Evaluation of fetotoxicity after 2nd and 3rd trimester exposure to NSAID, metamizole, acetylsalicylic acid and paracetamol
Organizational Data
- DRKS-ID:
- DRKS00015617
- Recruitment Status:
- Recruiting complete, study complete
- Date of registration in DRKS:
- 2018-11-02
- Last update in DRKS:
- 2023-01-31
- Registration type:
- Retrospective
Acronym/abbreviation of the study
Fetotoxicity of NSAID
URL of the study
No Entry
Brief summary in lay language
Due to the high prevalence of pain symptoms, analgesics are commonly used and needed in pregnancy. The aim of this study is to determine the risk and reevaluate the safety of analgesic treatment in the 2nd and 3rd trimester of pregnancy. Therefore, two groups of analgesic drugs are being explored. On one hand, Paracetamol (acetaminophen) that is considered safe in terms of teratogenicity and is recommended as analgesic of choice in any trimester of pregnancy. On the other hand, non-steroidal anti-inflammatory drugs (NSAID) e.g. ibuprofen, are a further option of first choice in the 1st and 2nd trimester of pregnancy. In the 3rd trimester, NSAID should not be used due to increased risk of adverse effects in the fetus. However, data are scarce to specify whether fetotoxic risks might occur after long‐term NSAID use in the second trimester. Although paracetamol is considered safe, further data are necessary to confirm the safety in regard of possible fetotoxic effects especially after long-term use in the late gestational weeks of the 3rd trimester.
Brief summary in scientific language
Due to the high prevalence of pain symptoms, analgesics are commonly used and needed in pregnancy. The aim of this study is to determine the risk and reevaluate the safety of analgesic treatment in the second and third trimester of pregnancy. Paracetamol (acetaminophen) is considered safe in terms of teratogenicity and recommended as analgesic of choice in any trimester of pregnancy. In addition, non-steroidal anti-inflammatory drugs (NSAID) as ibuprofen, other NSAIDs including coxibes, ASA in analgesic doses and metamizole, are a further option of first choice in the 1st and 2nd trimester of pregnancy. In the 3rd trimester, NSAID should not be used due to their prostaglandin antagonism and therefore increased risk of adverse effects in the fetus like ductus arteriosus constriction or potential fetal renal impairment. However, data are scarce to specify whether fetotoxic risks might occur after long‐term NSAID use in the 2nd trimester. Additionally, studies have shown that paracetamol might be as effective as ibuprofen or indomethacin in the treatment of patent ductus arteriosus Botalli in newborn children. This raises the questions whether paracetamol can be recommended as a safe treatment option during the entire 3rd trimester. Considering these issues, there is an urgent need to improve the evidence basis. Data analysis will be based on documented cases exposed to the study medication archived in the database of the Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy (2008-2017).
Health condition or problem studied
- Free text:
- MedDRA - 10049996 Ductus arteriosus premature closure
- Free text:
- MedDRA - 10013808 Ductus arteriosus stenosis foetal
- Free text:
- MedDRA - 10034130 Patent ductus arteriosus (PT, 21.1)
- Free text:
- MedDRA - 10030289 Oligohydramnios
- Free text:
- MedDRA - 10066470 Amniorrhoea
- Free text:
- MedDRA - 10042062 Stillbirth
- Free text:
- MedDRA - 10055690 Fetal death
- Free text:
- MedDRA - 10050701 Congenital pulmonary hypertension
- Free text:
- MedDRA - 10038447 Renal failure neonatal
- Free text:
- MedDRA - 10049778 Neonatal anuria
- Free text:
- MedDRA - 10030302 Oliguria
- Healthy volunteers:
- No Entry
Interventions, Observational Groups
- Arm 1:
- Patients exposed to paracetamol in the 3rd trimester. Treatment may have started before or during the 3rd trimester. Cases are not allowed to be exposed to NSAIDs (non-steroidal anti-inflammatory drugs), ASA (acetylsalicylic acid) or metamizole during the 2nd or 3rd trimester.
- Arm 2:
- Patients exposed to paracetamol at any time in the 1st and 2nd trimester but not in the 3rd trimester. Cases may be exposed to NSAIDs, ASA or metamizole only during the 1st trimester. Paracetamol cases already included in the exposed cohort (those with exposure also during the 3rd trimester) will be excluded. Arm 2 is the comparison cohort of arm 1.
- Arm 3:
- Patients exposed to NSAID, ASA or metamizole in the 2nd and/or 3rd trimester. Multiple exposure to study drugs is allowed. Treatment may have started before or during the 2nd/3rd trimester. Cases may be co-exposed to paracetamol.
- Arm 4:
- Patients exposed to NSAIDs, ASA or metamizole during the 1st trimester only. Patients may be exposed to paracetamol at any time during pregnancy. NSAID/ASA/metamizole cases already included in the exposed cohort (those with exposure also during the 2nd or 3rd trimester) will be excluded from the comparison cohort. Arm 3 is the comparison cohort of arm 3.
Endpoints
- Primary outcome:
- To estimate the risk of fetotoxic effects after exposure to the study medication 1) Paracetamol during 3rd trimester, and 2) NSAIDs during 2nd and/or 3rd trimester, the following pre- and postnatal primary study endpoints will be investigated: intrauterine narrowing or closure of ductus arteriosus Botalli, patent fetal ductus arteriosus Botalli in the newborn, primary pulmonary hypertension in the newborn, other adverse pregnancy outcomes possibly such as late fetal death and stillbirth. Initial collection of data during pregnancy are recorded by a structured questionnaire. Approximately eight weeks after the estimated date of birth another questionnaire is send to collect data about the pregnancy outcome.
- Secondary outcome:
- Optional, explorative: oligohydramnios and/or impaired renal function and prematurity/fetal distress
Study Design
- Purpose:
- Prevention
- Retrospective/prospective:
- No Entry
- Study type:
- Non-interventional
- Longitudinal/cross-sectional:
- No Entry
- Study type non-interventional:
- No Entry
Recruitment
- Recruitment Status:
- Recruiting complete, study complete
- Reason if recruiting stopped or withdrawn:
- No Entry
Recruitment Locations
- Recruitment countries:
-
- Germany
- Number of study centers:
- Monocenter study
- Recruitment location(s):
-
- University medical center Charité Universitätsmedizin Berlin Berlin
Recruitment period and number of participants
- Planned study start date:
- No Entry
- Actual study start date:
- 2008-01-01
- Planned study completion date:
- No Entry
- Actual Study Completion Date:
- 2019-12-31
- Target Sample Size:
- 4200
- Final Sample Size:
- 4000
Inclusion Criteria
- Sex:
- Female
- Minimum Age:
- no minimum age
- Maximum Age:
- no maximum age
- Additional Inclusion Criteria:
- These criteria apply for the exposed and comparison cohorts: Prospective case reports ascertained and archived in the database of the German Embryotox Pharmacovigilance Centre. Prospectively ascertainment means that neither pregnancy outcome was known nor prenatal pathology had been diagnosed at the time our institute was contacted. Follow-up of pregnancy outcome including relevant data on the infant. Data analysis will be based on documented cases exposed to the study medication archived in the database of the Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy (2008-2017).
Exclusion Criteria
Retrospective case reports
Addresses
Primary Sponsor
- Address:
- Pharmakovigilanzzentrum Embryonaltoxikologie, Charité Universitätsmedizin BerlinProf. Dr. med. Christof SchaeferAugustenburger Platz 113353 BonnGermany
- Telephone:
- No Entry
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
- Investigator Sponsored/Initiated Trial (IST/IIT):
- Yes
Contact for Scientific Queries
- Address:
- Pharmakovigilanzzentrum Embryonaltoxikologie Charité Universitätsmedizin BerlinPD Dr. med. Katarina DatheAugustenburger Platz 113353 BerlinGermany
- Telephone:
- 004930450525743
- Fax:
- 004930450525902
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- https://www.embryotox.de/
Contact for Public Queries
- Address:
- Pharmakovigilanzzentrum Embryonaltoxikologie Charité Universitätsmedizin BerlinPD Dr. med. Katarina DatheAugustenburger Platz 113353 BerlinGermany
- Telephone:
- 004930450525743
- Fax:
- 004930450525902
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- https://www.embryotox.de/
Principal Investigator
- Address:
- Pharmakovigilanzzentrum Embryonaltoxikologie Charité Universitätsmedizin BerlinPD Dr. med. Katarina DatheAugustenburger Platz 113353 BerlinGermany
- Telephone:
- 004930450525743
- Fax:
- 004930450525902
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- https://www.embryotox.de/
Sources of Monetary or Material Support
Public funding institutions financed by tax money/Government funding body (German Research Foundation (DFG), Federal Ministry of Education and Research (BMBF), etc.)
- Address:
- Bundesinstitut für Arzneimittel und MedizinprodukteKurt-Georg-Kiesinger-Allee 353175 BonnGermany
- Telephone:
- No Entry
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.bfarm.de/cln_103/DE/Home/home_node.html
Ethics Committee
Address Ethics Committee
- Address:
- Ethikkommission der Charité – Universitätsmedizin BerlinCharitéplatz 110117 BerlinGermany
- Telephone:
- (+49)30-450517222
- Fax:
- (+49)30-450517952
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Vote of leading Ethics Committee
- Vote of leading Ethics Committee
- Date of ethics committee application:
- 2018-06-21
- Ethics committee number:
- EA2/129/18
- Vote of the Ethics Committee:
- Approved
- Date of the vote:
- 2018-08-27
Further identification numbers
- Other primary registry ID:
- No Entry
- EudraCT Number:
- No Entry
IPD - Individual Participant Data
- Do you plan to make participant-related data (IPD) available to other researchers in an anonymized form?:
- No
- IPD Sharing Plan:
- No Entry
Study protocol and other study documents
- Study protocols:
- No Entry
- Study abstract:
- No Entry
- Other study documents:
- No Entry
- Background literature:
- No Entry
- Related DRKS studies:
- No Entry
Publication of study results
- Planned publication:
- No Entry
- Publikationen/Studienergebnisse:
- Dathe K, Frank J, Padberg S, Hultzsch S, Meixner K, Beck E, Meister R, Schaefer C. Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third-trimester paracetamol use: evaluation of the German Embryotox cohort. BJOG. 2019; 126(13):1560-7
- Dathe K, Frank J, Padberg S, Hultzsch S, Beck E, Schaefer C. Fetal adverse effects following NSAID or metamizole exposure in the 2nd and 3rd trimester: an evaluation of the German Embryotox cohort. BMC Pregnancy and Childbirth. 2022; 22(1):666
- Date of first publication of study results:
- 2019-08-07
- DRKS entry published for the first time with results:
- 2023-01-31
Basic reporting
- Basic Reporting / Results tables:
- No Entry
- Brief summary of results:
- see abstracts: https://pubmed.ncbi.nlm.nih.gov/31310697/ https://pubmed.ncbi.nlm.nih.gov/36028798/