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. 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.

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[2] 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.


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 Infections | Viral Infection | Bacterial Infection | Zoonotic Infection | Toxoplasmosis | Malaria | Maternal Diabetes | Maternal Hypertension | Maternal Hyperthermia | Maternal Inflammation | Maternal Obesity | Hypoxia | Biological Toxins | Chemicals | Heavy Metals | Radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis


Some Recent Findings

  • Australian Report - Poisoning in children and young people 2012–13[3] "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
  • Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis[4] "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[5] "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[6] "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[7] "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[8] "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 [9] "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[10] "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."
More recent papers
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

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.

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Search term: Drug teratogenicity

Lauren G Strange, Kerri Kochelek, Robert Keasling, Stacy D Brown, Brooks B Pond The pharmacokinetic profile of synthetic cathinones in a pregnancy model. Neurotoxicol Teratol: 2017; PubMed 28811141

Robert S Lindsay, Mary R Loeken Metformin use in pregnancy: promises and uncertainties. Diabetologia: 2017; PubMed 28770325

Dengtang Liu, Peiwei Xu, Kaida Jiang The Use of Psychotropic Drugs During Pregnancy. Shanghai Arch Psychiatry: 2017, 29(1);48-50 PubMed 28769545

Gideon Koren Safety considerations surrounding use of treatment options for nausea and vomiting in pregnancy. Expert Opin Drug Saf: 2017; PubMed 28749713

Isabelle Mouche, Laure Malésic, Olivier Gillardeaux FETAX Assay for Evaluation of Developmental Toxicity. Methods Mol. Biol.: 2017, 1641;311-324 PubMed 28748472


Australia - Advisory Committee on Prescription Medicines

The Australian Drug Evaluation Committee (ADEC) was established in 1963 following the thalidomide experience and in 2010 this committee was replaced by the Advisory Committee on Prescription Medicines (ACPM). The new ACPM advises and makes recommendations to the Therapeutic Goods Administration (TGA) on prescription medicines listed on the Australian Register of Therapeutic Goods (ARTG), established under the Therapeutic Goods Act 1989. There were approximately 54,000 products on the Australian Register of Therapeutic Goods as at 23 May 2008.

Advisory Committee on Prescription Medicines

  • inclusion of a prescription medicine on the Australian Register of Therapeutic Goods (the Register)
  • changes to an entry of a prescription medicine on the Register
  • removal or retention of a prescription medicine on the Register
Links: Advisory Committee on Prescription Medicines | A guide to labelling drugs and poisons (2007) | Labelling Guide PDF

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".[11]

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

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.[12] 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[13]

(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.[14] (More? Maternal Thyroid)

There has been recently identified in a Danish study is a risk of autism spectrum disorders and childhood autism.[5]

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.[15]

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.[16]

There have been several case studies of the limb development described with this drug.[17][18]


Species Difference for Teratogenic Dose (lowest) mg/kg/day[2]
Species Neural tube defects Skeletal defects Route
Man 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


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

Links: 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.[19]

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.[20] (See also a recent Japanese study.[21])

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 Development

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.

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).[22] 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."[23]


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

Oral Contraceptives

A recent 2016 Danish study[24] births 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: Abnormal Development - 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."[25] 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.[26]

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.


A USA clinical study[27] 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: Illegal Drugs | Neural System - Abnormalities


References

  1. M Bologa-Campeanu, G Koren, M Rieder, M McGuigan 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: 1988, 3(4);307-23 PubMed 3054428
  2. 2.0 2.1 H Nau Species differences in pharmacokinetics and drug teratogenesis. Environ. Health Perspect.: 1986, 70;113-29 PubMed 3104022 | PMC1474298
  3. AIHW 2016. Poisoning in children and young people 2012–13. Injury research and statistics series no. 97. Cat. no. INJCAT 173. Canberra: AIHW.
  4. Miki Tanoshima, Tohru Kobayashi, Reo Tanoshima, Joseph Beyene, Gideon Koren, Shinya Ito Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis. Clin. Pharmacol. Ther.: 2015; PubMed 26044279
  5. 5.0 5.1 Jakob Christensen, Therese Koops Grønborg, Merete Juul Sørensen, Diana Schendel, Erik Thorlund Parner, Lars Henning Pedersen, Mogens Vestergaard Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA: 2013, 309(16);1696-703 PubMed 23613074
  6. Michael Levine, Ayrn D O'Connor Obstetric toxicology: teratogens. Emerg. Med. Clin. North Am.: 2012, 30(4);977-90 PubMed 23137407
  7. Margaret P Adam, Janine E Polifka, J M Friedman Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet: 2011, 157C(3);175-82 PubMed 21766440
  8. Marleen M H J van Gelder, Nel Roeleveld, Hedvig Nordeng Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS ONE: 2011, 6(7);e22174 PubMed 21789231
  9. PMID 21722408
  10. 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
  11. W G McBride Thalidomide embryopathy. Teratology: 1977, 16(1);79-82 PubMed 331548
  12. Benzi M Kluger, Kimford J Meador Teratogenicity of antiepileptic medications. Semin Neurol: 2008, 28(3);328-35 PubMed 18777479
  13. Parmarth G Chandane, Ira Shah Fetal valproate syndrome. Indian J Hum Genet: 2014, 20(2);187-8 PubMed 25400349 | Indian J Hum Genet.
  14. Michal Meir, Ameer Bishara, Aniv Mann, Shiran Udi, Emma Portnoy, Miri Shmuel, Sara Eyal Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies. Epilepsia: 2016; PubMed 27142887
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Gian Maria Pacifici Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur. J. Clin. Pharmacol.: 2009, 65(4);419-27 PubMed 19104791

Eyad Al-Saleh, Jehad Al-Harmi, Moorkath Nandakumaran, Majed Al-Shammari Transport kinetics of cisplatin in the perfused human placental lobule in vitro. J. Matern. Fetal. Neonatal. Med.: 2008, 21(10);726-31 PubMed 19012189


Articles

W G McBride Prescription drugs in the first trimester and congenital malformations. Aust N Z J Obstet Gynaecol: 1992, 32(4);386 PubMed 1290446


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


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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. 2017 Embryology Abnormal Development - Drugs. Retrieved August 20, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Drugs

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