Developmental toxicity assessment of d,l‐Methylphenidate and d‐Methylphenidate in rats and rabbits

AIMSThe aims of this review were to summarize the scientific evidence about the risks of using methylphenidate for ADHD in pregnancy and lactation, to present a case in which interruption of treatment after delivery and during breastfeeding was harmful and to discuss the implications of treating or not treating ADHD in pregnancy and lactation. METHODSFor the systematic review, databases searched included Pubmed, Psychinfo, Web of Science, Embase, Biosis and Medline. RESULTSThree articles were found with a total sample of 41 children exposed to methylphenidate in pregnancy. Malformations reported included congenital heart defects (n = 2), finger abnormalities (syndactyly, adactyly and polydactyly n = 2) and limb malformations (n = 1). Other problems included premature birth, asphyxia and growth retardation. One case report (n = 1) and one case series (n = 3) were identified regarding exposure to methylphenidate through breast feeding. In all cases, children developed normally and no adverse effects were reported. In our case report we describe an infant exposed to methylphenidate during pregnancy and breast feeding, who developed normally having no detectable congenital abnormalities. CONCLUSIONSThe number and size of the studies found were small. Identified cases were not representative of the general adult ADHD population having methylphenidate as monotherapy during pregnancy as all the articles reported combinations of methylphenidate with either known teratogenic drugs or drugs of abuse. There is a paucity of data regarding the use of methylphenidate in pregnancy and further studies are required. Although the default medical position is to interrupt any non-essential pharmacological treatment during pregnancy and lactation, in ADHD this may present a significant risk. Doctors need to evaluate each case carefully before interrupting treatment.

show abstract

“…A low teratogenicity risk was found for rabbits and no teratogenic toxicity was observed in rats [14].…”

Section: Pharmacokinetics and Pharmacodynamics Of Methylphenidate In mentioning

confidence: 89%

Methylphenidate use in pregnancy and lactation: a systematic review of evidence

Bolea-Alamañac

Green

Verma

et al. 2013

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…In 1993 Debooy and colleagues described prematurity, growth retardation, and signs of neonatal withdrawal after intravenous methylphenidate abuse during pregnancy, but no particular teratogenic anomaly or severe developmental delay [69]. Apart from that, possible teratogenic effects of methylphenidate have recently only been addressed in rats, rabbits and mice [70][71][72].…”

Section: Discussionmentioning

confidence: 99%

Detection of drugs in paired maternal and umbilical cord blood samples

Veit¹,

Erdmann²,

Birngruber³

et al. 2017

RJLM

View full text Add to dashboard Cite

Objectives. The consumption of drugs during pregnancy or delivery leads to pre and intranatal drug exposure of the fetus. The purpose of this study was to examine paired blood samples of the mother and the umbilical cord regarding drug distribution. Methods. Over a period of two years, 22 pregnant women with known or admitted drug use were selected. Paired blood samples of the mothers and the umbilical cord blood were collected shortly before and during birth/caesarean section, respectively. The samples were subjected to systematic immunochemical, HPLC-DAD, GC/MS and LC-MS/MS analysis and compared regarding presence of drugs. Results. Methadone, THC-COOH, tramadol, benzoylecgonine, citalopram, carbamazepine, lamotrigine, perazine, methylphenidate, quetiapine, ranitidine and most constituents of spinal and epidural anaesthesia were found in both, maternal and umbilical cord blood samples. THC, 11-OH-THC, olanzapine, diphenhydramine and telmisartan were found in maternal blood only. Conclusions. As previously shown a variety of drugs is able to pass the placenta of pregnant woman. Umbilical cord blood appears to be a viable matrix for the detection of maternal drug consumption. Drugs administered during labour and birth could be detected in umbilical cord blood. Further studies with a greater collective of women with known drug use including analyses of fetal/infant samples will yield additional information in the future.

show abstract

“…But as adults are increasingly taking methylphenidate, the potential risk of early developmental exposure must be considered because some women taking methylphenidate to treat ADHD become pregnant. In terms of morphological indices methylphenidate was found to have low teratological potential in rat and rabbit models (Beckman et al, 2008; Teo et al, 2003; Teo et al, 2002). Given that methylphenidate has its key actions of increasing concentrations of norepinepherine and dopamine in the neocortex (Berridge et al, 2006), a likely target organ for methylphenidate-induced teratology is the brain.…”

Section: Introductionmentioning

confidence: 99%

Persistent behavioral impairment caused by embryonic methylphenidate exposure in zebrafish

Levin

Sledge

Roach

et al. 2011

Neurotoxicology and Teratology

View full text Add to dashboard Cite

As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to the potential risks of early developmental exposure if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it might also cause persistent behavioral impairment after developmental exposure. Zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0-5 days post fertilization (12.5-50 mg/l). They were tested for long-term behavioral effects as adults. Methylphenidate exposure (50 mg/l) caused significant increases in dopamine, norepinepherine and serotonin on day 6 but not day 30 after fertilization. In the novel tank diving test of predatory avoidance developmental methylphenidate (50 mg/l) caused a significant reduction in the normal diving response. In the three-chamber spatial learning task early developmental methylphenidate (50 mg/l) caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state.

show abstract

Developmental toxicity assessment of d,l‐Methylphenidate and d‐Methylphenidate in rats and rabbits

Abstract: There was no teratogenicity with d-MPH. There was a low teratogenic risk with d,l-MPH in only the rabbit. Higher C(max) may explain differences in results from previous studies.

Cited by 15 publications

References 12 publications

Methylphenidate use in pregnancy and lactation: a systematic review of evidence

Methylphenidate use in pregnancy and lactation: a systematic review of evidence

Detection of drugs in paired maternal and umbilical cord blood samples

Persistent behavioral impairment caused by embryonic methylphenidate exposure in zebrafish

Contact Info

Product

Resources

About