Background Analgesia during pregnancy is often necessary. Due to their widespread availability, many mothers opt to use over-the-counter (OTC) analgesics. Those analgesic compounds and their metabolites can readily cross the placenta and reach the developing foetus. Evidence for safety or associations with adverse health outcomes is conflicting, limiting definitive decision-making for healthcare professionals. Objective and rationale This review provides a detailed and objective overview of research in this field. We consider the global prevalence of OTC analgesia during pregnancy, explain the current mechanistic understanding of how analgesic compounds cross the placenta and reach the foetus, and review current research on exposure associations with offspring health outcomes. Search methods A comprehensive English language literature search was conducted using PubMed and Scopus databases. Different combinations of key search terms were used including 'over-the-counter/non-prescription analgesics', 'pregnancy', 'self-medication', 'paracetamol', 'acetaminophen', 'diclofenac', 'aspirin', 'ibuprofen', 'in utero exposure', 'placenta drug transport', 'placental transporters', 'placenta drug metabolism' and 'offspring outcomes'. Outcomes This article examines the evidence of foetal exposure to OTC analgesia, starting from different routes of exposure to evidence, or the lack thereof, linking maternal consumption to offspring ill health. There is a very high prevalence of maternal consumption of OTC analgesics globally, which is increasing sharply. The choice of analgesia selected by pregnant women differs across populations. Location was also observed to have an effect on prevalence of use, with more developed countries reporting the highest consumption rates. Some of the literature focuses on the association of in utero exposure at different pregnancy trimesters and the development of neurodevelopmental, cardiovascular, respiratory and reproductive defects. This is in contrast to other studies which report no associations. Wider implications The high prevalence and the challenges of reporting exact consumption rates make OTC analgesia during pregnancy a pressing reproductive health issue globally. Even though some healthcare policy-making authorities have declared the consumption of some OTC analgesics for most stages of pregnancy to be safe, such decisions are often based on partial review of literature. Our comprehensive review of current evidence highlights that important knowledge gaps still exist. Those areas require further research in order to provide pregnant mothers with clear guidance with regard to OTC analgesic use during pregnancy.

Over-the-counter analgesics during pregnancy: a comprehensive review of global prevalence and offspring safety.

Preterm birth after recurrent pregnancy loss: a systematic review and meta-analysis.

Resume La prevention de la pre-eclampsie, pathologie vasculo-placentaire a l’origine d’une part importante de la morbi-mortalite maternelle et fœtale, constitue un enjeu majeur de sante publique. L’aspirine a prouve son efficacite en prevention primaire et secondaire de la pre-eclampsie, en particulier lorsqu’elle est donnee a la dose de 150 mg/jour au coucher avant 15 SA chez une population de patientes a haut risque. Dans l’etude anglaise ASPRE, les femmes a haut risque de pre-eclampsie ont ete identifiees par le biais d’un algorithme prenant en compte le dosage des biomarqueurs angiogeniques a la fin du premier trimestre de grossesse. Cette mise au point rappelle les mecanismes physiopathologiques, les facteurs de risque de pre-eclampsie et l’interet du dosage sanguin precoce des biomarqueurs angiogeniques sFlt1 et PLGF au cours de la grossesse dans l’evaluation du risque de pre-eclampsie. Contrairement a l’Angleterre ou a Israel, l’application de cet algorithme en population generale n’a pas encore ete evaluee en France et il semblerait important de determiner si ce depistage y serait cout-efficace. Enfin, le lupus erythemateux systemique est associe a un sur-risque de pathologies vasculo-placentaires. Bien que peu nombreuses, les etudes sur l’interet du dosage des biomarqueurs angiogeniques au cours des grossesses lupiques identifient une correlation entre des taux eleves de sFlt1 a la fin du premier trimestre et la survenue ulterieure d’une pathologie vasculo-placentaire grave, avec une tres bonne valeur predictive negative de sFlt1. L’utilisation des biomarqueurs angiogeniques en depistage des pathologies vasculo-placentaires chez les femmes lupiques enceintes pourrait permettre de mieux cibler la population des femmes relevant d’un traitement par aspirine et d’une surveillance plus etroite.

Prévention de la pré-éclampsie en 2018 en population générale et chez la femme lupique : à l’aube d’une médecine personnalisée ?

Iconographies supplémentaires de l'article : Prévention de la pré-éclampsie en 2018 en population générale et chez la femme lupique : à l’aube d’une médecine personnalisée ?

Determine clinical risk factors for vasculo-placental disorders in singleton pregnancies.Prospective case-control study nested in HEMOTHEPP French cohort.Women delivered between June, 2015 and January, 2019 in any maternity ward of Finistère.Cases were women with vasculo-placental disorders (pre-eclampsia, intrauterine growth restriction (IUGR), placental abruption or stillbirth). Controls were women matched for age at delivery and parity.Clinical data were collected by obstetricians or midwives during antenatal care visits and delivery, and recorded by trained research assistants.Occurrence of a vasculo-placental disorder.505 women with vasculo-placental disorder (299 pre-eclampsia, 253 IUGR, 44 placental abruptions, 11 stillbirths) and 1515 matched controls were selected out of 20,075 participants. In multivariable analysis, four clinical parameters were associated with pre-eclampsia: obesity (Odd ratio (OR) = 3.11, 95%CI 2.11-4.58), French overseas origin (OR = 4.41, 95%CI 1.87-10.42), previous vasculo-placental disorder (OR = 5.14, 95%CI 2.72-9.70), aspirin during pregnancy (OR = 10.10, 95%CI 1.99-51.08). Three clinical parameters were associated with IUGR: auto-immune/inflammatory disorder (OR = 3.75, 95%CI 1.83-7.68), previous vasculo-placental disorder (OR = 3.63, 95%CI 2.06-6.41), smoking during pregnancy (OR = 2.66, 95%CI 1.91- 3.71). A previous venous thromboembolism (VTE) was associated with IUGR in univariable but not in multivariable analysis (OR = 3.72, 95%CI 0.82-17.00, p = 0.09).Clinical risk factors differ between IUGR and pre-eclampsia, the later, but not the former, being associated with cardiovascular risk factors. 

Clinical risk factors for vasculo-placental disorders: results from a prospective case-control study nested in HEMOTHEPP French cohort study.

Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages.

H. Isly

Papers

[Aspirin: Indications and use during pregnancy].