Steve N. Caritis

Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth

OBJECTIVEn17-alpha hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation.nnnSTUDY DESIGNnA single blood sample was obtained between 25 and 28 weeks gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha hydroxyprogesterone caproate concentration.nnnRESULTSnThere were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth (Pxa0= .03) and delivered at significantly earlier gestational ages (Pxa0= .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL.nnnCONCLUSIONnLow plasma 17-alpha hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage.

Pharmacokinetics of drugs in pregnancy

Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications.

Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery

OBJECTIVEnThe objective of the study was to compare the pharmacokinetics of 2 g and 3 g doses of cefazolin when used for perioperative prophylaxis in obese gravidae undergoing cesarean delivery.nnnSTUDY DESIGNnWe performed a double-blinded, randomized controlled trial from August 2013 to April 2014. Twenty-six obese women were randomized to receive either 2 or 3 g intravenous cefazolin within 30 minutes of a skin incision. Serial maternal plasma samples were obtained at specific time points up to 8 hours after drug administration. Umbilical cord blood was obtained after placental delivery. Maternal adipose samples were obtained prior to fascial entry, after closure of the hysterotomy, and subsequent to fascial closure. Pharmacokinetic parameters were determined via noncompartmental analysis.nnnRESULTSnThe median area under the plasma concentration vs time curve was significantly greater in the 3 g group than in the 2 g group (27204 μg/mL per minute vs 14058 μg/mL per minute; P = .001). Maternal plasma concentrations had an impact by body mass index. For every 1 kg/m(2) increase in body mass index at the time of the cesarean delivery, there was an associated 13.77 μg/mL lower plasma concentration of cefazolin across all time points (P = .01). By the completion of cesarean delivery, cefazolin concentrations in maternal adipose were consistently above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria with both the 2 g and 3 g doses. The median umbilical cord blood concentrations were significantly higher in the 3 g vs the 2 g group (34.5 μg/mL and 21.4 μg/mL; P = .003).nnnCONCLUSIONnCefazolin concentrations in maternal adipose both at time of hysterotomy closure and fascial closure were above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria when either 2 g or 3 g cefazolin was administered as perioperative surgical prophylaxis. Maternal cefazolin concentrations in plasma and maternal adipose tissue are related to both dose and body mass index.

Adverse Outcomes and Potential Targets for Intervention in Gestational Diabetes and Obesity.

OBJECTIVE: To evaluate the association of obesity with pregnancy outcomes in women with gestational diabetes mellitus (GDM) and identify potentially modifiable risk factors for adverse outcomes in obese women with GDM. METHODS: This was a retrospective cohort study of 1,344 women with GDM who delivered between 2009 and 2012. Demographic data, blood sugar values, gestational weight gain, and maternal and neonatal outcome data were abstracted from the medical record and compared among normal-weight, overweight, and obese women. RESULTS: Overweight and obese women had higher mean fasting and postprandial blood sugars despite higher doses of and more frequent use of medication. Obesity was independently associated with macrosomia (adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.07–3.89, P=.03), indicated preterm birth (adjusted OR 2.21, 95% CI 1.02–4.78, P=.04), and hypertensive disorders of pregnancy (adjusted OR 2.19, 95% CI 1.38–3.49, P=.001). In our stratified analyses, obese women with fasting blood sugars greater than 88.7 mg/dL and postprandial blood sugars greater than 123.8 mg/dL had higher rates of macrosomia (13.1% compared with 5.7%, P=.004 for fasting, 13.0% compared with 6.5%, P=.01 for postprandial blood sugars) and indicated preterm birth (11.4% compared with 6.1%, P=.04 for fasting, 11.9% compared with 5.8%, P=.01 for postprandial blood sugars) when compared with obese women with lower values. Hypertensive disorders of pregnancy were significantly increased in obese women with postdiagnosis weight gain greater than 0.6 lb per week (29.4% compared with 15.2%, P<.001) when compared with obese women with less weight gain. CONCLUSION: Prepregnancy obesity is independently associated with adverse pregnancy outcomes in women with GDM, and interventions to optimize glycemic control and limit weight gain postdiagnosis may improve outcomes in these high-risk women. LEVEL OF EVIDENCE: II

Prevention of preterm delivery with 17-hydroxyprogesterone caproate: Pharmacologic considerations

Despite advances in neonatal care, the burden of preterm birth remains high. Preterm birth is a multifactorial problem, and strategies to identify and treat medical risk factors in early pregnancy have not been effective in reducing preterm birth rates. In a sentinel clinical trial, prophylactic therapy with 17-hydoxyprogesterone caproate (17-OHPC) reduced the risk of recurrent, spontaneous preterm birth in 34% of women. As a result, clinical practice changed and extensive research on 17-OHPC followed. The increasing body of evidence demonstrated a variable efficacy of the drug. This review will examine the plausibility, pharmacology, clinical efficacy, and safety of 17-OHPC when used in the setting of preterm birth prevention. We will also discuss pharmacokinetic and pharmacodynamics data to highlight drug metabolism and mechanism of action, which will help clarify the variability in clinical outcomes and efficacy.

Timing of delivery and pregnancy outcomes in women with gestational diabetes

BACKGROUNDnWomen with gestational diabetes mellitus (GDM) commonly undergo induction of labor (IOL) at term, but the risks and benefits of IOL are incompletely understood.nnnOBJECTIVEnWe examined the relationship among gestational age, IOL, and the rate of cesarean delivery (CD) in women with GDM.nnnSTUDY DESIGNnWe identified 863 women with GDM who underwent either IOL or spontaneous labor ≥37 0/7 weeks. Demographic, cervical favorability, and outcome data were abstracted from the medical record. We compared the CD rate in women undergoing IOL at each week of gestation with expectant management to a later gestational age.nnnRESULTSnWhen compared to women who were expectantly managed, IOL at 37 weeks (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 0.76-3.06; Pxa0= .23), 38 weeks (aOR, 2.07; 95% CI, 0.89-4.80; Pxa0= .09), and 39 weeks (aOR, 0.79; 95% CI, 0.44-1.42; Pxa0= .43)) was associated with similar risk for CD as expectant management after adjustment for nulliparity, body mass index, baseline simplified Bishop score, and maternal age. CD rates were higher in nulliparous women, but did not differ significantly in those undergoing IOL or expectant management. In multiparous women, IOL was significantly associated with an increased risk for CD at 38 weeks (aOR, 7.47; 95% CI, 1.6-34.8; Pxa0= .01) and rates of CD (17.39% vs 2.2%, Pxa0= .001) were significantly higher in multiparous women with an unfavorable Bishop score induced <39 weeks. Neonatal morbidity was similar across gestational ages after adjustment for maternal body mass index and maternal glycemic control.nnnCONCLUSIONnIOL results in similar risk for CD as expectant management between 37-40 weeks of gestation. Rates of CD differed based on cervical exam and parity. These findings suggest that gestational age alone does not significantly impact maternal and neonatal outcomes, but that decisions regarding delivery in women with GDM should take into account cervical exam and parity.

Impact of 17-alpha-hydroxyprogesterone caproate on cytochrome P450s in primary cultures of human hepatocytes

OBJECTIVEnThe aim of this study was to examine the effects of 17-alpha-hydroxyprogesterone caproate (17OHP-C) on the activity and expression of several common hepatic cytochrome P450 (CYP) enzymes.nnnSTUDY DESIGNnPrimary human hepatocytes were pretreated with vehicle or 17OHP-C (0.1 and 1 μmol/L) for 72 hours, then incubated for 1 hour with a cocktail of CYP substrates. The activity of various CYP enzymes was determined by measuring the formation of the metabolites of specific CYP substrates, using liquid chromatography-tandem mass spectrometry. The messenger RNA expression of various CYP enzymes was determined by real-time polymerase chain reaction.nnnRESULTSnIn primary cultures of human hepatocytes, 17OHP-C minimally altered the activity or messenger RNA levels of CYP1A2, CYP2C9, CYP2D6, and CYP3A. However, 17OHP-C at 1 μmol/L increased CYP2C19 activity by 2.8-fold (P < .01) and CYP2C19 expression by 2.4-fold (P < .001), compared with vehicle-treated cells. A strong positive correlation between activity and expression of CYP2C19 was also observed (rxa0= 0.9, P < .001).nnnCONCLUSIONnThe activity and expression of hepatic CYP2C19 was significantly increased by 17OHP-C in primary cultures of human hepatocytes. This suggests that exposure to medications that are metabolized by CYP2C19 may be decreased in pregnant patients receiving 17OHP-C. Metabolism of substrates of CYP1A2, CYP2C9, CYP2D6, and CYP3A are not expected to be altered in patients receiving 17OHP-C.