses (administered at an unspecified interval) compared with a single dose. Serum concentrations in pregnant women were lower compared with nonpregnant women [48, 49] (Fig. 5D). Ogita et al. [46] observed a serum concentration about the PTA of 10 mg/l for 24 h following administration into the amniotic fluid. Regarding PK parameters, only Kafetzis et al. [48] assessed thet_1/2 of cefotaxime. After a single 1 g i.v. dose, the t_1/2 was 0.68 h, which was comparable to the 0.69 h observed after multiple doses [48]. However, both t_1/2 values were shorter than those reported in nonpregnant women [49]. According to Kafetzis et al. [48], this reduction in serum concentration and t_1/2 is due to physiological changes during pregnancy, including increased plasma volume, renal plasma flow, and glomerular filtration rate.

Despite reporting serum concentrations and t_1/2, Kafetzis et al. [48] did not provide dosing recommendations or statements on achieving adequate therapeutic efficacy in pregnant women relative to nonpregnant women. By contrast, Ogita et al. [46] concluded that a 0.1 g cefotaxime infusion into the amniotic cavity is sufficient to maintain maternal serum concentrations above the PTA of 10 mg/l for at least 24 h.

Ceftazidime

Three prospective studies investigated the PK and exposure of ceftazidime. A total of 31 women in their first, second, and third trimester, as well as postpartum, were included [35, 50, 51]. Ceftazidime was administered as either 1 g i.v. every 6 h, 1 g i.m. every 8 h, or a total of 1.36 g i.v. divided into a 0.4 g bolus followed by continuous infusion at 4 mg/min over 4 h [35, 50, 51]. Study characteristics and PK/exposure parameters are presented in Table 3.

Giamarellou et al. [35] did not report specific PK or exposure parameters but observed that serum concentrations of ceftazidime were reduced with approximately 50% compared with nonpregnant women. An overview of serum concentrations following ceftazidime administration in second and third trimester of pregnancy is shown in Fig. 5E [35, 51]. According to Dallmann et al. [51], population simulation of ceftazidime dosing at 1 g every 6 h in pregnant women was associated with Vd 29.9 l and CL 9.0 l/h. Nathorst-Böös et al. [50] reported that CL increased with 50% in women during the first trimester to 100% in the third trimester, compared with postpartum women (Fig. 2E).

Only Nathorst-Böös et al. [50] recommended an evidence-based dose increase of approximately 40% in pregnant women to ensure therapeutic efficacy comparable to nonpregnant women. The 50% reduction in ceftazidime serum concentrations observed by Giamarellou et al. [35] supports the dosing recommendation by Nathorst-Böös et al. [50].

Ceftizoxime

The PK and exposure of ceftizoxime in pregnant women were investigated in a single prospective study conducted during the third trimester. In this study, women received 2 g of i.v. ceftizoxime every 8 h. However, no PK or exposure parameters were reported, only maternal serum concentrations were provided [52] (Table 3).

Fortunato et al. [52] observed a mean maternal serum concentration of 12.0 mg/l and concluded that a dosing regimen of 2 g i.v. three times daily is sufficient to achieve an MIC of < 1.0 mg/l for most gram-negative bacteria. Nonetheless, the study reported that a dose increase may be required to achieve an MIC of < 16.0 mg/l to effectively target anaerobic bacteria, including those classified as susceptible [52].

Ceftriaxone

Three prospective studies and one case report investigated the PK and exposure of ceftriaxone in pregnant women. A total of 81 pregnant women were included [23, 27, 53, 54]. Two studies focused on pregnant women undergoing caesarean delivery or gynecological surgery [23, 27], while the other two studies examined ceftriaxone administration during the third trimester in women presenting with fever or signs of infection [53, 54]. In all cases, ceftriaxone was administered i.v. at a dose of 2 g, 10 min before surgery [23, 27, 53, 54]. Study characteristics and PK/exposure parameters are presented in Table 3.

Total ceftriaxone C_min and C_max were reported in two studies [53, 54]. On day 1, C_min ranged from 12.7 to 12.9 mg/l and C_max from 224.3 to 234.2 mg/l. By day 7, C_min increased from 12.5 to 19.7 mg/l and C_max from 214.8 to 245.1 mg/l. According to Grujić et al., ceftriaxone serum concentrations were higher in pregnant women undergoing caesarean delivery compared with those undergoing gynecological surgery (Fig. 5F). AUC was calculated in two studies, with values of 1588 and 1610 mg*h/l on day 1, and 1713 and 1982 mg*h/l on day 7 [53, 54]. Bourget et al. [53, 54] additionally reported unbound ceftriaxone concentrations. On day 1, unbound C_max ranged from 33.2 to 35.6 mg/l, while unbound AUC ranged from 107.6 to 146.0 mg*h/l. The CL of unbound ceftriaxone (13.7–15.0 l/h) was approximately ten-fold higher than that of total ceftriaxone (0.98–1.4 l/h). Similarly, the Vd of unbound ceftriaxone (138.1–152.0 l) was markedly higher than that of total ceftriaxone (10.5–12.5 l) during the third trimester of pregnancy. Notably, Gruijic et al. [27] and Popović et al. [23] observed a 19% reduction in Vd at delivery compared with nonpregnancy women (Fig. 3E). CL also decreased with approximately 50% at delivery relative to nonpregnant women [23, 27] (Fig. 2F). These findings are remarkable because they differ substantially from the PK changes typically reported for other β-lactam antibiotics during pregnancy, which more commonly show increased CL and Vd in pregnant women.

The available data of ceftriaxone PK and exposure in pregnant women present conflicting findings. In addition, no PTA or dosing recommendations have been provided. Two studies measured both total and unbound ceftriaxone concentrations [53, 54], highlighting the potential impact of altered protein binding during pregnancy. Given that ceftriaxone is highly protein-bound, assessing unbound concentrations may provide a more clinically relevant estimate of pharmacologically active exposure than measuring total drug concentrations alone. Gruijic et al. [27] and Popović et al. [23] suggest a potential risk of overdosing at delivery due to altered albumin levels and body fluid shifts. By contrast, Bourget et al. [53, 54] reported that ceftriaxone PK and exposure during the third trimester are comparable to those in healthy nonpregnant women, concluding that no dose adjustment is necessary.

Fourth Generation Cephalosporins

No studies were identified that investigated the PK or exposure of cefclidine, cefpirome, cefquinome, and cefuprenam. Table 4 presents the study characteristics and the PK/exposure parameters of pregnant women (with comparisons to nonpregnant and/or postpartum women when available) from the study on cefepime.

Table 4.

Study and patient characteristics, PK and exposure parameters, probability of target attainment, and dose advice of the included fourth generation cephalosporin studies, in alphabetical order by cephalosporin followed by author

Author (year) (citation)	Study design	Patient population number	Age (years)	Weight (kg)	Condition	Trimester (T0–T5) / GA (weeks)	Dose and administration route	PK/exposure parameters	PTA	Dosing advice
Cefepime
Ozyuncu et al. (2010) [47]	Prospective study	9	28.7 ± 4.5	70.9 ± 6.9	Pregnant women undergoing caesarean delivery	T4: 38.4 ± 0.37* (269.1 ± 2.6 days)	I.v., 1 g	Concentration (mg/l): 37.3 ± 7.1	NR	NR

Values are given as mean ± SD or median [interquartile range] or mean (range), unless otherwise specified

GA gestational age, i.v. intravenous, PK pharmacokinetics, PTA probability of target attainment, NR not reported, T4 intrapartum

*Values calculated manually from the available data

Cefepime

Only one prospective study investigated the PK and exposure of cefepime in pregnant women. Nine women undergoing caesarean delivery were included [47]. However, the study described only maternal serum concentrations (Table 4), without reporting PK or exposure parameters. Therefore, no definitive conclusion can be drawn regarding PK and exposure of cefepime in pregnant women, PTA, or the need for dose adjustments.

Fifth Generation Cephalosporins

No studies have been identified investigating the PK or exposure of any fifth generation cephalosporins (ceftaroline fosamil and ceftobiprole).

Discussion

Cephalosporin antibiotics are commonly prescribed to treat bacterial infections and prophylactically during pregnancy. This systematic literature review provides an overview of the current evidence on the PK, exposure, and target attainment of cephalosporins across different stages of pregnancy. A key finding is that during the second and third trimesters, cefazolin, cefuroxime, cephradine, and ceftazidime demonstrate increased CL (30.8–100%) and Vd (9.2–18.4%) compared with nonpregnant, first trimester, or postpartum women. These changes result in reduced systemic exposure, leading to frequently suboptimal target attainment in pregnant women. The observed interindividual variability in PK parameters likely reflects differences in gestational age, renal function, body composition, and route of administration (e.g., i.v., i.m., or local administration). Clinically, this variability may contribute to suboptimal target attainment in certain pregnant patients, supporting the need for individualized dosing strategies. For cephalosporins, therapeutic efficacy depends on maintaining free (unbound) drug concentrations above the MIC (fT > MIC). When target concentrations are not achieved, dosing adjustments may be necessary. Despite the importance of unbound exposure of cephalosporins, only a limited number of studies reported measured free drug concentrations or incorporated free concentrations in PK simulations. For ceftriaxone, two studies reported both total and unbound concentrations and demonstrated substantial differences in PK parameters between total and unbound drug exposure, reflecting the high degree of protein binding of ceftriaxone [53, 54]. For cefazolin, two studies reported measured free concentrations [8, 14], while Van Hasselt et al. incorporated both free and total cefazolin concentrations in PK simulations and suggested that shortening the dosing interval from every 8 h to every 6 h may help maintain therapeutic concentrations during pregnancy [25]. Given the physiological changes in albumin concentrations during pregnancy and the fact that only the unbound fraction is microbiologically active, future PK studies should more consistently report both total and free cephalosporin concentrations.

Of the 35 cephalosporins included in the search strategy of this systematic literature review, PK and exposure parameters during pregnancy were reported for only 14 agents. The majority of the studies (33/44) focused on women receiving prophylactic treatment during caesarean delivery. Studies conducted during the second and third trimester primarily included women at elevated risk of infection, including those undergoing in utero surgery, termination of pregnancy, fetal intrauterine transfusions, or experiencing premature rupture of membranes. These indications often necessitate hospitalization in the latter half of pregnancy, thereby providing opportunities to collect PK/PD data. By contrast, evidence on cephalosporin use in the first trimester is scarce, leaving PK and exposure data from early pregnancy relatively limited. Only 6 out of 44 studies reported both Vd and CL. Furthermore, dosing guidance for clinicians was provided in only 11 studies, covering cephradine, cefoxitin, cefuroxime, cefoperazone, cefotaxime, ceftazidime, and ceftizoxime. In addition to the limited number of available studies, 50.0% of the included studies were conducted more than 30 years ago. Since then, clinical practices have evolved substantially, particularly regarding perioperative management and surgical techniques for caesarean delivery. In addition, several cephalosporin evaluated in older studies are currently less frequently used or have been replaced by newer agents in certain regions. Therefore, the clinical applicability of some findings may be limited, although these studies remain valuable for understanding pregnancy-related alterations in cephalosporin PK. Another limitation was the limited heterogeneity of patient populations. Most studies included women in their second or third trimester or at delivery, while comorbidities and concomitant medications were generally excluded. To illustrate, among the 22 studies on cefazolin, only 10 specifically examined women with obesity undergoing caesarean section. This likely reflects both the increased likelihood of caesarean delivery among women with obesity and the widespread use of cefazolin as the first-line agent for perioperative prophylaxis during caesarean delivery [55]. Consequently, PK data in pregnant women with obesity are largely limited to the perioperative caesarean setting. Moreover, the PK of pregnant women with obesity was not consistently compared with women without obesity across these studies. Because serum and adipose tissue concentrations were reduced in this population, these studies recommended dose adjustments, either increasing the dose, administering an additional dose, or shortening the dosing interval, to achieve adequate concentrations. Furthermore, only one study compared healthy pregnant women with those affected by hypertension or diabetes, concluding that decreased Vd and CL should be considered when determining cefuroxime dosing, with Vd reduced in both pregnant women with diabetes and hypertension, while CL was decreased in diabetes but increased in hypertension. Moreover, most studies were restricted to singleton pregnancies, resulting in relatively homogeneous populations. In addition, substantial heterogeneity existed in the routes of administration across studies, including i.v., i.m., and local administration (e.g., intraamniotic infusion). Since administration route may influence absorption, tissue distribution, and systemic exposure, direct comparison of PK parameters and target attainment across studies should be interpreted with caution. This homogeneity may limit the quantification and generalizability of variability in PK parameters across the entire pregnant population.

A limited number of studies have evaluated the PK of cephalosporins in pregnant women, and even fewer have examined the PD targets and PTA for individual agents (16/44). A total of 13 studies reported PTA for cefazolin, two for cefuroxime, and one for cefoperazone. An important next step for further research is to evaluate cephalosporin PK in larger and more heterogeneous pregnant cohorts to refine exposure targets. It should also be emphasized that, in addition to advancing PK knowledge, the PK/PD relationship currently used to inform evidence-based dosing requires further investigation, as this largely relies on theoretical frameworks and homogeneous study populations. Subsequently it can be determined which evidence-based doses are needed to attain target concentrations to consequently enlarge target attainment. This is already adequately studied for seven cephalosporins, namely cefazolin, cefuroxime, cefoxitin, ceftazidime, cephradine, cefatrizine, and ceftizoxime, but additional research is needed across the broader class. For future research, physiologically based PK models may support the evaluation of pregnancy-related dose adjustments. Importantly, such approaches should not assume uniform behavior across the cephalosporin class, as individual compounds may differ in transporter involvement of placental transfer. Therefore, compound-specific evaluation is required prior to any class-based extrapolation. When applied in a compound-specific manner, PBPK models can integrate pregnancy-related physiological changes and facilitate the assessment of fetal exposure, supporting safer and more precise dosing strategies. Furthermore, clinical context is relevant, as prophylactic antibiotic administration of cephalosporins during caesarean section is commonly performed after umbilical cord clamping, which largely limits direct fetal exposure, as recommended in current clinical guidelines.

This systematic review has several limitations. First, the scope was restricted to maternal PK and target attainment and therefore does not include fetal PK or safety considerations. Data from cord blood sampling in intrapartum women provide insights into placental transfer and fetal drug exposure. Although some studies reported cord blood levels, these were not included in this review. Second, while PD parameters such as PTA and MIC were extracted, clinical outcomes were not evaluated. As a result, it remains unknown whether reduced maternal exposure necessarily translates into reduced therapeutic effectiveness, as some underexposed pregnant women may still achieve an adequate therapeutic response.

Conclusions

This systematic literature review demonstrates that the PK of most cephalosporins is substantially altered during pregnancy. Increases in Vd and CL were observed, leading to elevated risk of suboptimal target attainment in pregnant women. The larger Vd and higher CL in pregnant women in the second and third trimesters may necessitate consideration of higher doses, additional doses, or shortened dosing intervals to improve target attainment. Despite the availability of PK data, evidence-based dosing recommendations for pregnant women are frequently lacking. Our study reveals critical gaps in current knowledge and highlights the importance of future studies providing evidence-based dosing guidance for cephalosporins in this specific population.

Funding

This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors. Femke A. Elzinga, Kaylee R.M. Ferrier, Fabian Mulder, Eline H. van der Veen, Jelmer R. Prins, Lars C. Nijdam, Marjolijn N. Lub-de Hooge, Rik L. J. Winter, Jos G.W. Kosterink, Daan J. Touw, and Paola Mian declare that they have no financial interests that are directly or indirectly related to the work submitted for publication.

Declarations

Conflict of interest

Daan J. Touw is an Editorial Board member of Clinical Pharmacokinetics, and was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. All other authors declare no conflicts of interest related to this manuscript.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Data can be accessed upon reasonable request through the corresponding author.

Author contributions

F.A.E. contributed to the literature search, data analysis and writing the initial draft of the manuscript. K.R.M.F. contributed to the data-extraction, data analysis and writing the initial draft of the manuscript. F.M. contributed to the literature search, data analysis and writing the initial draft of the manuscript. E.H.V. contributed to the data analysis and writing the initial draft of the manuscript. J.R.P., L.C.N., M.N.L.H., R.L.J.W., and J.G.W.K. contributed to the study design. D.J.T. contributed to the conceptualization of the study, data analysis, and reviewing the manuscript. P.M. contributed to the conceptualization of the study, literature search, data extraction, data analysis, and writing and reviewing the manuscript.