Maternal and Fetal/Neonatal Pharmacokinetics and - Dynamics of Corticosteroids During Pregnancy (MaDyCo)

Maternal and Fetal/Neonatal Pharmacokinetics and - Dynamics of Corticosteroids During Pregnancy as Treatment for Fetal Lung Maturation MaDyCo-study

Improving pregnancy outcome is essential in improving health of both parents and their offspring during the life course. Preterm birth (PTB) occurs in 10-15% of all pregnancies, is the leading cause of perinatal mortality and morbidity {Goldenberg, 2008}, has long-term adverse consequences for postnatal health {Huddy, 2001} and is a burden for health care expenditure. In order to improve neonatal outcome, antenatal corticosteroids (ACS) are routinely administered to women at risk for preterm delivery before 34 weeks of pregnancy. {Jobe, 2018;Roberts, 2017;Travers, 2018} However, the current, worldwide standard of care, for the use of ACS is still based on animal experiments performed in the 1970's. {Liggins, 1969} Although ACS treatment to improve neonatal outcome was clinically introduced in the 70's, still only two dosing regimens are used, neither of which have been investigated, re-evaluated or refined to determine the optimal doses or treatment interval. With the current health care approach of personalized medicine in mind, the same universal approach for everybody, independent of gestational age, number of fetus, maternal weight or comorbidity one dose does not fit all since it often has not the desired effect. Due to the lack of optimization of the above mentioned synthetic corticosteroid drug regimens {Kemp, 2019}, significant gaps in knowledge exist. An important aspect to set up, investigate and understand dosing and also dosing interval experiments, is knowledge of the maternal individual pharmacokinetics and pharmacogenetics of the drug of interest during pregnancy.

Study Overview

• Status: Recruiting
• Conditions: Preterm Birth

Detailed Description

A clinical observational study will be performed in women admitted at the Department of Obstetrics at the Sophia Children's Hospital/Erasmus MC for suspicion of preterm birth with a gestational age of 23+5 weeks until 33+6 weeks. Antenatal corticosteroids will be administered according to the local standard protocol (12 mg betamethasone intramuscular with a 24 hours intervall). Importantly, clinical management of women with suspicion of preterm birth will not be affected by the proposed study. After inclusion, repetitive blood sampling according to the following schedule: t0 (administration), t0-30 min, t10-12hrs and t20-24 hrs. Umbilical cord will be sampled directly after birth as fetal determinant in which corticosteroids and their metabolites will be measured. Also, neonatal blood samples (drawn by the paediatricians as part of standard care) will be used for measurement of corticosteroids and their metabolites. Maternal blood samples will furthermore be analysed for determinants effecting pharmacokinetics such as oestradiol.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Sam Schoenmakers, MD, PhD; Phone Number: 0031107037439; Email: s.schoenmakers@erasmusmc.nl
• Study Contact Backup: Name: Emma Ronde-Salminen, MD; Phone Number: 0031683997312; Email: e.ronde@erasmusmc.com

Study Locations

• Netherlands
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015GD
      • Recruiting
      • Erasmus Medical Center
      • Contact: Sam Schoenmakers, MD, PhD; Phone Number: +31107037439; Email: s.schoenmakers@erasmusmc.nl
      • Contact: Emma Ronde-Salminen, MD; Phone Number: 0031683997312; Email: e.ronde@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

Pregnant women admitted at the Department of Obstetrics at Erasmus MC - Sophia for suspicion of preterm birth with a gestational age of 23+5 weeks until 33+6 weeks. Postpartum, the neonates will also be included in the study.

Description

Inclusion Criteria:

1. Older than 18 years of age.
2. Admitted at the Department of Obstetrics at Erasmus MC - Sophia for suspicion of preterm birth with a gestational age of 23+5 weeks until 33+6 weeks.
3. Understanding of Dutch in speaking and reading.

4. Written informed consent.

   In order for the neonate to be able to participate in this study, the parent must meet the following criteria:

5. Older than 18 years of age.
6. Admitted at the Department of Obstetrics at Erasmus MC - Sophia for suspicion of preterm birth with a gestational age of 23+5 weeks until 33+6 weeks.
7. Understanding of Dutch in speaking and reading.
8. Written informed consent for the neonate.

Exclusion Criteria:

1. Women unable or unwilling to agree with the procedures.
2. Women unable or unwilling to give written informed consent.
3. Women with acute obstetric complications requiring immediate delivery at time of admission.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of antenatal corticosteroids by investigation of betamethasone concentrations in serum using mmol/l	To examine the pharmacokinetics in maternal blood of standard regimen at the Erasmus MC of two doses of 12 mg betamethasone intramuscular with a 24 hours interval	2 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal age	To examine the relation between maternal age and the pharmacokinetics of the primary objective	2 days
Fetal sex	To examine the relation between fetal sex and the pharmacokinetics of the primary objective	2 days
Number of fetus	To examine the relation between the number of fetus and the pharmacokinetics of the primary objective	2 days
Parity: the number of times a woman has given birth to a live neonate (any gestation) or at 24 weeks or more	To examine the relation between parity the pharmacokinetics of the primary objective	2 days
PE by urine measurement of protein-creatinine ratio	To examine the relation between pre-eclampsia and the pharmacokinetics of the primary objective	2 days
Maternal weight/BMI in kg and kg/m2	To examine the relation between maternal weight/BMI and the pharmacokinetics of the primary objective	2 days
Oestradiol concentration in serum in mmol/l	To examine the relation between oestradiol on pharmacokinetics of the primary objective	2 days
Cord blood and neonatal blood concentration in mmol/l of corticosteroids	To examine the relation between pharmacokinetics in cord blood and neonatal blood	Delivery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CYP3A4 level	To examine the relation between CYP3A4 genotype and the pharmacokinetics of the primary objective	2 days

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Investigators: Principal Investigator: Sam Schoenmakers, MD, PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 4, 2023
• First Submitted That Met QC Criteria: February 16, 2024
• First Posted (Actual): February 20, 2024

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth
• Other Study ID Numbers: NL9318

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No