Abnormal Development - Drugs

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Introduction

Area under plasma concentration-time curve

This page introduces the possible effects of maternal use of some selected legal drugs (therapeutic chemicals/agents) on development.[1] In some cases these drugs are prescribed to treat pre-existing or pregnancy related maternal medical conditions. This is not a comprehensive drug list and includes some known teratogens as well as data from early studies that require further confirmation. In all cases, a discussion with a medical practioner should be had prior to any reproductive decision.

The placenta and fetal tissues may deal with drugs differently from adult target tissues. In particular, drugs are "cleared", metabolised and excreted, at a different rate in both the fetus and in newborn infants. In general there is a much lower rate of clearance.


Legal drugs are classified, usually by each country's appropriate regulatory body, on the safety of drugs during pregnancy. In Australia, the Therapeutic Goods Authority has classes (A, B1, B2, B3, C, D and X) to define their safety. The USA used to have (before 2015) a similar Food and Drug Administration (FDA) labelling classes (A, B, C, D, and X) to define their safety. Since 2015 these drug categories has been replaced with the "FDA Pregnancy and Lactation Labeling Rule" (PLLR).[2]


Note that pregnant and breastfeeding women are generally excluded from drug clinical trials[3] and most data relies on animal studies.


There are also a growing range of herbal drugs which may not have undergone this type of study and classification.


The importance of careful evaluation of drugs and differences between species[4] can be historically demonstrated with the teratogenic effects of thalidomide, a drug given to treat "morning sickness" in the first trimester of pregnancy, which affected musculoskeletal development. This current page also gives examples of some other current drugs which have been shown to impact on development.


Currently, there is a USA population specific abuse of the prescription drug Oxycodone, commercial name "OxyContin".[5] Oxycodone is a strong opioid analgesic, semisynthetic opioid synthesized from thebaine, that binds μ- and κ-opioid receptors.


Environmental Links: Introduction | low folic acid | iodine deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | thalidomide | herbal drugs | Illegal Drugs | smoking | Fetal Alcohol Syndrome | TORCH | viral infection | bacterial infection | fungal infection | zoonotic infection | toxoplasmosis | Malaria | maternal diabetes | maternal hypertension | maternal hyperthermia | Maternal Inflammation | Maternal Obesity | hypoxia | biological toxins | chemicals | heavy metals | air pollution | radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis


Some Recent Findings

  • Prenatal Risk Factors and Perinatal and Postnatal Outcomes Associated With Maternal Opioid Exposure in an Urban, Low-Income, Multiethnic US Population[6] "The opioid epidemic increasingly affects pregnant women and developing fetuses, resulting in high rates of neonatal abstinence syndrome. However, longitudinal studies that prospectively observe newborns with neonatal abstinence syndrome or with maternal opioid use and examine their long-term physical and neurodevelopmental outcomes are lacking. To examine prenatal risk factors associated with maternal opioid use during pregnancy and the short-term and long-term health consequences on their children. This cohort study analyzed data from the Boston Birth Cohort, an urban, low-income, multiethnic cohort that enrolled mother-newborn pairs at birth at Boston Medical Center (Boston, Massachusetts) starting in 1998, and a subset of children were prospectively observed at Boston Medical Center pediatric primary care and subspecialty clinics from birth to age 21 years. Data analysis began in June 2018 and was completed in May 2019. In utero opioid exposure was defined as maternal self-reported opioid use and/or clinical diagnosis of neonatal abstinence syndrome. ...In this sample of urban, high-risk, low-income mother-child pairs, in utero opioid exposure was significantly associated with adverse short-term and long-term outcomes across developmental stages, including higher rates of physical and neurodevelopmental disorders in affected children. Efforts to prevent the opioid epidemic and mitigate its health consequences would benefit from more intergenerational research."
  • Review - Impact of chloroform exposures on reproductive and developmental outcomes[7] "We assessed the animal and epidemiological data to determine if chloroform exposure causes developmental and/or reproductive toxicity. The available animal data suggest that exposures lower than those causing maternal toxicity should be without developmental effects in the offspring. Also, most studies in humans rely on group-level geographic exposure data, providing only weak epidemiologic evidence for an association with development outcomes and fail to establish a causal role for chloroform in the induction of adverse developmental outcomes at environmentally relevant concentrations."
  • Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis[8] "Evidence on adverse effects of maternal macrolide use during pregnancy is inconsistent. We conducted a systematic review and meta-analysis to investigate the association between macrolide use during pregnancy and adverse fetal and child outcomes. We included observational studies and randomised controlled trials (RCTs) that recorded macrolide use during pregnancy and child outcomes. We prioritized comparisons of macrolides with alternative antibiotics (mainly penicillins or cephalosporins) for comparability of indication and effect. Random effects meta-analysis was used to derive pooled odds ratios (OR) for each outcome. Subgroup analyses were performed according to specific types (generic forms) of macrolide. Of 11,186 citations identified, 19 (10 observational, 9 RCTs) studies were included (21 articles including 228,556 participants). Macrolide prescribing during pregnancy was associated with an increased risk of miscarriage (pooled ORobs 1·82, 95% CI 1·57-2·11, three studies, I2 = 0%), cerebral palsy and/or epilepsy (ORobs 1·78, 1·18-2·69; one study), epilepsy alone (ORobs 2·02, 1·30-3·14, one study; ORRCT 1.03, 0.79-1.35, two studies), and gastrointestinal malformations (ORobs 1·56, 1·05-2·32, two studies) compared with alternative antibiotics. We found no evidence of an adverse effect on 12 other malformations, stillbirth, or neonatal death. Results were robust to excluding studies with high risk of bias.Consistent evidence of an increased risk of miscarriage in observational studies and uncertain risks of cerebral palsy and epilepsy warrant cautious use of macrolide in pregnancy with warnings in drug safety leaflets and use of alternative antibiotics where appropriate. As macrolides are the third most commonly used class of antibiotics, it is important to confirm these results with high quality studies."
  • Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study[9] "The early life microbiome contributes to immune development. Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. We investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection. METHODS: We used population-based Danish national databases for pregnancies between 1995 and 2009. Infants were followed from birth until their first infection-related hospitalization, death, 14th birthday, emigration or end-2009. Exposure was maternal antibiotics prescribed before and during pregnancy. Outcome was infection-related hospitalization. CONCLUSIONS: Antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms."
  • Characteristics of drug use among pregnant women in the United States: Opioid and non-opioid illegal drug use[10] "The opioid epidemic in the US is affecting pregnant women and their offspring, with rising numbers of maternal and neonatal treatment episodes. The aim of this study was to characterize pregnant drug users in order to inform intervention strategies based on sociodemographic, mental health, and substance use characteristics. Data on pregnant women aged 18-44 reporting past-year, nonmedical opioid use or use of non-opioid illegal drugs (other than marijuana) were analyzed from the National Survey on Drug Use and Health (2005-2014). ...: Pregnant drug-using women were often of low socioeconomic status, with mental health and substance use patterns suggesting the need for targeted mental health/substance use screening and interventions before and during pregnancy, particularly for opioid-polydrug users."
  • Review - Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System[11] "The endogenous opioid system, comprised of multiple opioid neuropeptide and receptor gene families, is highly expressed by developing neural cells and can significantly influence neuronal and glial maturation. In many central nervous system (CNS) regions, the expression of opioid peptides and receptors occurs only transiently during development, effectively disappearing with subsequent maturation only to reemerge under pathologic conditions, such as with inflammation or injury. Opiate drugs with abuse liability act to modify growth and development by mimicking the actions of endogenous opioids. Although typically mediated by μ-opioid receptors, opiate drugs can also act through δ- and κ-opioid receptors to modulate growth in a cell-type, region-specific, and developmentally regulated manner. Opioids act as biological response modifiers and their actions are highly contextual, plastic, modifiable, and influenced by other physiological processes or pathophysiological conditions, such as neuro-acquired immunodeficiency syndrome. "
  • Australian Report - Poisoning in children and young people 2012–13[12] "almost half (49%) of all cases occurred among 18-24 year olds, and a quarter among 15-17 year olds (26%). The highest rate of poisoning by pharmaceuticals was seen in 15–17 year old girls (589 cases per 100,000)." Australian Statistics
More recent papers  
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References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Drug teratogenicity | Opioid teratogenicity

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis[13] "Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, risks of VPA-associated CMs are 2 to 7 fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient."
  • Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism[14] "Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism. Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). ...Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control."
  • Obstetric toxicology: teratogens[15] "The emergency physician frequently encounters women who seek care because of pregnancy- and nonpregnancy-related complaints. Many medications are safe for use during pregnancy, including several that are listed as potential teratogens based on the Food and Drug Administration's (FDA) pregnancy classification; but it is important that the emergency physician know and recognize which drugs can be given in pregnancy and which drugs are absolutely contraindicated. Expert resources should be identified and used because the FDA's classification of drugs based on pregnancy risk does not represent the most up-to-date or accurate assessment of a drug's safety."
  • Evolving knowledge of the teratogenicity of medications in human pregnancy[16] "Sources of data that led to a revised risk were derived from exposure cohort studies performed through record linkage studies, teratogen information services, large population-based case-control studies, and pregnancy registries. The mean time for a treatment initially classified as having an "undetermined" risk to be assigned a more precise risk was 27 years (95% confidence interval 26-28 years). The lack of information needed to assess the safety of drug treatments during human pregnancy remains a serious public health problem. A more active approach to post-marketing surveillance for teratogenic effects is necessary."
  • Exposure to Non-Steroidal Anti-Inflammatory Drugs during Pregnancy and the Risk of Selected Birth Defects: A Prospective Cohort Study[17] "We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. ...Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded."
  • Valproic acid inhibits neural progenitor cell death by activation of NF-kappaB signaling pathway and up-regulation of Bcl-XL [18] "At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IkappaBalpha and the activation of NF-kappaB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behaviour."
  • Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study[19] "Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations."

Drug Use During Pregnancy

USA

A 2011 study of USA data from 1976-2008 has shown:[20]

  • 6 million pregnancies every year
  • 50% of pregnant women reported taking at least one medication
  • Pregnant women take an average of 2.6 medications at any time during pregnancy
  • First trimester use of prescription medications has increased by more than 60%
  • Use of 4 or more medications in the first trimester has tripled (9.9% to 27.6%)

The USA has also recently (2015) replaced the drug classification with the "FDA Pregnancy and Lactation Labeling Rule" (PLLR).[2]

Links: USA Drug Categories

Europe

A 2017 study of European data from 15 European countries from October 2011 to February 2012 has shown:[21]

  • 69% of women used medications classified as safe
  • 28% used medications classified as risky
  • 3% used medications with no classification available
  • Socio-demographic and medical factors were associated with use of risky medications during pregnancy
  • Having a chronic disorder was the factor with the strongest association with the use of risky medications during pregnancy

Australia

A 2017 study of pregnancy-related calls to Australian national medicines call centre covering 8 years has shown:[22]

  • 1166 calls with stage of pregnancy available concerned safety
  • 34% of questions related to medication classified as 'safe' during pregnancy
  • After antidepressants, most calls were made about over-the-counter (OTC) medicines
    • paracetamol, dexchlorpheniramine, codeine
  • Safe treatment for everyday conditions was of increasing concern as pregnancy progressed

Neural Development

Opioids and neural development timeline.jpg

Opioids and neural development timeline effects.[11]


Advisory Committee on Medicines

  • 1963 - Australian Drug Evaluation Committee (ADEC) was established in 1963 following the thalidomide experience.
  • 2010 - the ADEC committee was replaced by the Advisory Committee on Prescription Medicines (ACPM)
  • 2017 - ACPM committee was replaced by the Advisory Committee on Medicines (ACM).
The ACM provides independent medical and scientific advice to the Minister for Health and the Therapeutic Goods Administration (TGA) on issues relating to the safety, quality and efficacy of medicines supplied in Australia including issues relating to pre-market and post-market functions for medicines.
Australian Drug Categories 
Legal drugs are classified, usually by each country's appropriate regulatory body, on the safety of drugs during pregnancy. In Australia, the Therapeutic Goods Authority has classes (A, B1, B2, B3, C, D and X) to define their safety. In the USA, drugs are classified by the Food and Drug Administration (FDA) into classes (A, B, C, D, and X) to define their safety. (More? Australian Drug Categories)


  • Pregnancy Category A - Have been taken by a large number of pregnant women and women of childbearing age without an increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
  • Pregnancy Category B1 - Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
  • Pregnancy Category B2 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
  • Pregnancy Category B3 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
  • Pregnancy Category C - Have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
  • Pregnancy Category D - Have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
  • Pregnancy Category X - Have such a high risk of causing permanent damage to the fetus that they should NOT be used in pregnancy or when there is a possibility of pregnancy.

Abnormal Development - Drugs

Drug Testing 
Typical testing of new drug compound today involves a lengthy series of animal and human studies.

Animal studies

Usually tested in at least two mammalian species (rats and guinea pigs) using both single and repeated doses. For determining reproductive effects, tests on both male and female animals with dosing begins 4 weeks prior to mating are conducted to determine effects on fertility in both sexes, on embryogenesis, and on fetal malformation.

Human Clinical trials

Following animal studies to determine dose, efficacy and apparent safety, human studies can commence. Clinical trials are carried out under very strict conditions, set by international regulatory bodies in agreement with the principles espoused in the Declaration of Helsinki. There are four phases to the trials.

  • Phase I trials - conducted in small groups of 10 to 20 healthy young male volunteers. Designed to examine how the drug is absorbed, distributed, metabolised and excreted by the body and to establish the safe dose for phase II trials.
  • Phase II trials - conducted in 50 to 100 patients with the disease rather than healthy volunteers as in phase I. Designed to examine what effect the drug has on the body (heart rate, blood pressure and cognitive effects) depending on the disease the drug is being developed to treat.
  • Phase III trials - conducted in 100’s of patients (larger numbers) with a particular disease or condition and are generally randomised comparative double-blinded studies. Using a comparator of either placebo, another active drug already used, or both. Several phase III trials are usually required by the regulatory authorities. Note that even these studies may not identify uncommon adverse effects, until used widely in the community.
  • Phase IV trials - (post-registration) conducted in 1000’s of patients over several years, these trials are randomised controlled trials undertaken after the drug has been registered.
After phase I to III the pharmaceutical company compiles all study data for independent assessment by government regulatory authorities in each country.

Regulatory Authorities: FDA in the USA, Therapeutic Goods Administration (TGA) in Australia, Medsafe in New Zealand, Medicines & Healthcare products Regulatory Agency (MHRA) in the UK, and Health Products and Food Branch (HPFB) in Canada.

Declaration of Helsinki
The Declaration of Helsinki was developed by The World Medical Association (WMA) as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied without consideration of all other relevant paragraphs. It is widely regarded as the cornerstone document on human research ethics. It is named after the location of its initial adoption in Helsinki, Finland, in June 1964.


Links: Advisory Committee on Medicines


Australian Drug Categories

Australian Drug Categories 
Legal drugs are classified, usually by each country's appropriate regulatory body, on the safety of drugs during pregnancy. In Australia, the Therapeutic Goods Authority has classes (A, B1, B2, B3, C, D and X) to define their safety. In the USA, drugs are classified by the Food and Drug Administration (FDA) into classes (A, B, C, D, and X) to define their safety. (More? Australian Drug Categories)


  • Pregnancy Category A - Have been taken by a large number of pregnant women and women of childbearing age without an increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
  • Pregnancy Category B1 - Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
  • Pregnancy Category B2 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
  • Pregnancy Category B3 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
  • Pregnancy Category C - Have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
  • Pregnancy Category D - Have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
  • Pregnancy Category X - Have such a high risk of causing permanent damage to the fetus that they should NOT be used in pregnancy or when there is a possibility of pregnancy.

Abnormal Development - Drugs

Legal drugs are classified, usually by each country's appropriate regulatory body, on the safety of drugs during pregnancy. In Australia, the Therapeutic Goods Authority has classes (A, B1, B2, B3, C, D and X) to define their safety. In the USA, drugs are classified by the Food and Drug Administration (FDA) into classes (A, B, C, D, and X) to define their safety. (More? Australian Drug Categories)

Pregnancy Category A

Have been taken by a large number of pregnant women and women of childbearing age without an increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

Pregnancy Category B1

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

Pregnancy Category B2

Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

Pregnancy Category B3

Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

Pregnancy Category C

Have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.

Pregnancy Category D

Have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.

Pregnancy Category X

Have such a high risk of causing permanent damage to the fetus that they should NOT be used in pregnancy or when there is a possibility of pregnancy.

Infant Drug Clearance

Drug clearance rates

The drug clearance data below are only approximate calculated rates for the fetus and infant from NZ Drug Safety in Lactation

Post-conceptual Age (weeks) Clearance of Drug (percentage of adults)
24-28 5%
28-34 10%
34-40 33%
40-44 50%
44-68 66%
> 68 100%

Drug Testing

Drug Testing 
Typical testing of new drug compound today involves a lengthy series of animal and human studies.

Animal studies

Usually tested in at least two mammalian species (rats and guinea pigs) using both single and repeated doses. For determining reproductive effects, tests on both male and female animals with dosing begins 4 weeks prior to mating are conducted to determine effects on fertility in both sexes, on embryogenesis, and on fetal malformation.

Human Clinical trials

Following animal studies to determine dose, efficacy and apparent safety, human studies can commence. Clinical trials are carried out under very strict conditions, set by international regulatory bodies in agreement with the principles espoused in the Declaration of Helsinki. There are four phases to the trials.

  • Phase I trials - conducted in small groups of 10 to 20 healthy young male volunteers. Designed to examine how the drug is absorbed, distributed, metabolised and excreted by the body and to establish the safe dose for phase II trials.
  • Phase II trials - conducted in 50 to 100 patients with the disease rather than healthy volunteers as in phase I. Designed to examine what effect the drug has on the body (heart rate, blood pressure and cognitive effects) depending on the disease the drug is being developed to treat.
  • Phase III trials - conducted in 100’s of patients (larger numbers) with a particular disease or condition and are generally randomised comparative double-blinded studies. Using a comparator of either placebo, another active drug already used, or both. Several phase III trials are usually required by the regulatory authorities. Note that even these studies may not identify uncommon adverse effects, until used widely in the community.
  • Phase IV trials - (post-registration) conducted in 1000’s of patients over several years, these trials are randomised controlled trials undertaken after the drug has been registered.
After phase I to III the pharmaceutical company compiles all study data for independent assessment by government regulatory authorities in each country.

Regulatory Authorities: FDA in the USA, Therapeutic Goods Administration (TGA) in Australia, Medsafe in New Zealand, Medicines & Healthcare products Regulatory Agency (MHRA) in the UK, and Health Products and Food Branch (HPFB) in Canada.

Declaration of Helsinki
The Declaration of Helsinki was developed by The World Medical Association (WMA) as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied without consideration of all other relevant paragraphs. It is widely regarded as the cornerstone document on human research ethics. It is named after the location of its initial adoption in Helsinki, Finland, in June 1964.

Typical testing of new drug compound today involves a lengthy series of animal and human studies.

Animal studies

Usually tested in at least two mammalian species (rats and guinea pigs) using both single and repeated doses. For determining reproductive effects, tests on both male and female animals with dosing begins 4 weeks prior to mating are conducted to determine effects on fertility in both sexes, on embryogenesis, and on fetal malformation.

Human Clinical trials

Following animal studies to determine dose, efficacy and apparent safety, human studies can commence. Clinical trials are carried out under very strict conditions, set by international regulatory bodies in agreement with the principles espoused in the Declaration of Helsinki. There are four phases to the trials.

  • Phase I trials - conducted in small groups of 10 to 20 healthy young male volunteers. Designed to examine how the drug is absorbed, distributed, metabolised and excreted by the body and to establish the safe dose for phase II trials.
  • Phase II trials - conducted in 50 to 100 patients with the disease rather than healthy volunteers as in phase I. Designed to examine what effect the drug has on the body (heart rate, blood pressure and cognitive effects) depending on the disease the drug is being developed to treat.
  • Phase III trials - conducted in 100’s of patients (larger numbers) with a particular disease or condition and are generally randomised comparative double-blinded studies. Using a comparator of either placebo, another active drug already used, or both. Several phase III trials are usually required by the regulatory authorities. Note that even these studies may not identify uncommon adverse effects, until used widely in the community.
  • Phase IV trials - (post-registration) conducted in 1000’s of patients over several years, these trials are randomised controlled trials undertaken after the drug has been registered.

After phase I to III the pharmaceutical company compiles all study data for independent assessment by government regulatory authorities in each country.

Regulatory Authorities: USA FDA | Australia Therapeutic Goods Administration (TGA) | New Zealand Medsafe | UK Medicines & Healthcare products Regulatory Agency (MHRA) | Canada Health Products and Food Branch (HPFB)

Declaration of Helsinki

The Declaration of Helsinki was developed by The World Medical Association (WMA) as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied without consideration of all other relevant paragraphs. It is widely regarded as the cornerstone document on human research ethics. It is named after the location of its initial adoption in Helsinki, Finland, in June 1964.


Teratology

Now consider how different environmental effects during pregnancy may influence developmental outcomes. The terms listed below are often used to describe these environmental effects

  • Teratogen (Greek, teraton = monster) any agent that causes a structural abnormality (congenital abnormalities) following fetal exposure during pregnancy. The overall effect depends on dosage and time of exposure. (More? Critical Periods of Development)
  • Absolute risk the rate of occurrence of an abnormal phenotype among individuals exposed to the agent. (e.g. fetal alcohol syndrome)
  • Relative risk the ratio of the rate of the condition among the exposed and the nonexposed. (e.g. smokers risk of having a low birth weight baby compared to non-smokers) A high relative risk may indicate a low absolute risk if the condition is rare.
  • Mutagen a chemical or agent that can cause permanent damage to the deoxyribonucleic acid (DNA) in a cell. DNA damage in the human egg or sperm may lead to reduced fertility, spontaneous abortion (miscarriage), birth defects and heritable diseases.
  • Fetotoxicant is a chemical that adversely affects the developing fetus, resulting in low birth weight, symptoms of poisoning at birth or stillbirth (fetus dies before it is born).
  • Synergism when the combined effect of exposure to more than one chemical at one time, or to a chemical in combination with other hazards (heat, radiation, infection) results in effects of such exposure to be greater than the sum of the individual effects of each hazard by itself.
  • Toxicogenomics the interaction between the genome, chemicals in the environment, and disease. Cells exposed to a stress, drug or toxicant respond by altering the pattern of expression of genes within their chromosomes. Based on new genetic and microarray technologies.

Thalidomide

Thalidomide molecular structure

Thalidomide is a drug that was introduced on to the market on October 1, 1957 in West Germany. Thalidomide soon became a drug prescribed to pregnant women to combat symptoms associated with morning sickness. When taken during the first trimester of pregnancy, thalidomide prevented the proper growth of the fetus resulting in horrific birth defects in thousands of children around the world.

It was the linking of newborn abnormalities with the taking of thalidomide by an Australian clinician, William McBride, that identified it as a teratogenic agent causing a "thalidomide embryopathy".[23]

Not all species embryos are affected by the drug in the same way, with human and rabbit being most susceptible to the teratogenic effects. In addition, the effect on human development is also dependent upon the time and dose of the drug exposure, the "critical periods".

Links: Abnormal Development - Thalidomide | Musculoskeletal System - Abnormalities

Antiepileptic Drugs

 ICD-11 LD2F.01 Foetal hydantoin syndrome - a fetopathy likely to occur when a pregnant woman takes the anticonvulsant drug phenytoin (diphenylhydantoin) for epileptic seizures. In utero exposure to this drug may result in a characteristic dysmorphic syndrome in the newborn, including low-set hair, short neck with pterygium colli, small nose, deep nasal bridge, epicanthus, hypertelorism, large mouth, malformed ears, hypoplastic distal phalanges of the fingers and toes and finger-like thumbs. These dysmorphic features are often associated with growth retardation and delayed psychomotor development. The mechanism underlying these anomalies has been shown to depend on maternal genetic characteristics, i.e. on maternal capacity to detoxify intermediate metabolites of phenytoin.


This class of drugs are prescribed for a range of neurological conditions and are generally in a class of medications called anticonvulsants. There has been a recent review of information about the teratogenicity of antiepileptic medications.[24] Infant development affected by these drugs has also been called "fetal anticonvulsant syndrome", only a few drug examples are shown below.

Valproic Acid

Fetal Valproate Syndrome facial dysmorphism
Fetal Valproate Syndrome facial dysmorphism[25]

(Divalproex sodium, Valproate sodium, VPA)

Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid.

Valproic acid may also have direct effects on the placenta, altering the expression of transporters required for maternal thyroid hormone to cross to the fetus.[26] (More? Maternal Thyroid)

There has been recently identified in a Danish study is a risk of autism spectrum disorders and childhood autism.[14]

There is a risk of neural tube defects (NTDs) associated with this drug apparently due to a common polymorphism (677C→T) in humans for the methylene tetrahydrofolate reductase gene (MHTFR), that affects folate metabolism. Both genotypes (homozygote and heterozygote) show an increased risk with maternal heterozygotes greater.[27]

Increased risk of heart defects, craniofacial abnormalities, skeletal and limb defects. A recent study suggests that changes in cellular reactive oxygen species (ROS) levels may also lead to increased apoptosis during development.[28]

There have been several case studies of the limb development described with this drug.[29]


Valproic Acid Species Difference for Teratogenic Dose (lowest) mg/kg/day
Species Neural tube defects Skeletal defects Route
Human 30 20-30 Oral
monkey not observed 150 oral
rabbit not observed 150 oral
rat not observed 150 oral
hamster 300 not investigated ip
mouse 200 200, 250, 400 ip, sc, oral
Table Data[4]    Links: valproic acid | drugs


Links: Maternal Thyroid | MedlinePlus - Valproic Acid | valproic acid teratogenicity | Apoptosis

Carbamazepine

Carbamazepine is an anticonvulsant and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder.


Links: MedlinePlus - Carbamazepine | Carbamazepine teratogenicity

Phenytoin

 ICD-11 LD2F.01 Foetal hydantoin syndrome - a fetopathy likely to occur when a pregnant woman takes the anticonvulsant drug phenytoin (diphenylhydantoin) for epileptic seizures. In utero exposure to this drug may result in a characteristic dysmorphic syndrome in the newborn, including low-set hair, short neck with pterygium colli, small nose, deep nasal bridge, epicanthus, hypertelorism, large mouth, malformed ears, hypoplastic distal phalanges of the fingers and toes and finger-like thumbs. These dysmorphic features are often associated with growth retardation and delayed psychomotor development. The mechanism underlying these anomalies has been shown to depend on maternal genetic characteristics, i.e. on maternal capacity to detoxify intermediate metabolites of phenytoin.


A study has identified mild abnormalities of the craniofacial skeletal, maxillary hypoplasia, among individuals exposed in utero to phenytoin monotherapy or phenytoin polytherapy.[30]


Links: skull | MedlinePlus - Phenytoin | Phenytoin teratogenicity

Antithyroid Drugs

Graves' disease (GD) is the most common cause of hyperthyroidism during pregnancy (estimated 1 in 500 to 1,000 women) and has been treated with the antithyroid drugs propylthiouracil (PTU) and methimazole (MMI).

Propylthiouracil

Propylthiouracil (PTU) is an antithyroid drug used to treat maternal hyperthyroidism, commonly Graves' disease, during pregnancy. A recent study showed cranial neural tube defects in the mouse developmental model.[31]

Danish Study

The following information is from a recent Danish nationwide register-based cohort study of birth defects after early pregnancy use of antithyroid drugs.[32] (See also a recent Japanese study.[33])

Objective: Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects.

Methods: This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008.

Results: The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]).

Conclusions: Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.

(above text edited from abstract)


Links: neural abnormalities | thyroid

Anticoagulant Therapy

 ICD-11 LD2F.02 Embryofetopathy due to oral anticoagulant therapy - A condition caused by exposure of the embryo or fetus to anticoagulants during the antenatal period. This disease may present with optic nerve anomaly, optic atrophy, anomaly of the papilla, blindness, or choanal atresia.

Search term: Anticoagulant Therapy Embryofetopathy

Pain Relief

There has been some recent interest in drugs used for maternal pain relief during pregnancy. Like all data from new research, these findings require more detailed and additional studies to confirm any finding related to pain relief during pregnancy. This section is included to show how today all drugs today can come under a more complex research spotlight, compared to earlier times.

Oxycodone

Currently, there is a USA population specific abuse of the prescription drug Oxycodone, commercial name "OxyContin".{{#pmid27513641|PMID27513641}} Oxycodone is a strong opioid analgesic, semisynthetic opioid synthesized from thebaine, that binds μ- and κ-opioid receptors. Animal studies appear to show no teratogenic effects at clinical doses (TGA 2010 report), though the drug can also pass into breast milk and there may also be untested polysubstance abuse by maternal abusers.

Acetaminophen

A single recent 2014 retrospective study of the Danish National Birth Cohort (1996 - 2002) 64 322 of live-born children using a phone interview has suggested a possible linkage between acetaminophen (paracetamol) and attention-deficit/hyperactivity disorder (ADHD).[34] More than half of all mothers reported acetaminophen use while pregnant.


A second earlier 2013 published study of the Norwegian Mother and Child Cohort (1999 - 2008) of 48 631 children on maternal use of paracetamol at gestational weeks GA 17 and 30 and at 6 months found: "Children exposed prenatally to short-term use of paracetamol (1-27 days) also had poorer gross motor outcomes, but the effects were smaller than with long-term use. Ibuprofen exposure was not associated with neurodevelopmental outcomes."[35]


Links: MedLine Plus | MedLine Plus Overdose information | Search PubMed - acetaminophen+pregnancy | Search PubMed - ibuprofen+pregnancy


Antibiotics

There is some evidence that the use of some classes of antibiotics (macrolides) may have a weak association with neural teratogenic effects[8][36], see also the review.[37] Macrolides are the third most common prescribed antibiotic, derived from Saccharopolyspora erythraea, they inhibit the growth of bacteria (bacteriostatic) and are often used to treat common bacterial infections. Examples of macrolides include: erythromycin, roxithromycin, azithromycin and clarithromycin.

One suggested model[8] postulates short term fetal hypoxia results from the potential fetal cardiac arrhythmia effects of this drug, blocking the rapidly activating component of delayed rectifier K current ( I(Kr) ) associated with the Human-ether-a-go-go-related channel (hERG). Cardiac repolarization is controlled by both the rapidly ( I(Kr) ) and slowly ( I(Ks) ) activating delayed rectifier potassium channels, and decreases in I(Kr) or I(Ks) can also cause long QT syndrome (LQTS). Note that an isoform of the hERG channel (KCNH2-3.1) is also expressed at high levels in the fetal human brain.[38]


Antibiotics can also impact upon both the maternal and the neonatal microbiome.[9]


Links: Search PubMed - macrolides+pregnancy | neural abnormalities

Oral Contraceptives

A recent 2016 Danish study[39] ofbirths from Danish registries between 1997 and 2011 identified that "Oral contraceptive exposure just before or during pregnancy does not appear to be associated with an increased risk of major birth defects."

Links: menstrual cycle

Herbal Drugs

The following herbal drugs have been used for a number of different maternal conditions: Ginkgo Biloba, Kava (Piper methysticum), St. John's wort (Hypericum perforatum), Tian Ma (Gastrodia elata), Valerian (Valeriana officinalis). In some cases very little is known about the potential teratogenic effects of these drugs (More? Herbal Drugs).

HSTAT St. John's Wort | Appendix II: Side Effects, Adverse Effects, Precautions, and Warnings "The safety of using hypericum during pregnancy or lactation has not been proven so it should be avoided." "St. John's wort induces the CYP 450 3A4 metabolic pathway which is also used by many prescription drugs used to prevent conditions (transplant rejection or pregnancy oral contraceptives), health care providers should alert patients about these potential drug interactions."


Links: herbal drugs

Anaesthesia

"Under usual circumstances, surgery is only conducted during pregnancy when it is absolutely necessary for the wellbeing of the mother, fetus, or both."[40] Maternal conditions requiring surgery, either related or not related to a pregnancy, may require anaesthesia and all general anaesthetic drugs cross the placenta. Teratogenic effects have not been identified with anaesthesia drugs, though there are suggestions of some impact on neurodevelopment.[41]

Opioids

Neonatal abstinence syndrome(NAS) describes neonatal affects of abrupt discontinuation at birth of opioids exposure and fetal dependence during development in the uterus. Prenatal opioid exposure can occur through prescription or illegal drug use. Prescription opioids include: codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocin, propoxyphene, buprenorphine, tapentadol, and tramadol.


A USA clinical study[42] has identified a trend increase in NAS live birth incidence (2000, 1.2/1,000; 2009 3.39/1000). Animal models have identified neural development abnormalities associated with prenatal opioid exposure.


Links: Template:Illegal drugs | neural abnormalities

Diethylstilbestrol

Diethylstilbestrol structure

Diethylstilbestrol (DES or diethylstilbetrol) was a drug prescribed to women from 1938-1971 to prevent miscarriage in high-risk pregnancies. Acts as a potent estrogen (mimics natural hormone) and therefore a potential endocrine disruptor. Banned by the USA FDA in 1979 as a teratogen, previously used as livestock growth promoter.

  • Female fetus - increased risk abnormal reproductive tract and cancer.
  • Male fetus - abnormal genitalia.


DES induces vaginal abnormalities (vaginal adenosis) by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a down-regulation of RUNX1.[43] Has also been shown to induces autophagy in thymocytes through epigenetic modulation.[44]

A recent French study of birth defects in children of men exposed in utero to diethylstilbestrol has shown a trans-generational effect in male offspring, with an increased incidence of cryptorchidism and hypoplasia of the penis.[45]


Links: endocrine abnormalities

References

  1. Bologa-Campeanu M, Koren G, Rieder M & McGuigan M. (1988). Prenatal adverse effects of various drugs and chemicals. A review of substances of frequent concern to mothers in the community. Med Toxicol Adverse Drug Exp , 3, 307-23. PMID: 3054428
  2. 2.0 2.1 Pernia S & DeMaagd G. (2016). The New Pregnancy and Lactation Labeling Rule. P T , 41, 713-715. PMID: 27904304
  3. Illamola SM, Bucci-Rechtweg C, Costantine MM, Tsilou E, Sherwin CM & Zajicek A. (2018). Inclusion of pregnant and breastfeeding women in research - efforts and initiatives. Br J Clin Pharmacol , 84, 215-222. PMID: 28925019 DOI.
  4. 4.0 4.1 Nau H. (1986). Species differences in pharmacokinetics and drug teratogenesis. Environ. Health Perspect. , 70, 113-29. PMID: 3104022
  5. Jones CM, Muhuri PK & Lurie PG. (2017). Trends in the Nonmedical Use of OxyContin, United States, 2006 to 2013. Clin J Pain , 33, 452-461. PMID: 27513641 DOI.
  6. Azuine RE, Ji Y, Chang HY, Kim Y, Ji H, DiBari J, Hong X, Wang G, Singh GK, Pearson C, Zuckerman B, Surkan PJ & Wang X. (2019). Prenatal Risk Factors and Perinatal and Postnatal Outcomes Associated With Maternal Opioid Exposure in an Urban, Low-Income, Multiethnic US Population. JAMA Netw Open , 2, e196405. PMID: 31251378 DOI.
  7. Williams AL, Bates CA, Pace ND, Leonhard MJ, Chang ET & DeSesso JM. (2018). Impact of chloroform exposures on reproductive and developmental outcomes: A systematic review of the scientific literature. Birth Defects Res , 110, 1267-1313. PMID: 30350414 DOI.
  8. 8.0 8.1 8.2 Fan H, Li L, Wijlaars L & Gilbert RE. (2019). Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis. PLoS ONE , 14, e0212212. PMID: 30779772 DOI.
  9. 9.0 9.1 Miller JE, Wu C, Pedersen LH, de Klerk N, Olsen J & Burgner DP. (2018). Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study. Int J Epidemiol , , . PMID: 29415232 DOI.
  10. Metz VE, Brown QL, Martins SS & Palamar JJ. (2018). Characteristics of drug use among pregnant women in the United States: Opioid and non-opioid illegal drug use. Drug Alcohol Depend , 183, 261-266. PMID: 29310077 DOI.
  11. 11.0 11.1 Hauser KF & Knapp PE. (2017). Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System. Front Pediatr , 5, 294. PMID: 29410949 DOI.
  12. AIHW 2016. Poisoning in children and young people 2012–13. Injury research and statistics series no. 97. Cat. no. INJCAT 173. Canberra: AIHW.
  13. Tanoshima M, Kobayashi T, Tanoshima R, Beyene J, Koren G & Ito S. (2015). Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis. Clin. Pharmacol. Ther. , 98, 417-41. PMID: 26044279 DOI.
  14. 14.0 14.1 Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH & Vestergaard M. (2013). Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA , 309, 1696-703. PMID: 23613074 DOI.
  15. Levine M & O'Connor AD. (2012). Obstetric toxicology: teratogens. Emerg. Med. Clin. North Am. , 30, 977-90. PMID: 23137407 DOI.
  16. Adam MP, Polifka JE & Friedman JM. (2011). Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet , 157C, 175-82. PMID: 21766440 DOI.
  17. van Gelder MM, Roeleveld N & Nordeng H. (2011). Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS ONE , 6, e22174. PMID: 21789231 DOI.
  18. Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY & Ko KH. (2011). Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL. J. Biomed. Sci. , 18, 48. PMID: 21722408 DOI.
  19. Janneke Jentink, Helen Dolk, Maria A Loane, Joan K Morris, Diana Wellesley, Ester Garne, Lolkje de Jong-van den Berg, for the EUROCAT Antiepileptic Study Working Group Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study BMJ 2010; 341:c6581 BMJ
  20. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C & Hernández-Díaz S. (2011). Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am. J. Obstet. Gynecol. , 205, 51.e1-8. PMID: 21514558 DOI.
  21. Trønnes JN, Lupattelli A & Nordeng H. (2017). Safety profile of medication used during pregnancy: results of a multinational European study. Pharmacoepidemiol Drug Saf , 26, 802-811. PMID: 28449197 DOI.
  22. Pijpers EL, Kreijkamp-Kaspers S, McGuire TM, Deckx L, Brodribb W & van Driel ML. (2017). Women's questions about medicines in pregnancy - An analysis of calls to an Australian national medicines call centre. Aust N Z J Obstet Gynaecol , 57, 334-341. PMID: 27624748 DOI.
  23. Bologa-Campeanu M, Koren G, Rieder M & McGuigan M. (1988). Prenatal adverse effects of various drugs and chemicals. A review of substances of frequent concern to mothers in the community. Med Toxicol Adverse Drug Exp , 3, 307-23. PMID: 3054428
  24. Kluger BM & Meador KJ. (2008). Teratogenicity of antiepileptic medications. Semin Neurol , 28, 328-35. PMID: 18777479 DOI.
  25. Chandane PG & Shah I. (2014). Fetal valproate syndrome. Indian J Hum Genet , 20, 187-8. PMID: 25400349 DOI.
  26. Meir M, Bishara A, Mann A, Udi S, Portnoy E, Shmuel M & Eyal S. (2016). Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies. Epilepsia , 57, e108-12. PMID: 27142887 DOI.
  27. Dean JC, Moore SJ, Osborne A, Howe J & Turnpenny PD. (1999). Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene. Clin. Genet. , 56, 216-20. PMID: 10563481
  28. Tung EW & Winn LM. (2011). Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol. Pharmacol. , 80, 979-87. PMID: 21868484 DOI.
  29. Pandya NA & Jani BR. (2000). Post-axial limb defects with maternal sodium valproate exposure. Clin. Dysmorphol. , 9, 143-4. PMID: 10826630
  30. Orup HI, Holmes LB, Keith DA & Coull BA. (2003). Craniofacial skeletal deviations following in utero exposure to the anticonvulsant phenytoin: monotherapy and polytherapy. Orthod Craniofac Res , 6, 2-19. PMID: 12627792
  31. Benavides VC, Mallela MK, Booth CJ, Wendler CC & Rivkees SA. (2012). Propylthiouracil is teratogenic in murine embryos. PLoS ONE , 7, e35213. PMID: 22529993 DOI.
  32. Andersen SL, Olsen J, Wu CS & Laurberg P. (2013). Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J. Clin. Endocrinol. Metab. , 98, 4373-81. PMID: 24151287 DOI.
  33. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Ito K & Ito K. (2012). Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J. Clin. Endocrinol. Metab. , 97, 2396-403. PMID: 22547422 DOI.
  34. Liew Z, Ritz B, Rebordosa C, Lee P, Olsen J. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatr. 2014;():. doi:10.1001/jamapediatrics.2013.4914.
  35. Brandlistuen RE, Ystrom E, Nulman I, Koren G & Nordeng H. (2013). Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol , 42, 1702-13. PMID: 24163279 DOI.
  36. Mallah N, Tohidinik HR, Etminan M, Figueiras A & Takkouche B. (2019). Prenatal Exposure to Macrolides and Risk of Congenital Malformations: A Meta-Analysis. Drug Saf , , . PMID: 31721138 DOI.
  37. Hantoushzadeh S, Anvari Aliabad R & Hossein Norooznezhad A. (2020). Antibiotics, Pregnancy, and Fetal Mental Illnesses: Where is the link?. Am. J. Obstet. Gynecol. , , . PMID: 32017921 DOI.
  38. Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, Lipska BK, Hyde TM, Song J, Rujescu D, Giegling I, Mayilyan K, Proust MJ, Soghoyan A, Caforio G, Callicott JH, Bertolino A, Meyer-Lindenberg A, Chang J, Ji Y, Egan MF, Goldberg TE, Kleinman JE, Lu B & Weinberger DR. (2009). A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat. Med. , 15, 509-18. PMID: 19412172 DOI.
  39. Charlton BM, Mølgaard-Nielsen D, Svanström H, Wohlfahrt J, Pasternak B & Melbye M. (2016). Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study. BMJ , 352, h6712. PMID: 26738512
  40. Reitman E & Flood P. (2011). Anaesthetic considerations for non-obstetric surgery during pregnancy. Br J Anaesth , 107 Suppl 1, i72-8. PMID: 22156272 DOI.
  41. Palanisamy A. (2012). Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth , 21, 152-62. PMID: 22405978 DOI.
  42. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM & Davis MM. (2012). Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. JAMA , 307, 1934-40. PMID: 22546608 DOI.
  43. Laronda MM, Unno K, Ishi K, Serna VA, Butler LM, Mills AA, Orvis GD, Behringer RR, Deng C, Sinha S & Kurita T. (2013). Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium. Dev. Biol. , 381, 5-16. PMID: 23830984 DOI.
  44. Singh NP, Miranda K, Singh UP, Nagarkatti P & Nagarkatti M. (2018). Diethylstilbestrol (DES) induces autophagy in thymocytes by regulating Beclin-1 expression through epigenetic modulation. Toxicology , 410, 49-58. PMID: 30153466 DOI.
  45. Tournaire M, Devouche E, Epelboin S, Cabau A, Dunbavand A & Levadou A. (2018). Birth defects in children of men exposed in utero to diethylstilbestrol (DES). Therapie , 73, 399-407. PMID: 29609831 DOI.

Reviews

Koren G, Berkovitch M & Ornoy A. (2018). Dose-Dependent Teratology in Humans: Clinical Implications for Prevention. Paediatr Drugs , 20, 331-335. PMID: 29725877 DOI.

Saunders EJ & Saunders JA. (1990). Drug therapy in pregnancy: the lessons of diethylstilbestrol, thalidomide, and bendectin. Health Care Women Int , 11, 423-32. PMID: 2228814 DOI.

Pacifici GM. (2009). Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur. J. Clin. Pharmacol. , 65, 419-27. PMID: 19104791 DOI.

Al-Saleh E, Al-Harmi J, Nandakumaran M & Al-Shammari M. (2008). Transport kinetics of cisplatin in the perfused human placental lobule in vitro. J. Matern. Fetal. Neonatal. Med. , 21, 726-31. PMID: 19012189 DOI.

Articles

McBride WG. (1992). Prescription drugs in the first trimester and congenital malformations. Aust N Z J Obstet Gynaecol , 32, 386. PMID: 1290446

Search Pubmed

June 2010 "infant drug clearance rates" All (168) Review (22) Free Full Text (45)


Search Pubmed: infant drug clearance rates | thalidomide teratogenicity |

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WHO - The Anatomical Therapeutic Chemical Classification System with Defined Daily Doses (ATC/DDD)



Terms

Drug Terms  
  • adverse reaction - (adverse event) An unwanted effect caused by the administration of drugs. Onset may be sudden or develop over time (See Side Effects).
  • approved drugs - In the U.S., the Food and Drug Administration (FDA) must approve a substance as a drug before it can be marketed. The approval process involves several steps including pre-clinical laboratory and animal studies, clinical trials for safety and efficacy, filing of a New Drug Application by the manufacturer of the drug, FDA review of the application, and FDA approval/rejection of application (See Food and Drug Administration).
  • AUC - acronym for Area Under the plasma concentration versus time Curve is an important parameter when determining drug effects, both therapeutic and teratogenic.
  • clinical trial - A research study to answer specific questions about vaccines or new therapies or new ways of using known treatments. Clinical trials (also called medical research and research studies) are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people. Trials are in four phases: Phase I tests a new drug or treatment in a small group; Phase II expands the study to a larger group of people; Phase III expands the study to an even larger group of people; and Phase IV takes place after the drug or treatment has been licensed and marketed. (See Phase I, II, III, and IV Trials).
  • cohort - In epidemiology, a group of individuals with some characteristics in common.
  • contraindication - A specific circumstance when the use of certain treatments could be harmful.
  • double-blind study - A clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental drug and which are receiving a placebo (or another therapy). Double-blind trials are thought to produce objective results, since the expectations of the doctor and the participant about the experimental drug do not affect the outcome; also called double-masked study. See Blinded Study, Single-Blind Study, and Placebo.
  • drug clearance - measured as the volume of blood or plasma from which a compound is irreversibly removed per unit time.
  • drug distribution - movement of a drug from one location in the body to another, generally by passive diffusion down the concentration gradient.
  • drug-drug interaction - A modification of the effect of a drug when administered with another drug. The effect may be an increase or a decrease in the action of either substance, or it may be an adverse effect that is not normally associated with either drug.
  • drug metabolism - (drug biotransformation)
  • efficacy - Referring to a drug or treatment, the maximum ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the procedure mandated by the FDA, Phase II clinical trials gauge efficacy, and Phase III trials confirm it (See Food and Drug Administration (FDA), Phase II and III Trials).
  • Food and Drug Administration - (FDA) The U.S. Department of Health and Human Services agency responsible for ensuring the safety and effectiveness of all drugs, biologics, vaccines, and medical devices, including those used in the diagnosis, treatment, and prevention of HIV infection, AIDS, and AIDS-related opportunistic infections. The FDA also works with the blood banking industry to safeguard the nation's blood supply. Internet address: http://www.fda.gov/.
  • informed consent - The process of learning the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants. To help someone decide whether or not to participate, the doctors and nurses involved in the trial explain the details of the study.
  • oral bioavailability - refers to the percentage of the oral dose of that drug that ends up in the systemic circulation, few drugs have complete oral bioavailability.
  • orphan drugs - An FDA category that refers to medications used to treat diseases and conditions that occur rarely. There is little financial incentive for the pharmaceutical industry to develop medications for these diseases or conditions. Orphan drug status, however, gives a manufacturer specific financial incentives to develop and provide such medications.
  • pharmacokinetics - The processes (in a living organism) of absorption, distribution, metabolism, and excretion of a drug or vaccine.
  • Phase I trials - Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients.
  • Phase II trials - Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks.
  • Phase III trials - Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling.
  • Phase IV trials - Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use.
  • placebo - A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness. (See Placebo Controlled Study).
  • placebo controlled study - A method of investigation of drugs in which an inactive substance (the placebo) is given to one group of participants, while the drug being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment is more effective in treating the condition.
  • placebo effect - A physical or emotional change, occurring after a substance is taken or administered, that is not the result of any special property of the substance. The change may be beneficial, reflecting the expectations of the participant and, often, the expectations of the person giving the substance.
  • plasma proteins - can bind drugs, acidic drugs bind to albumin, basic drugs bind to lipoproteins or to alpha-1 acid glycoprotein.
  • Preclinical - Refers to the testing of experimental drugs in the test tube or in animals - the testing that occurs before trials in humans may be carried out.
  • side effects - Any undesired actions or effects of a drug or treatment. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems. Experimental drugs must be evaluated for both immediate and long-term side effects (See Adverse Reaction).
  • statistical significance - The probability that an event or difference occurred by chance alone. In clinical trials, the level of statistical significance depends on the number of participants studied and the observations made, as well as the magnitude of differences observed.
  • toxicity - An adverse effect produced by a drug that is detrimental to the participant's health. The level of toxicity associated with a drug will vary depending on the condition which the drug is used to treat.
  • treatment IND - Investigational New Drug (IND) application, which is part of the process to get approval from the FDA for marketing a new prescription drug in the U.S. It makes promising new drugs available to desperately ill participants as early in the drug development process as possible. Treatment INDs are made available to participants before general marketing begins, typically during Phase III studies. To be considered for a treatment IND a participant cannot be eligible to be in the definitive clinical trial.
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Cite this page: Hill, M.A. (2024, March 19) Embryology Abnormal Development - Drugs. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Drugs

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G