United States Food and Drug Administration (US-FDA) has issued a safety communication on the potential risk of oligohydramnios in pregnant women when exposed to medicinal products that belongs to the class of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) during pregnancy of 20 weeks gestational age. FDA issued this communication to alert health care professionals and consumers for safe and effective use of these category of pain-relieving medications, considering specific benefit risk evaluation for use in pregnant population.

Oligohydramnios refers to an inadequate level of amniotic fluid during pregnancy (volume less than expected level at gestational age). Amniotic fluid is like a cushion for foetus and umbilical cord from uterine compression. This fluid is critical for the normal fetal movement and lung development.

NSAIDs are class of drugs which act by inhibiting cyclo-oxygenase (COX) enzymes, which play key role in the production of inflammatory mediators like prostaglandins and thromboxanes inside the body, thereby producing ant-inflammatory and pain reliving therapeutic effects. These medicines are used in the treatment of pain, fever, arthritis, menstrual cramps, headaches, migraine, colds, acute gout etc., The commonly used NSAIDs are aspirin, acetaminophen, ibuprofen, diclofenac, indomethacin and naproxen.

NSAID use in Pregnant women

There is literature evidence for adverse effects to foetus associated with NSAID exposure. Inhibition of prostaglandin synthesis during foetus development interferes with blood circulation for various organs of foetus which could be attributed to the teratogenic effects of NSAIDs. Monika E et.al., published a review article related to COX inhibitors association with miscarriage.  Many recent studies demonstrated the relationship between congenital cardiac malformations, ductus arteriosus associated with the maternal use of NSAIDs. In 2015, USFDA released a drug safety communication on the possible risks of pain reliving medicines usage during pregnancy which highlighted the risk of miscarriage with NSAIDs. Ideally, physicians prescribe NSAIDs to pregnant women when the maternal benefits of the particular NSAID outweighs the potential fetal risks associated with respective NSAID.

The current prescribing information documents for NSAID class of drugs contain a warning to restrict the usage in pregnant women at 30 weeks gestational age due to potential risk of premature closure of fetal ductus arteriosus.

On 15-Oct-2020, USFDA released a drug safety communication which states an additional warning to avoid using NSAIDs in pregnant women at 20 weeks of gestational age due to oligohydramnios which causes rare serious renal issues like neonatal renal dysfunction in the foetus.

Safety Evidence on ‘NSAID-Low level of Amniotic fluid’

USFDA reviewed the data from medical literature and from the case reports which are present in their database, FAERS (FDA adverse event reporting system) which were received from marketing authorization holders and from general public involving both consumers and health care professionals. 20 case reports were identified which comprise NSAID exposure in uterus who experienced neonatal renal dysfunction within few days following birth.  The severity of renal dysfunction varied greatly from normalization at 3 days to persistent anuria (no passage of urine) requiring dialysis and/or exchange transfusion. There are total 11 fatal reports, out of which eight neonates were reported to have died as a direct consequence of renal failure or due to complications from dialysis.

The case reports and most of published literature articles described the safety concerns of oligohydramnios (low level of amniotic fluid) and neonatal renal dysfunction associated with NSAID exposure during pregnancy with the below key information suggesting relationship.

Temporal relationship: Detection of low level of amniotic fluids within 48 hours to multiple weeks from the NSAID use.

Dechallenge positive: Reversal of adverse reaction, oligohydramnios within 72 hours to 6 days in response to NSAID discontinuation.

Rechallenge positive: In some case reports, oligohydramnios re-appeared after re-introduction of NSAID drug.

Important information for heath care professionals:

  • Be aware of safety concerns – oligohydramnios and neonatal renal impairment associated with NSAID exposure during pregnancy (20 weeks gestational age).
  • Be aware of potential complications due to oligohydramnios which included limb contractures and delayed lung maturation.
  • Lowest effective dose – If treatment with NSAID drugs is deemed necessary limit the usage with least possible dose and duration of treatment.
  • Monitor amniotic fluid – If NSAID treatment is scheduled for more than 2 days, consider ultrasound monitoring of amniotic fluid level.
  • Be informed that this safety alert is not applicable to low dose aspirin (81 mg).
  • Strictly consider weighing maternal benefits and potential risks to mother and foetus before prescribing.

Important information for Pregnant women:

  • Be informed that many OTC (over the counter medicines) contain drugs which belong to NSAID class and consider discussing with your respective health care professional before using NSAID during pregnancy, especially at 20 weeks of gestational age.
  • Be aware of potential safety concerns for unborn baby when exposed to NSAID which could lead to complications – miscarriage, delay in development, premature delivery etc.,
  • Note that medicinal products contain both benefits and risks too. There are many medicinal products in the market (both prescription and OTC medicines) in which safety profile was not established for use in special populations like pregnant women, children, and elderly population. So, always liaise with your health care professional for any questions or concerns on information, usage, and safety of medicinal products during pregnancy.

Voluntary ADR reporting:

All health care professionals and consumers are encouraged to consciously observe and monitor for safety outcomes of medicinal products used during pregnancy in order to accumulate safety evidence for medicinal products in these special population groups who are not included/studied during clinical trial period. If you encounter any adverse reaction or event which is suspected to the use of any drug during pregnancy, report the same to US-FDA via MedWatch Online Voluntary Reporting Form.

error: Content is protected !!