Potential developmental effects of licit and illicit substances in humans: An approach to risk-specific dose and incidence

SANTOS JR, ARNALDO R.; LIMA, CAROLLINE M.

doi:10.1590/0001-3765202420240445

Brasil

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HEALTH SCIENCES • An. Acad. Bras. Ciênc. 96 (suppl 1) • 2024 • https://doi.org/10.1590/0001-3765202420240445 linkcopy

Potential developmental effects of licit and illicit substances in humans: An approach to risk-specific dose and incidence

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Abstract

Teratogens encompass any agent capable of causing a birth defect or elevating the incidence of defects within the population. This category includes substances like drugs, both legal and illegal. These substances cause congenital anomalies depending on the stage of development at the time of exposure, the dose, and the exposure time associated with the embryo. The most sensitive period is the embryonic stage, when the three leaflets give rise to tissues and organs. Susceptibility to teratogenesis decreases during the fetal phase but morphological and functional disturbance of the fetus may still occur. Substance use during pregnancy and its adverse effects are a public health problem and the lay population does not have access to this information. Particularly concerning is the period within the first six weeks of pregnancy, often before a woman realizes she is pregnant. Developmental data for many substances are simply not available, which makes the problem more serious. The aim of this study is to reflect on the teratogenic effects of licit and illicit substances in humans, focusing particularly on the dose that can induce malformations and their incidence in humans.

Key words environmental teratogenesis; congenital malformations; drugs; alcohol; medications

Substance	“Safe” dose	Dose associated with alterations	Absorbed dose	Exposure time	Incidence	Most common symptom at birth	References
Alcohol	Less than 30 to 60 g/day	From 30 to 60 g/day	15 mg : 100 ml	Within one hour	0.1 to 0.2% of exposed neonates	Fetal alcohol syndrome: IUGR, intellectual disability, microcephaly, ocular and joint abnormalities, small ocular fissures, and behavioral problems	Hepper et al. (2012) Moore et al. (2016) Oliveira et al. (2012)
Nicotine	Less than 0.04 mg/ml	From 0.04 mg/ml	0.03 mg/kg every 20 cigarettes	Within one day	5.01% of exposed neonates	Developmental and maturational delays demonstrated by measures of pinna detachment, fur appearance, incisor eruption, eye opening, and righting reflex	Morales-Suárez-Varela et al. (2006) Schneider et al. (2010)
Caffeine	Less than 300 mg per day	From 300 mg per day	Approximately 300 mg of the maximum dose	Per day	3.71% of exposed neonates	Fetal reabsorption, skeletal alterations, behavioral and nociceptive changes. The association with other substances can cause birth weight reduction when co-administered with cigarettes and intrauterine growth retardation when co-administered with paracetamol	Brent et al. (2011) Burdan (2003) Furuhashi et al. (1985) Souza et al. (2016)
Cocaine	Less than 10 mg/kg/day	From 10 mg/kg/day	2 to 3 mg	Within one day	20.45% of exposed neonates	Linked to low birth weight and height, skull defects, smaller head circumference, and a trend towards prematurity, in addition to neonatal complications and high perinatal mortality	Bingol et al. (1987) Coe et al. (2018) Cunha (2007) Ross et al. (2015) Smith et al. (1989)
Thalidomide	Less than 50 mg (single dose)	From 50 mg	40 to 50 mg of the maximum dose	Single dose	50% of pregnancies	Phocomelia, malformations in the head, bladder, genital organs and especially the heart, with congenital heart disease being the main cause of death among newborns	Rehman et al. (2011) Vargesson (2015) Vianna et al. (2017)
Paracetamol	Less than 75 mg/kg/day	From 75 mg/kg/day	47.5 to 66.75 mg of the maximum dose	Per day	62.16% of exposed neonates	Affecting the liver of both the pregnant woman and the fetus and maternal problems such as hemolytic anemia	Da Conceição Moura et al. (2022) Fernandes (2017) Quintilio et al. (2022) Wanderley & Artigalás (2011)
Aspirin	Less than 60 to 150 mg/day	From 150 mg/kg	60 to 75 mg per 150 mg	Within one day	12.79% of exposed neonates	Fetal hypocoagulability, with an increased incidence of hemorrhagic phenomena, gastroschisis in the first trimester, and inhibition of function and ductus arteriosus closure in the third trimester	Aragão & Tobias (2019) Tagashira et al. (1981) Tanaka et al. (1973) Wanderley & Artigalás (2011)
Ibuprofen	Less than 3 g per day	From 3 g per day	2.4 g of the maximum dose	Per day	4.76% of exposed neonates	Gastroschisis, implantation disorders, ductus arteriosus constriction, prolonged labor, and glomerular defects that can lead to renal failure	Bushra & Aslam (2010) Dathe et al. (2018) Pereira et al. (2020) Wanderley & Artigalás (2011)
Dipyrone	Less than 2 to 3 g per day	From 2 to 3 g per day	1.78 to 2.67 g of the maximum dose, respectively	Per day	6.05% of exposed neonates	Use associated with the risk of Wilms tumor and leukemia in children under two years of age, in addition to the risk of aplastic anemia and agranulocytosis	Aragão & Tobias (2019) Bánhidy et al. (2007) Da Conceição Moura et al. (2022) Quintilio et al. (2022) Wanderley & Artigalás (2011)
Diclofenac	Less than 200 mg per day	From 200 mg per day	100 mg of the maximum dose	Per day	1,81% of exposed neonates	Congenital septal heart defects, double kidney, cerebral atrophy with secondary macrocephaly and microcephaly	Cassina et al. (2010) Ertekin et al. (2019) Padberg et al. (2018)
Methotrexate	11 to 17 weeks: < 100 mg, 17 to 23 weeks:< 200 mg	11 to 17 weeks: > 100 mg, 17 to 23 weeks: > 200 mg	70 mg per 100 mg of the dose administered	Fortnightly	17.24% of exposed neonates	Skeletal and intracranial abnormalities, lack of frontal bone, hypertelorism, jaw hypoplasia, and heart defects	Moore et al. (2016) Schünemann Jr. et al. (2007)

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