Teratology#Teratogenesis

The term was borrowed in 1842 from the French {{lang|fr|tératologie}}, where it was formed in 1830 from the Greek {{lang|grc|τέρας}} {{transliteration|grc|teras}} (word stem {{lang|grc|τέρατ-}} {{transliteration|grc|terat-}}), meaning "sign sent by the gods, portent, marvel, monster", and {{lang|fr|-ologie}} (-ology), used to designate a discourse, treaty, science, theory, or study of some topic.{{cite web | url = https://www.merriam-webster.com/dictionary/teratology | title = Teratology | work = Merriam-Webster Dictionary }}

Old literature referred to abnormalities of all kinds under the Latin term Lusus naturae ({{lit|freak of nature}}). As early as the 17th century, Teratology referred to a discourse on prodigies and marvels of anything so extraordinary as to seem abnormal. In the 19th century, it acquired a meaning more closely related to biological deformities, mostly in the field of botany. Currently, its most instrumental meaning is that of the medical study of teratogenesis, congenital malformations or individuals with significant malformations. Historically, people have used many pejorative terms to describe/label cases of significant physical malformations. In the 1960s, David W. Smith of the University of Washington Medical School (one of the researchers who became known in 1973 for the discovery of fetal alcohol syndrome),{{cite journal | vauthors = Jones KL, Smith DW, Ulleland CN, Streissguth P | title = Pattern of malformation in offspring of chronic alcoholic mothers | journal = Lancet | volume = 1 | issue = 7815 | pages = 1267–1271 | date = June 1973 | pmid = 4126070 | doi = 10.1016/S0140-6736(73)91291-9 }} popularized the term teratology. With the growth of understanding of the origins of birth defects, the field of teratology {{as of|2015|lc=on}} overlaps with other fields of science, including developmental biology, embryology, and genetics.

Until the 1940s, teratologists regarded birth defects as primarily hereditary. In 1941, the first well-documented cases of environmental agents being the cause of severe birth defects were reported.{{cite web |title=Birth Defects|date=24 July 2011 |publisher=Howmed.net |url=http://howmed.net/anatomy/embryology/birth-defects/ |access-date= 1 November 2015 |quote=Until 1940, it was assumed that congenital defects were caused primarily by hereditary factors. In 1941, the first well-documented cases were reported that an environmental agent (rubella virus) could produce severe anatomic anomalies.}}

{{for|the Revocation extended play|Teratogenesis (EP)}}

Teratogenesis occurs when the development of an embryo is altered negatively due to the presence of teratogens. Teratogens are the causes of teratogenesis. Common examples of teratogens include genetic disorders, maternal nutrition and health, and chemical agents such as drugs and alcohol.{{Cite web |title=Teratogens: Effects, Types, Risks & Prevention |url=https://my.clevelandclinic.org/health/articles/24325-teratogens |archive-url=http://web.archive.org/web/20250213093957/https://my.clevelandclinic.org/health/articles/24325-teratogens |archive-date=2025-02-13 |access-date=2025-02-16 |website=Cleveland Clinic |language=en}} Lesser known examples that will be covered include stress,{{cite journal |last1=DiPietro |first1=Janet A. |title=Maternal Stress in Pregnancy: Considerations for Fetal Development |journal=Journal of Adolescent Health |date=August 2012 |volume=51 |issue=2 |pages=S3–S8 |doi=10.1016/j.jadohealth.2012.04.008 |pmid=22794531 |pmc=3402207 }} caffeine,{{cite journal |last1=Nehlig |first1=Astrid |last2=Debry |first2=Gérard |title=Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: A review on human and animal data |journal=Neurotoxicology and Teratology |date=November 1994 |volume=16 |issue=6 |pages=531–543 |doi=10.1016/0892-0362(94)90032-9 |pmid=7862054 |bibcode=1994NTxT...16..531N }} and deficiencies in diet and nutrition.{{Cite web |title=Society for Birth Defects Research and Prevention |url=https://www.birthdefectsresearch.org/primer/nutrition.asp |access-date=2025-03-08 |website=www.birthdefectsresearch.org}} Although teratogens can affect a fetus during any time in the pregnancy, one of the most sensitive time frames for them to be exposed to the developing embryo is during the embryonic period. This period is in effect from about the fourteenth day following when a female's egg is implanted into a specific place in the reproductive organs and sixty days after conception.{{Cite journal |last1=Alwan |first1=Sura |last2=Chambers |first2=Christina D |date=Jun 2015 |title=Identifying Human Teratogens: An Update |journal=Journal of Pediatric Genetics |language=en |volume=4 |issue=2 |pages=39–41 |doi=10.1055/s-0035-1556745 |pmid=27617116 |pmc=4918715 }} Teratogens are able to cause abnormal defects through certain mechanisms that occur throughout the development of the embryo.

{{anchor|Wilson's 6 principles}}

In 1959 and in his 1973 monograph Environment and Birth Defects, embryologist James Wilson put forth six principles of teratogenesis to guide the study and understanding of teratogenic agents and their effects on developing organisms.{{cite book |url=https://archive.org/details/environmentbirth00wils |title=Environment and Birth Defects (Environmental Science Series) |vauthors=Wilson JG |publisher=Academic Pr |year=1973 |isbn=0-12-757750-5 |location=London}} These principles were derived from and expanded on by those laid forth by zoologist Camille Dareste in the late 1800s:{{Cite encyclopedia |title=James G. Wilson's Six Principles of Teratology | encyclopedia = The Embryo Project Encyclopedia |url=https://embryo.asu.edu/pages/james-g-wilsons-six-principles-teratology |access-date=20 March 2023 |language=en}}

1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors.
2. Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence. There are critical periods of susceptibility to agents and organ systems affected by these agents.
3. Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events.
4. The access of adverse influences to developing tissues depends on the nature of the influence. Several factors affect the ability of a teratogen to contact a developing conceptus, such as the nature of the agent itself, route and degree of maternal exposure, rate of placental transfer and systemic absorption, and composition of the maternal and embryonic/fetal genotypes.
5. There are four manifestations of deviant development (death, malformation, growth retardation and functional defect).
6. Manifestations of deviant development increase in frequency and degree as dosage increases from the No Observable Adverse Effect Level (NOAEL) to a dose producing 100% lethality (LD₁₀₀).

The mechanisms of these teratogens lie in specific alterations to genes, cells, and tissues within the developing organism that cause deviation from normal development and can result in functional defects, growth stunts, malformation, and even death. Finally, susceptibility to teratogens is more elevated during specific, critical periods during development.{{sfn|Gilbert|2015|pp=187–88}}

The natural metabolic processes of the human body produce highly reactive oxygen-containing molecules called reactive oxygen species.{{Cite journal |last1=Wells |first1=Peter G. |last2=McCallum |first2=Gordon P. |last3=Chen |first3=Connie S. |last4=Henderson |first4=Jeffrey T. |last5=Lee |first5=Crystal J. J. |last6=Perstin |first6=Julia |last7=Preston |first7=Thomas J. |last8=Wiley |first8=Michael J. |last9=Wong |first9=Andrea W. |date=March 2009 |title=Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer |journal=Toxicological Sciences |volume=108 |issue=1 |pages=4–18 |doi=10.1093/toxsci/kfn263 |pmid=19126598 }} Being highly reactive, these molecules can oxidatively damage fats, proteins, and DNA, and alter signal transduction. Teratogens such as thalidomide, methamphetamine, and phenytoin are known to enhance ROS formation, potentially leading to teratogenesis

ROS damage a certain class of reactions called redox reactions, which are chemical processes in which substances change their oxidation states by donating or accepting electrons.{{Cite book |last=Zumdahl |first=Stephen |title=Chemistry |date=2013 |publisher=Cengage Learning |isbn=9781285470412 |edition=9th |pages=148–162 |language=English}} In these reactions, ROS act as strong oxidizing agents. They accept electrons from other molecules, causing those molecules to become oxidized. This shifts the balance of redox reactions in cells, inducing oxidative stress when ROS levels are high, leading to cellular damage.

Developmental processes such as rapid cell division, cell differentiation into different types, and apoptosis rely on pathways that involve communication between cells through a process called signal transduction. These pathways' proper functioning is highly dependent on a certain class of reactions called redox reactions; many of these pathways are vulnerable to disruption due to oxidative stress. Therefore, one mechanism by which teratogens induce teratogenesis is by triggering oxidative stress and derailing redox-dependent signal transduction pathways in early development.{{Cite journal |last=Hansen |first=Jason M. |date=2006 |title=Oxidative stress as a mechanism of teratogenesis |journal=Birth Defects Research Part C: Embryo Today: Reviews |volume=78 |issue=4 |pages=293–307 |doi=10.1002/bdrc.20085 |pmid=17315243 }}

Folate plays key roles in DNA methylation and in synthesis of nitrogenous bases found in DNA and RNA. These processes are crucial for cell division, cell growth, gene regulation, protein synthesis, and cell differentiation. All these processes ensure normal fetal development. Since the developing fetus requires rapid cell growth and division, the demand for folate increase during pregnancy, which if not met, can lead to teratogenic complications.{{cite journal |last1=Lloyd |first1=K. A. |title=A scientific review: mechanisms of valproate-mediated teratogenesis |journal=Bioscience Horizons |date=15 May 2013 |volume=6 |pages=hzt003 |doi=10.1093/biohorizons/hzt003 |doi-access=free }}

Epigenetic modifications are any heritable modifications to the expression of genes in the DNA that do not include direct code alteration of the base genome. These modifications can include heritable alterations in transcriptional and translational processes of certain genes and even their interactions with other genes.{{cite journal |last1=Bishop |first1=Jack B. |last2=Witt |first2=Kristine L. |last3=Sloane |first3=Richard A. |title=Genetic toxicities of human teratogens |journal=Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis |date=December 1997 |volume=396 |issue=1–2 |pages=9–43 |doi=10.1016/S0027-5107(97)00173-5 |pmid=9434858 |bibcode=1997MRFMM.396....9B }} Many known teratogens affect fetal development by inducing these epigenetic modifications including turning on/off transcriptional processes of certain genes, regulating the location and distribution of proteins inside the cell, and regulating cell differentiation by modifying which mRNA molecules are translated into protein.

During embryo development, a temporary organ called a placenta forms in the womb, connecting the mother to the fetus. The placenta provides oxygen and nutrients to the developing fetus throughout the pregnancy. Environmental influences such as under-nutrition, drugs, alcohol, tobacco smoke, and even abnormal hormonal activity can lead to epigenetic changes in the placental cells and harm the fetus in the long term, though specific mechanisms by which developmental damage takes place remains unclear.{{Cite journal |last1=Zuccarello |first1=Daniela |last2=Sorrentino |first2=Ugo |last3=Brasson |first3=Valeria |last4=Marin |first4=Loris |last5=Piccolo |first5=Chiara |last6=Capalbo |first6=Antonio |last7=Andrisani |first7=Alessandra |last8=Cassina |first8=Matteo |date=April 2022 |title=Epigenetics of pregnancy: looking beyond the DNA code |journal=Journal of Assisted Reproduction and Genetics |volume=39 |issue=4 |pages=801–816 |doi=10.1007/s10815-022-02451-x |pmc=9050975 |pmid=35301622 }}

Common causes of teratogenesis include:{{Cite encyclopedia |title=Teratogens | encyclopedia = The Embryo Project Encyclopedia |url=https://embryo.asu.edu/pages/teratogens |access-date=27 March 2023 |language=en}}{{cite journal | vauthors = Gilbert-Barness E | title = Teratogenic causes of malformations | journal = Annals of Clinical and Laboratory Science | volume = 40 | issue = 2 | pages = 99–114 | date = 20 March 2010 | pmid = 20421621 | url = http://www.annclinlabsci.org/content/40/2/99 }}

• Genetic disorders and chromosomal abnormalities
• Maternal health factors
• Nutrition during pregnancy (e.g., spina bifida resulting from folate deficiency)
• Metabolic disorders such as diabetes and thyroid disease
• Stress
• Chemical agents
• Prescription and recreational drugs (e.g., alcohol,{{cite journal |last1=Welch-Carre |first1=Elizabeth |title=The Neurodevelopmental Consequences of Prenatal Alcohol Exposure |journal=Advances in Neonatal Care |date=August 2005 |volume=5 |issue=4 |pages=217–229 |doi=10.1016/j.adnc.2005.04.007 |pmid=16084479 }} thalidomide)
• Environmental toxins and contaminants (e.g., heavy metals such as mercury{{cite journal | vauthors = Holt D, Webb M | title = The toxicity and teratogenicity of mercuric mercury in the pregnant rat | journal = Archives of Toxicology | volume = 58 | issue = 4 | pages = 243–248 | date = April 1986 | pmid = 3718227 | doi = 10.1007/BF00297114 | bibcode = 1986ArTox..58..243H }} and lead,{{cite journal | vauthors = Bellinger DC | title = Teratogen update: lead and pregnancy | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 73 | issue = 6 | pages = 409–420 | date = June 2005 | pmid = 15880700 | doi = 10.1002/bdra.20127 | doi-access = free }} polychlorinated biphenyls (PCBs){{cite journal | vauthors = Jacobson JL, Jacobson SW | title = Teratogen update: polychlorinated biphenyls | journal = Teratology | volume = 55 | issue = 5 | pages = 338–347 | date = May 1997 | pmid = 9261928 | doi = 10.1002/(SICI)1096-9926(199705)55:5<338::AID-TERA6>3.0.CO;2-V }})
• Vertically transmitted infections such as rubella and syphilis
• Ionizing radiation such as X-rays and that emitted from nuclear fallout
• Temperatures outside the accepted range for a given organism{{cite journal | vauthors = Ziskin MC, Morrissey J | title = Thermal thresholds for teratogenicity, reproduction, and development | journal = International Journal of Hyperthermia | volume = 27 | issue = 4 | pages = 374–387 | date = June 2011 | pmid = 21591900 | doi = 10.3109/02656736.2011.553769 }}

{{Main|Congenital disorder}}

In humans, congenital disorders resulted in about 510,000 deaths globally in 2010.{{cite journal | vauthors = Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA | title = Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 | journal = Lancet | volume = 380 | issue = 9859 | pages = 2095–2128 | date = December 2012 | pmid = 23245604 | pmc = 10790329 | doi = 10.1016/S0140-6736(12)61728-0 | hdl-access = free | hdl = 10536/DRO/DU:30050819 }}

About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance.{{cite book | veditors = Abas AK, Fausto N, Kumar V | title = Robbins and Cotran's Pathologic Basis of Disease | edition = 7th | page = 470 | isbn = 978-0-7216-0187-8 | last1 = Kumar | first1 = Vinay | date = 2005 | publisher = Elsevier Saunders }} Developmental defects manifest in approximately 3% to 5% of newborns in the United States, between 2% to 3% of which are teratogen-induced.{{cite journal |last1=Finnell |first1=R |title=Teratology: General considerations and principles |journal=Journal of Allergy and Clinical Immunology |date=February 1999 |volume=103 |issue=2 |pages=S337–S342 |doi=10.1016/S0091-6749(99)70259-9 |pmid=9949334 }} Congenital disorders are responsible for 20% of infant deaths.{{Cite web |last=CDC |date=21 December 2022 |title=Data & Statistics on Birth Defects {{!}} CDC |url=https://www.cdc.gov/ncbddd/birthdefects/data.html |access-date=5 February 2023 |website=Centers for Disease Control and Prevention |language=en-us}} The most common congenital diseases are heart defects, Down syndrome, and neural tube defects. Trisomy 21 is the most common type of Down Syndrome. About 95% of infants born with Down Syndrome have this disorder and it consists of 3 separate copies of chromosomes. Translocation Down syndrome is not as common, as only 3% of infants with Down Syndrome are diagnosed with this type.{{Cite web |last=CDC |date=18 November 2022 |title=Facts about Down Syndrome {{!}} CDC |url=https://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html |access-date=5 April 2023 |website=Centers for Disease Control and Prevention |language=en-us}} VSD, ventricular septal defect, is the most common type of heart defect in infants. If an infant has a large VSD it can result into heart failure.{{Cite web |title=Ventricular Septal Defect (VSD) (for Parents) – Nemours KidsHealth |url=https://kidshealth.org/en/parents/vsd.html#:~:text=Infants%20with%20a%20large%20VSD,by%20bacteria%20in%20the%20bloodstream |access-date=5 April 2023 |website=kidshealth.org}} Infants with a smaller VSD have a 96% survival rate and those with a moderate VSD have about an 86% survival rate.{{Citation needed|date=March 2024}} Lastly, NTD, neural tube defect, is a defect that forms in the brain and spine during early development. If the spinal cord is exposed and touching the skin it can require surgery to prevent an infection.{{Cite web |date=8 August 2021 |title=Neural Tube Defects |url=https://www.hopkinsmedicine.org/health/conditions-and-diseases/neural-tube-defects |access-date=5 April 2023 |website=www.hopkinsmedicine.org |language=en}}

Though many pregnancies are accompanied with prescription drugs, there is limited knowledge regarding the potential teratogenic risks. Only medications that are commonly taken during pregnancies that are known to cause structural birth defects are considered teratogenic agents.{{cite journal |last1=van Gelder |first1=M. M. H. J. |last2=van Rooij |first2=I. A. L. M. |last3=Miller |first3=R. K. |last4=Zielhuis |first4=G. A. |last5=de Jong-van den Berg |first5=L. T. W. |last6=Roeleveld |first6=N. |title=Teratogenic mechanisms of medical drugs |journal=Human Reproduction Update |date=July 2010 |volume=16 |issue=4 |pages=378–394 |doi=10.1093/humupd/dmp052 |pmid=20061329 |hdl=2066/89039 |hdl-access=free }} One common drug in particular that is teratogenic is isotretinoin, known by many as Accutane. It became popular through its success in the care and treatment of skin cancer and severe acne. However, over time it has become clear that it causes severe teratogenic effects with 20-35% of exposed embryos experiencing developmental defects. Exposure of isotretinoin has led to severe skull, facial, cardiovascular, and neurological defects – to name a few.{{cite journal |last1=Draghici |first1=Carmen-Cristina |last2=Miulescu |first2=Raluca-Gabriela |last3=Petca |first3=Răzvan-Cosmin |last4=Petca |first4=Aida |last5=Dumitrașcu |first5=Mihai |last6=Șandru |first6=Florica |title=Teratogenic effect of isotretinoin in both fertile females and males (Review) |journal=Experimental and Therapeutic Medicine |date=23 March 2021 |volume=21 |issue=5 |page=534 |doi=10.3892/etm.2021.9966 |pmid=33815607 |pmc=8014951 }} Another drug known as carbamazepine is sometimes prescribed during pregnancy if the mother experiences more extreme concerns regarding epilepsy or bipolar disorder.{{Cite web |title=Carbamazepine |url=https://www.medicinesinpregnancy.org/leaflets-a-z/carbamazepine/#:~:text=Use%20of%20carbamazepine%20in%20pregnancy,make%20decisions%20about%20your%20treatment. |access-date=2025-03-20 |website=www.medicinesinpregnancy.org}} Unfortunately, this drug can also cause birth and developmental defects especially during the early stages of pregnancy such as defects of the neural tube, which develops into the brain and spinal cord.{{cite book |doi=10.1016/B978-012436643-5/50028-6 |quote=The neural tube expands in the head to form the brain and in the trunk to form the spinal cord. Thus, the neural tube generates the entire vertebrate CNS. |chapter=Neural Crest Cells |title=Handbook of Stem Cells |date=2004 |pages=219–232 |isbn=978-0-12-436643-5 | vauthors = Trainor PA, Bronner-Fraser M, Krumlauf R }} An example of this is spina bifida.{{Cite journal |last1=Matlow |first1=Jeremy |last2=Koren |first2=Gideon |date=February 2012 |title=Is carbamazepine safe to take during pregnancy? |journal=Canadian Family Physician |volume=58 |issue=2 |pages=163–164 |pmc=3279268 |pmid=22337738 }} Oral and topical antifungal agents such as fluconazole, ketoconazole, and terbinafine are commonly prescribed in pregnancy. Some fungal infections are asymptomatic and therefore do not really cause discomfort, but some are slightly more severe and can negatively affect a pregnant woman's life quality and even the fetus. This is primarily when antifungal agents are prescribed during pregnancy. Unfortunately, the use of antifungal agents can lead to spontaneous abortions and defects mainly regarding the cardiovascular and musculoskeletal systems, as well as some eye defects.{{Cite journal |last1=Patel |first1=Madhuri A. |last2=Aliporewala |first2=Veeral M. |last3=Patel |first3=Disha A. |date=December 2021 |title=Common Antifungal Drugs in Pregnancy: Risks and Precautions |journal=The Journal of Obstetrics and Gynecology of India |language=en |volume=71 |issue=6 |pages=577–582 |doi=10.1007/s13224-021-01586-8 |pmid=34898894 |pmc=8617216 }} It is safer to avoid taking medications during pregnancy to keep the likelihood of teratogenicity low, as the chances of any pregnancy resulting in birth defects is only 3-5%.{{cite book |title=Mother To Baby {{!}} Fact Sheets |date=1994 |publisher=Organization of Teratology Information Specialists (OTIS) |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK582659/ |chapter=Critical Periods of Development |pmid=35951922 }} However, it is necessary and cannot be avoided in certain cases. As with any medical concern, a doctor should always be consulted in order for the pregnancy to have the best outcome possible for both mother and baby.

Acitretin is a retinoid and vitamin A derivative that is used in the treatment of psoriasis.{{Cite journal |last1=Sadowska |first1=Magdalena |last2=Narbutt |first2=Joanna |last3=Skibińska |first3=Małgorzata |last4=Lesiak |first4=Aleksandra |date=February 2022 |title=Pros and cons of using systemic acitretin in the paediatric population |journal=Postepy Dermatologii I Alergologii |volume=39 |issue=1 |pages=34–38 |doi=10.5114/ada.2020.98558 |pmc=8953885 |pmid=35369612 }} Acitretin is highly teratogenic and noted for the possibility of severe birth defects. It was initially suggested as a replacement for Etretinate.{{Cite web |date=2003-09-10 |title=Hoffmann-La Roche, Inc.; Withdrawal of Approval of a New Drug Application |url=https://www.federalregister.gov/documents/2003/09/10/03-22956/hoffmann-la-roche-inc-withdrawal-of-approval-of-a-new-drug-application |access-date=2025-02-10 |website=Federal Register |language=en}} It should not be used by pregnant women or women planning to get pregnant within 3 years following the use of acitretin. Sexually active women of childbearing age who use acitretin should also use at least two forms of birth control concurrently. Men and women who use it should not donate blood for three years after using it, because of the possibility that the blood might be used in a pregnant patient and cause birth defects. In addition, it may cause nausea, headache, itching, dry, red or flaky skin, dry or red eyes, dry or chapped lips, swollen lips, dry mouth, thirst, cystic acne or hair loss.{{cite web|url=http://www.webmd.com/drugs/drug-4719-soriatane+oral.aspx?drugid=4719&drugname=soriatane+oral|title=Soriatane|work=WebMD|access-date=15 August 2015}}{{cite web|url=https://www.drugs.com/sfx/soriatane-side-effects.html|title=Soriatane Side Effects|work=Drugs.com|access-date=15 August 2015}}{{cite web|url=http://www.rxlist.com/soriatane-drug.htm|title=Soriatane (Acitretin) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList|work=RxList|access-date=15 August 2015|archive-url=https://web.archive.org/web/20131202230458/http://www.rxlist.com/soriatane-drug.htm|archive-date=2 December 2013|url-status=dead}}

Etretinate (trade name Tegison) is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis. It is a second-generation retinoid.{{cite book | vauthors = Mutschler E, Schäfer-Korting M |title=Arzneimittelwirkungen |language=German |location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|page=728f|isbn=3-8047-1763-2}} It was subsequently removed from the Canadian market in 1996 and the United States market in 1998 due to the high risk of birth defects. It remains on the market in Japan as Tigason.{{Cite web |title=NCATS Inxight Drugs — ETRETINATE |url=https://drugs.ncats.io/drug/65M2UDR9AG |access-date=2025-02-10 |website=drugs.ncats.io |language=en}}

Isotretinoin is classified as a retinoid drug and is used as a treatment for severe acne, other skin conditions, and some cancer types.{{cite web |title=Isotretinoin |url=https://medlineplus.gov/druginfo/meds/a681043.html |website=MedlinePlus Drug Information }} In treatment against acne, it functions by hindering the activity of skin's sebaceous glands.{{cite journal |last1=Bagatin |first1=Edileia |last2=Costa |first2=Caroline Sousa |title=The use of isotretinoin for acne – an update on optimal dosing, surveillance, and adverse effects |journal=Expert Review of Clinical Pharmacology |date=2 August 2020 |volume=13 |issue=8 |pages=885–897 |doi=10.1080/17512433.2020.1796637 |pmid=32744074 }} It is extremely effective in its use in treatment against severe acne, but does have some negative side effects such as dry skin, nausea, joint and muscle pain, blistering skin, and the development of sores on mucous membranes. Some brand names for isotretinoin are Accutane, Absorica, Claravis, and Myorisan. Accutane is no longer on the market, but many other generic alternatives are available.

File:Isotretinoin2DACS2.svg

Prenatal exposure to isotretinoin can cause neurocognitive impairment in some children.{{cite journal |last1=Choi |first1=June Seek |last2=Koren |first2=Gideon |last3=Nulman |first3=Irena |title=Pregnancy and isotretinoin therapy |journal=Canadian Medical Association Journal |date=19 March 2013 |volume=185 |issue=5 |pages=411–413 |doi=10.1503/cmaj.120729 |pmid=23296582 |pmc=3602257 }} Isotretinoin is able to cross the placenta, potentially harming the developing fetus. If a fetus is exposed to isotretinoin during the first trimester of pregnancy, craniofacial, cardiac, and central nervous system malformations can occur.{{cite journal |last1=Jordan |first1=Amy Y. |last2=Parks |first2=Lauren |last3=Chen |first3=Suephy C. |last4=Higgins |first4=Kristen |last5=Fleischer |first5=Alan B. |last6=Feldman |first6=Steven R. |title=Does the teratogenicity of isotretinoin outweigh its benefits? |journal=Journal of Dermatological Treatment |date=January 2005 |volume=16 |issue=4 |pages=190–192 |doi=10.1080/09546630510044904 |pmid=16249139 }} Some prenatal exposures to isotretinoin can result in still births or spontaneous abortions. The use of isotretinoin during pregnancy can increase cell apoptosis, leading to malformations, as well as heart defects.{{cite journal |last1=Williams |first1=Sarah S. |last2=Mear |first2=John P. |last3=Liang |first3=Hung-Chi |last4=Potter |first4=S. Steven |last5=Aronow |first5=Bruce J. |last6=Colbert |first6=Melissa C. |title=Large-scale reprogramming of cranial neural crest gene expression by retinoic acid exposure |journal=Physiological Genomics |date=4 October 2004 |volume=19 |issue=2 |pages=184–197 |doi=10.1152/physiolgenomics.00136.2004 |pmid=15466718 }}

In humans, vaccination has become readily available, and is important for the prevention of various communicable diseases such as polio and rubella, among others. There has been no association between congenital malformations and vaccination — for example, a population-wide study in Finland in which expectant mothers received the oral polio vaccine found no difference in infant outcomes when compared with mothers from reference cohorts who had not received the vaccine.{{cite journal | vauthors = Harjulehto-Mervaala T, Aro T, Hiilesmaa VK, Saxén H, Hovi T, Saxén L | title = Oral polio vaccination during pregnancy: no increase in the occurrence of congenital malformations | journal = American Journal of Epidemiology | volume = 138 | issue = 6 | pages = 407–414 | date = September 1993 | pmid = 8213746 | doi = 10.1093/oxfordjournals.aje.a116873 }}

However, on grounds of theoretical risk, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection.{{cite web |title=Guidelines for Vaccinating Pregnant Women |url=https://www.cdc.gov/vaccines/pregnancy/hcp/guidelines.html#polio |website=cdc.gov |date=13 January 2021 |publisher=Centers for Disease Control and Prevention: Advisory Committee on Immunization Practices (ACIP) |quote=Although no adverse effects of IPV have been documented among pregnant women or their fetuses, vaccination of pregnant women should be avoided on theoretical grounds. However, if a pregnant woman is at increased risk for infection and requires immediate protection against polio, IPV can be administered in accordance with the recommended schedules for adults.}}

An important exception to this relates to provision of the influenza vaccine while pregnant. During the 1918 and 1957 influenza pandemics, mortality from influenza in pregnant women was 45%. In a 2005 study of vaccination during pregnancy, Munoz et al. demonstrated that there was no adverse outcome observed in the new infants or mothers, suggesting that the balance of risk between infection and vaccination favored preventative vaccination.{{cite journal | vauthors = Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, Glezen WP | title = Safety of influenza vaccination during pregnancy | journal = American Journal of Obstetrics and Gynecology | volume = 192 | issue = 4 | pages = 1098–1106 | date = April 2005 | pmid = 15846187 | doi = 10.1016/j.ajog.2004.12.019 }}

{{main|hormone replacement therapy}}

There are a number of ways that a fetus can be affected in pregnancy, specifically due to exposure to various substances. There are a number of drugs that can do this, specifically drugs such as female reproductive hormones or hormone replacement drugs such as estrogen and progesterone that are not only essential for reproductive health, but also pose concerns when it comes to the synthetic alternatives to these. This can cause a multitude of congenital abnormalities and deformities, many of which can ultimately affect the fetus and even the mother's reproductive system in the long term. According to a study conducted from 2015 till 2018, it was found that there was an increased risk of both maternal and neonatal complications developing as a result of hormone replacement therapy cycles being conducted during pregnancy, especially in regards to hormones such as estrogen, testosterone and thyroid hormone.{{cite journal | vauthors = Zong L, Liu P, Zhou L, Wei D, Ding L, Qin Y | title = Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer | journal = Reproductive Biology and Endocrinology | volume = 18 | issue = 1 | pages = 36 | date = May 2020 | pmid = 32366332 | pmc = 7199365 | doi = 10.1186/s12958-020-00601-3 | doi-access = free }}{{cite journal | vauthors = van den Broek S, Lupattelli A, Frank AS, Haug LS, Nordeng H | title = Thyroid hormone replacement therapy in pregnancy and motor function, communication skills, and behavior of preschool children: The Norwegian Mother, Father, and Child Cohort Study | journal = Pharmacoepidemiology and Drug Safety | volume = 30 | issue = 6 | pages = 716–726 | date = June 2021 | pmid = 33314561 | pmc = 8247290 | doi = 10.1002/pds.5184 }}{{cite journal | vauthors = Steckler T, Wang J, Bartol FF, Roy SK, Padmanabhan V | title = Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment | journal = Endocrinology | volume = 146 | issue = 7 | pages = 3185–3193 | date = July 2005 | pmid = 15802500 | doi = 10.1210/en.2004-1444 }} When hormones such as estrogen and testosterone are replaced, this can cause the fetus to become stunted in growth, born prematurely with a lower birth weight, develop mental retardation, while in turn causing the mother's ovarian reserve to be depleted while increasing ovarian follicular recruitment.{{cite journal | vauthors = Knox RV | title = Recruitment and selection of ovarian follicles for determination of ovulation rate in the pig | journal = Domestic Animal Endocrinology | volume = 29 | issue = 2 | pages = 385–397 | date = August 2005 | pmid = 15998504 | doi = 10.1016/j.domaniend.2005.02.025 }}

It is rare for cancer and pregnancy to coincide, occurring in only 1 in 1,000 pregnancies and making up less than 0.1% of all recorded malignant tumors.{{cite journal |last1=Stephens |first1=Trent D |last2=Bunde |first2=Carolyn J.W |last3=Fillmore |first3=Bradley J |title=Mechanism of action in thalidomide teratogenesis |journal=Biochemical Pharmacology |date=June 2000 |volume=59 |issue=12 |pages=1489–1499 |doi=10.1016/S0006-2952(99)00388-3 |pmid=10799645 }} However, when this does occur, there are many complications and great, although not well understood, risks to the fetus in the event that chemotherapy drugs are used. The majority of these drugs are cytotoxic, meaning that they have the potential to be carcinogenic, mutagenic, and teratogenic.{{Cite journal |last1=Gilani |first1=S. |last2=Giridharan |first2=S. |date=2014-04-10 |title=Is it safe for pregnant health-care professionals to handle cytotoxic drugs? A review of the literature and recommendations |url=https://ecancer.org/en/journal/article/418-is-it-safe-for-pregnant-health-care-professionals-to-handle-cytotoxic-drugs-a-review-of-the-literature-and-recommendations |access-date=2025-03-03 |journal=ecancermedicalscience |volume=8 |page=418 |doi=10.3332/ecancer.2014.418 |pmid=24761159 |pmc=3990661 |language=en}} If used during the first two weeks of pregnancy, they may inhibit implantation of the fetus and led to miscarriage. They may particularly act as teratogenic agents if used from the second to eighth week, as this is a critical stage for tissue differentiation. The highest risk continues through the first trimester, making up 14% of major malformations.{{Cite journal |last=National Toxicology Program |date=May 2013 |title=NTP Monograph: Developmental Effects and Pregnancy Outcomes Associated With Cancer Chemotherapy Use During Pregnancy |journal=NTP Monograph |issue=2 |pages=i–214 |pmid=24736875 }} Chemotherapeutic drugs are considered safer to use during the second and third trimester, but there is limited research to fully support this.

File:Thalidomide-2D-skeletal.png agent.{{cite journal | vauthors = Stephens TD, Bunde CJ, Fillmore BJ | title = Mechanism of action in thalidomide teratogenesis | journal = Biochemical Pharmacology | volume = 59 | issue = 12 | pages = 1489–1499 | date = June 2000 | pmid = 10799645 | doi = 10.1016/S0006-2952(99)00388-3 }}]]

Thalidomide, also known as Thalomid, was used in the mid-1900s primarily, as a sedative.{{cite book |doi=10.1002/9780470015902.a0026056 |chapter=Teratogenesis |title=Encyclopedia of Life Sciences |date=2017 |pages=1–7 |isbn=978-0-470-01617-6 | vauthors = Vargesson N, Fraga L }} It is a drug that was first introduced in Germany and spread to other countries as a therapeutic prescription from the 1950s to early 1960s in Europe as an anti-nausea medication to alleviate morning sickness among pregnant women.{{cite book |title=Mother To Baby {{!}} Fact Sheets |date=1994 |publisher=Organization of Teratology Information Specialists (OTIS) |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK582976/ |chapter=Thalidomide |pmid=35952249 }} While the exact mechanism of action of thalidomide is not known, it is thought to be related to inhibition of angiogenesis through interaction with the insulin like growth factor(IGF-1) and fibroblast like growth factor 2 (FGF-2) pathways. This drug acted upon the immune system causing the overall blood cell count be reduced after repeated usage and hindered the generation of the cells. In the 1960s, it became apparent that thalidomide altered embryo development and led to limb deformities such as thumb absence, underdevelopment of entire limbs, or phocomelia. It is among the first known drugs that research pointed towards the possibility of it causing birth defects. Thalidomide may have caused teratogenic effects in over 10,000 babies worldwide.{{cite journal | vauthors = Kim JH, Scialli AR | title = Thalidomide: the tragedy of birth defects and the effective treatment of disease | journal = Toxicological Sciences | volume = 122 | issue = 1 | pages = 1–6 | date = July 2011 | pmid = 21507989 | doi = 10.1093/toxsci/kfr088 | doi-access = free }}{{cite journal | vauthors = Martínez-Frías ML | title = [The thalidomide experience: review of its effects 50 years later] | language = Spanish | journal = Medicina Clinica | volume = 139 | issue = 1 | pages = 25–32 | date = June 2012 | pmid = 22177324 | doi = 10.1016/j.medcli.2011.10.011 }} As it became more well known, other uses were found, such as its use in leprosy treatment, cancer treatment, and HIV infections.

{{Main|Fetal alcohol spectrum disorder}}

File:Photo of baby with FAS.jpg

In the US, alcohol is subject to the FDA drug labeling Pregnancy Category X (Contraindicated in pregnancy). Alcohol is known to cause fetal alcohol spectrum disorder.{{citation needed|date=January 2025}}

There are a wide range of affects that Prenatal Alcohol Exposure (PAE) can have on a developing fetus. Some of the most prominent possible outcomes include the development of Fetal Alcohol Syndrome, a reduction in brain volume, still births, spontaneous abortions, impairments of the nervous system, and much more. Fetal Alcohol Syndrome has numerous symptoms which may include cognitive impairments and impairment of the facial features.{{cite journal | vauthors = Popova S, Dozet D, Shield K, Rehm J, Burd L | title = Alcohol's Impact on the Fetus | journal = Nutrients | volume = 13 | issue = 10 | pages = 3452 | date = September 2021 | pmid = 34684453 | pmc = 8541151 | doi = 10.3390/nu13103452 | doi-access = free }} PAE remains the leading cause of birth defects and neurodevelopmental abnormalities in the United States, affecting 9.1 to 50 per 1000 live births in the U.S. and 68.0 to 89.2 per 1000 in populations with high levels of alcohol use.{{cite web |title=Fetal Alcohol Exposure and the Brain |url=https://pubs.niaaa.nih.gov/publications/aa50.htm |website=National Institute on Alcohol Abuse and Alcoholism |vauthors=Gordis E}}

Consuming tobacco products while pregnant or breastfeeding can have significant negative impacts on the health and development of the unborn child and newborn infant.{{Cite journal |last=Haustein |first=K. O. |date=September 1999 |title=Cigarette smoking, nicotine and pregnancy |journal=International Journal of Clinical Pharmacology and Therapeutics |volume=37 |issue=9 |pages=417–427 |pmid=10507240 }} In a research study conducted in 1957, the relationship between tobacco consumption during pregnancy and premature births was studied. The research showed that there was significant evidence that tobacco consumption during pregnancy can cause the mother to go into labor and deliver earlier than determined due date. Some of the data showed conflicting evidence because tobacco reduces premature birth via gestational hypertension but increases other symptom risks. From 1957 to 1986 there were over 500,000 babies observed in studies that showed pregnant mothers intaking tobacco have increased probability that the baby birthed will weigh less than babies birthed by non-smoking mothers. A research study was conducted on six year old's and found a correlation between lower birth weights and lower IQ levels. This can be harmful to the child potentially affecting their brain development overtime as the fetus was not able to have the development of the neurological pathways needed to grow. Tobacco use can also cause stillbirths in mothers who are pregnant, increasing the probability up to three times more risk than non tobacco users. Research shows that the earlier in the pregnancy the mother is the higher chance of a still birth baby being born. Babies that are exposed to nicotine and tobacco can develop an addiction to this substance while still developing, causing addict-like behavioral patterns when born.

E-Cigarettes are electronic devices that contain a heating device as well as a cartage to hold liquid in. The liquid in the cartages contain nicotine in about one-third to two-thirds the amount in regular cigarettes. This means that the nicotine still crosses the placenta, and can be detected in the fetus' blood and plasma at higher levels than the maternal concentrations.{{Cite journal |last=Wickström |first=R. |date=September 2007 |title=Effects of nicotine during pregnancy: human and experimental evidence |journal=Current Neuropharmacology |volume=5 |issue=3 |pages=213–222 |doi=10.2174/157015907781695955 |pmc=2656811 |pmid=19305804 }} It can be harmful to the developing fetus' brain and lungs.{{Cite web |last=CDC |date=2024-05-20 |title=E-Cigarettes and Pregnancy |url=https://www.cdc.gov/maternal-infant-health/pregnancy-substance-abuse/e-cigarettes.html#:~:text=E-cigarettes%20and%20other%20products,cigarettes%20may%20also%20be%20harmful. |access-date=2025-02-26 |website=Maternal Infant Health |language=en-us}} The liquid also contains artificial flavoring agents that can be harmful to the body. A pregnant mother can have issues that form during development of the baby due to nicotine like birth deformities or retardation. Many of the deformities can include the skull not fully forming, limbs forming partially, or cardiovascular issues.

File:Kokain - Cocaine.svg

Cocaine can act as a teratogen, having various effects on the developing fetus.{{Cite web |title=Cocaine as a Teratogen {{!}} Embryo Project Encyclopedia |url=https://embryo.asu.edu/pages/cocaine-teratogen |access-date=2025-04-07 |website=embryo.asu.edu |language=en}} Some common teratogenic defects caused by cocaine include hydronephrosis, cleft palate, polydactyly, and down syndrome. Cocaine as a drug has a low molecular weight and high water and lipid solubility which enables it to cross the placenta and fetal blood-brain barrier.{{cite journal | vauthors = Singer L, Arendt R, Minnes S | title = Neurodevelopmental effects of cocaine | journal = Clinics in Perinatology | volume = 20 | issue = 1 | pages = 245–262 | date = March 1993 | pmid = 8458168 | pmc = 4181371 | doi = 10.1016/S0095-5108(18)30422-6 }} Because cocaine is able to pass through the placenta and enter the fetus, the fetus' circulation can be negatively affected. With restriction of fetal circulation, the development of organs in the fetus can be impacted, even resulting in intestines developing outside of the fetus' body. Cocaine use during pregnancy can also result in obstetric labor complications such as preterm birth or delivery, uterine rupture, miscarriage, and stillbirth.

There is currently no reliable data to suggest that marijuana consistently acts as a teratogen. However, some studies show that it may have negative effects on the development of the fetus and consequent neurobehavioral outcomes. Frequent use of marijuana during pregnancy has been related to a reduction in birth weight, although the association is not strong.{{Cite journal |last1=Kozer |first1=E. |last2=Koren |first2=G. |date=February 2001 |title=Effects of prenatal exposure to marijuana |journal=Canadian Family Physician |volume=47 |pages=263–264 |issn=0008-350X |pmc=2016243 |pmid=11228023}}  The neurodevelopmental effects include sleep disturbances, hyperactivity, increased delinquency, and worsened problem-solving. However, this data is not conclusive because there are a variety of other factors that tend to be associated with prenatal use of marijuana, including poorer economic status and exposure to other illicit drugs. Complications with maternal use of cannabis also stem from the fact that it is excreted into breast milk in small quantities and may harm motor development if fetal exposure is regular.{{Citation |title=Cannabis |date=2006 |work=Drugs and Lactation Database (LactMed®) |url=https://www.ncbi.nlm.nih.gov/books/NBK501587/ |access-date=2025-04-16 |place=Bethesda (MD) |publisher=National Institute of Child Health and Human Development |pmid=30000647}} It is advised that mothers refrain from using any products containing THC while they are breastfeeding or pregnant.

File:Caffeine as a individualistic teratogen.jpg

Caffeine consumption during pregnancy has been linked to intrauterine growth retardation and spontaneous abortion during the first trimester. Other teratogenic effects include low birthweight,{{Cite journal |last=James |first=Jack E. |date=2021-06-01 |title=Maternal caffeine consumption and pregnancy outcomes: a narrative review with implications for advice to mothers and mothers-to-be |journal=BMJ Evidence-Based Medicine |language=en |volume=26 |issue=3 |pages=114–115 |doi=10.1136/bmjebm-2020-111432 |issn=2515-446X |pmid=32843532|doi-access=free |pmc=8165152 }} problems with neural tube development, decreased head circumference, excessive infant growth, and cognitive impairments at birth. Caffeine's chemical structure allows it to be transmitted across biological membranes, including the placental barrier,{{Cite journal |last1=Fernandes |first1=Olavo |last2=Sabharwal |first2=Mona |last3=Smiley |first3=Tom |last4=Pastuszak |first4=Anne |last5=Koren |first5=Gideon |last6=Einarson |first6=Thomas |date=1998-07-01 |title=Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: a meta-analysis |url=https://www.sciencedirect.com/science/article/abs/pii/S0890623898000240#:~:text=Several%20mechanisms%20for%20caffeine%20to,and%20birth%20weight%20in%20humans. |journal=Reproductive Toxicology |volume=12 |issue=4 |pages=435–444 |doi=10.1016/S0890-6238(98)00024-0 |pmid=9717693 |bibcode=1998RepTx..12..435F |issn=0890-6238}} which is then transmitted to the developing embryo.

The inability to breakdown caffeine results in a build up of caffeine in the embryo. The build up of caffeine in embryos can produce teratogenic effects by blocking adenosine receptors, which regulate several neurotransmitters, including dopamine, serotonin, norepinephrine, and GABA.{{Citation |last=Research |first=Institute of Medicine (US) Committee on Military Nutrition |title=Pharmacology of Caffeine |date=2001 |work=Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations |url=https://www.ncbi.nlm.nih.gov/books/NBK223808/#:~:text=Caffeine%20action%20is%20thought%20to,et%20al.,%201999). |access-date=2025-04-25 |publisher=National Academies Press (US) |language=en}} The teratogenic effects of caffeine are variable, and affects individuals differently depending on their sensitivity to caffeine.{{Cite journal |last1=Qian |first1=Jingjing |last2=Chen |first2=Qi |last3=Ward |first3=Sean M. |last4=Duan |first4=Enkui |last5=Zhang |first5=Ying |date=March 2020 |title=Impacts of Caffeine during Pregnancy |journal=Trends in Endocrinology and Metabolism |volume=31 |issue=3 |pages=218–227 |doi=10.1016/j.tem.2019.11.004 |issn=1879-3061 |pmc=7035149 |pmid=31818639}} One mother may not have any teratogenic effects from caffeine consumption during pregnancy, while another could have significant complications.{{cite journal |last1=Qian |first1=Jingjing |last2=Chen |first2=Qi |last3=Ward |first3=Sean M. |last4=Duan |first4=Enkui |last5=Zhang |first5=Ying |date=March 2020 |title=Impacts of Caffeine during Pregnancy |journal=Trends in Endocrinology & Metabolism |volume=31 |issue=3 |pages=218–227 |doi=10.1016/j.tem.2019.11.004 |pmc=7035149 |pmid=31818639}}

One example of a physical agent which may give rise to developmental complications is heat. Women may be exposed to heat from external sources such as extreme heat conditions and hot-tub exposures. External temperatures that exceed 102 °Fahrenheit can give rise to fetal complications via the mechanism of neural tube malformation.{{sfn|Gilbert|2015|pp=209, 211}} The exact mechanisms relating heat to neural tube defects are not well-known. A potential theory connects heat to multiple cell-related issues, including cell movement, cell division, and apoptosis. The disruption in these normal processes may ultimately feed into the mechanism of neural tube malformation.{{cite journal |last1=LaPointe |first1=Sarah |last2=Beagle |first2=Lauren E. |last3=Zheng |first3=Xiaping |last4=Kancherla |first4=Vijaya |last5=Mutic |first5=Abby |last6=Chang |first6=Howard H. |last7=Gaskins |first7=Audrey J. |title=Associations between exposure to extreme ambient heat and neural tube defects in Georgia, USA: A population-based case-control study |journal=Environmental Research |date=November 2024 |volume=261 |pages=119756 |doi=10.1016/j.envres.2024.119756 |pmid=39117054 |pmc=11390300 |pmc-embargo-date=November 15, 2025 |bibcode=2024ER....26119756L }}

Another method of exposure to heat can be seen as a result of the pregnancy itself. This phenomenon can be associated with maternal weight gain as well the heat produced via fetal metabolism, both of which may cause dysregulation of heat escape. The exact mechanisms beyond these surface-level causes are not clear. One theory associates this heat with producing heat-shock proteins, which then disrupt a certain normal protein balance. This deviation from a normal protein balance may then interfere with fetal development. Another theory draws potential connections between elevated temperature, oxidative stress, and inflammation with blood flow restriction to the fetus.{{Cite journal |last=Konkel |first=Lindsey |date=2019 |title=Taking the Heat: Potential Fetal Health Effects of Hot Temperatures |journal=Environmental Health Perspectives |language=en |volume=127 |issue=10 |doi=10.1289/EHP6221 |pmid=31652107 |pmc=6910775 |bibcode=2019EnvHP.127j2002K }}

Although large exposures to radiation during pregnancies are often rare, when such exposures occur the resulting teratogenic complications occur due to various factors and/or mechanisms. The negative effects associated with radiation in general have to do with the interaction of said radiation with the stem cells of the developing fetus. There are also associations with DNA damage, oxidative stress responses, and changes in protein expression. In terms of ionizing radiation in particular, such forms of radiation often cause chemical changes to occur that yields abnormal chemical species. These chemical materials can then act on two different structures: they can either alter specific tissue-level structures in a predictable way, or act on DNA structures in a more random fashion.{{cite book |doi=10.1016/B978-0-323-95235-4.00044-X |chapter=Possible health effects of radiation exposure on unborn babies |title=Hazardous Chemicals |date=2025 |pages=785–793 |isbn=978-0-323-95235-4 | vauthors = Arora M, Arora N, Arora S }}

While some ranges of sound are kept from reaching the fetus due to the presence of the mother's abdomen and uterus as barrier of sorts, there is still evidence that both high intensity sounds and continuous exposure to sound can be harmful to the fetus. Such sounds may bring about many potential problems within the fetus, including chromosomal abnormalities, altered social behavior after birth, and issues with hearing.{{Cite journal |last1=Krueger |first1=Charlene |last2=Horesh |first2=Elan |last3=Crossland |first3=Brian Adam |date=2012 |title=Safe Sound Exposure in the Fetus and Preterm Infant |journal=Journal of Obstetric, Gynecologic & Neonatal Nursing |language=en |volume=41 |issue=2 |pages=166–170 |doi=10.1111/j.1552-6909.2012.01342.x|pmid=22834845 |pmc=3665292 }} In terms of hearing damage specifically, it is thought that these external sounds cause damage to the developing fetal cochlea and its constituent parts, particularly the inner and outer hairs of the structure.{{Cite journal |last1=Guven |first1=Selis Gülseven |last2=Taş |first2=Memduha |last3=Bulut |first3=Erdoğan |last4=Tokuç |first4=Burcu |last5=Uzun |first5=Cem |last6=Karasalihoğlu |first6=Ahmet Rifat |date=2019 |title=Does noise exposure during pregnancy affect neonatal hearing screening results? |journal=Noise & Health |volume=21 |issue=99 |pages=69–76 |doi=10.4103/nah.NAH_18_19 |doi-broken-date=25 March 2025 |doi-access=free |pmc=7158898 |pmid=32174641 }}

Long before modern science, it was understood that heavy metals could cause negative effects to those who were exposed. The Greek physician Pedanius Dioscorides described the effects of lead exposure as something that "makes the mind give way". Lead exposure in adults can lead to cardiological, renal, reproductive, and cognitive issues that are often irreversible, however, lead exposure during pregnancy can be detrimental to the long-term health of the fetus.{{cite journal |vauthors=Kasten-Jolly J, Lawrence DA |date=November 2017 |title=Sex-specific effects of developmental lead exposure on the immune-neuroendocrine network |journal=Toxicology and Applied Pharmacology |volume=334 |pages=142–157 |bibcode=2017ToxAP.334..142K |doi=10.1016/j.taap.2017.09.009 |pmid=28911972}} Exposure to lead during pregnancy is well known to have teratogenic effects on the development of a fetus.{{cite journal |vauthors=Hu H, Téllez-Rojo MM, Bellinger D, Smith D, Ettinger AS, Lamadrid-Figueroa H, Schwartz J, Schnaas L, Mercado-García A, Hernández-Avila M |date=November 2006 |title=Fetal lead exposure at each stage of pregnancy as a predictor of infant mental development |journal=Environmental Health Perspectives |volume=114 |issue=11 |pages=1730–1735 |bibcode=2006EnvHP.114.1730H |doi=10.1289/ehp.9067 |pmc=1665421 |pmid=17107860}} Specifically, fetal exposure to lead can cause cognitive impairment, premature births, unplanned abortions, ADHD, and much more.{{cite journal |vauthors=RÍsovÁ V |date=September 2019 |title=The pathway of lead through the mother's body to the child |journal=Interdisciplinary Toxicology |volume=12 |issue=1 |pages=1–6 |doi=10.2478/intox-2019-0001 |pmc=7061448 |pmid=32189981}} Lead exposure during the first trimester of pregnancy leads to the greatest predictability of cognitive development issues after birth.

Low socioeconomic status correlates to a higher probability of lead exposure.{{cite journal |vauthors=Cory-Slechta DA, Virgolini MB, Thiruchelvam M, Weston DD, Bauter MR |date=May 2004 |title=Maternal stress modulates the effects of developmental lead exposure |journal=Environmental Health Perspectives |volume=112 |issue=6 |pages=717–730 |bibcode=2004EnvHP.112..717C |doi=10.1289/ehp.6481 |pmc=1241967 |pmid=15121516}} A well-known recent example of lead {{nowrap|poisoning{{tsp}}{{mdash}}{{tsp}}}}and the impacts it can have on a {{nowrap|community{{tsp}}{{mdash}}{{tsp}}}}was the 2014 water crisis in Flint, Michigan. Researchers have found that female fetuses developed at a higher rate than male fetuses in Flint when compared to surrounding areas. The higher rate of female births indicated a problem because male fetuses are more sensitive to pregnancy hazards than female fetuses.{{Cite web |date=2017-09-22 |title=Flint Water Tied to Fetal Death and Lower Fertility Rates |url=https://www.pbs.org/wgbh/nova/article/flint-water-tied-to-fetal-death-and-lower-fertility-rates/ |access-date=2024-03-24 |website=www.pbs.org |language=en-US}}

File:DEHP.png

Phthalate acid esters (PAEs) are a classification of chemical plasticizers used to increase flexibility in commercial plastics, such as polyethylene terephthalate (PET) and polyvinyl chloride (PVC). Phthalates are currently used in several consumer goods, including food packaging, cosmetics, clothing, fragrance, and toys.{{Cite journal |last1=Ungewitter |first1=Erica |last2=Rotgers |first2=Emmi |last3=Bantukul |first3=Tanika |last4=Kawakami |first4=Yasuhiko |last5=Kissling |first5=Grace E. |last6=Yao |first6=Humphrey Hung-Chang |date=2017-05-01 |title=From the Cover: Teratogenic Effects of in Utero Exposure to Di-(2-Ethylhexyl)-Phthalate (DEHP) in B6:129S4 Mice |url=https://academic.oup.com/toxsci/article/157/1/8/2953393 |journal=Toxicological Sciences |volume=157 |issue=1 |pages=8–19 |doi=10.1093/toxsci/kfx019 |pmid=28123099 |issn=1096-6080|pmc=6074946 }} Additionally, they have wide-spread use in pharmaceutical and medical products, including in coatings and fillers of extend-release medications,{{Cite journal |last1=Sree |first1=Chendruru Geya |last2=Buddolla |first2=Viswanath |last3=Lakshmi |first3=Buddolla Anantha |last4=Kim |first4=Young-Joon |date=2023-01-01 |title=Phthalate toxicity mechanisms: An update |url=https://www.sciencedirect.com/science/article/abs/pii/S1532045622002332#:~:text=It%20is%20estimated%20that%20phthalates,chemical%20and%20molecular%20mechanisms%20involved. |journal=Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology |volume=263 |pages=109498 |doi=10.1016/j.cbpc.2022.109498 |pmid=36374650 |issn=1532-0456}} blood bag packaging, tubes used in blood transfers, and hemodialysis units.{{Cite journal |last1=Shiota |first1=K. |last2=Nishimura |first2=H. |date=November 1982 |title=Teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice |journal=Environmental Health Perspectives |volume=45 |pages=65–70 |doi=10.1289/ehp.824565 |issn=0091-6765 |pmc=1568998 |pmid=7140698|bibcode=1982EnvHP..45...65S }}

The most common phthalates include di(2-ethylhexyl) phthalate and di-n-butyl phthalate. As of 2017, di(2-ethylhexyl) phthalate is estimated to make up 30% of plastic produced in the United States and European Union, and up to 80% of plastic produced in China.

Several animal studies have been conducted to observe the specific effects of DEHP in vitro, including rats, mice, and chick embryos. Observed effects of high phthalate exposure in utero included neural tube malformations, encephalopathy, limb malformations, decreased vasculature,{{Cite journal |last1=Song |first1=Ge |last2=Wang |first2=Rui |last3=Cui |first3=Yi |last4=Hao |first4=Chan Juan |last5=Xia |first5=Hong-Fei |last6=Ma |first6=Xu |date=September 2020 |title=Diethylhexyl phthalate induces teratogenic effects through oxidative stress response in a chick embryo model |journal=Toxicology Research |volume=9 |issue=5 |pages=622–631 |doi=10.1093/toxres/tfaa058 |issn=2045-452X |pmc=7640930 |pmid=33178422}} vascular malformations,{{Cite journal |last1=Wang |first1=Ling |last2=Duan |first2=Wei |last3=Zhao |first3=Yun |last4=Sun |first4=Guoqiang |last5=Lin |first5=Ying |last6=Gao |first6=Ying |date=2021-12-01 |title=The exposure levels of phthalates in pregnant women and impact factors of fetal malformation |url=https://journals.sagepub.com/doi/10.1177/09603271211049551?icid=int.sj-full-text.similar-articles.1& |journal=Human & Experimental Toxicology |language=EN |volume=40 |issue=12_suppl |pages=S622–S631 |doi=10.1177/09603271211049551 |pmid=34766523 |bibcode=2021HETox..40S.622W |issn=0960-3271}} decreased bodyweight and interuterine death at high concentrations. Higher concentrations of phthalates and phthalate metabolites have also been observed in the urine of mothers to children with neural tube malformations.

Phthalate exposure induces teratogenic effects through multiple mechanisms of action. High levels of di-(2-ethylhexyl)-phthalate create oxidative stress in utero, which results in cellular apoptosis in developing fetuses. In vivo, di-(2-ethylhexyl)-phthalate is hydrolyzed into 2-ethylhexanol. It's hypothesized that the metabolic byproduct of 2-ethylhexanol, ethylhexanoic acid, is the primary teratogen responsible for developmental defects in embryos exposed to di-(2-ethylhexyl)-phthalate.{{Cite journal |last1=Ritter |first1=E. J. |last2=Scott Jr. |first2=W. J. |last3=Randall |first3=J. L. |last4=Ritter |first4=J. M. |date=1987 |title=Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/tera.1420350107 |journal=Teratology |language=en |volume=35 |issue=1 |pages=41–46 |doi=10.1002/tera.1420350107 |pmid=3105103 |issn=1096-9926}}

The use of di-n-butyl phthalate in children's products was restricted in the United States in 2008, and is restricted in cosmetics in the European Union. Several phthalates, including di-n-butyl phthalate, di-n-hexyl phthalate, and butyl benzyl phthalate, were issued a Proposition 65 warning by the state of California in March, 2005 following evidence of reproductive toxicity and teratogenic effects.{{Cite web |date=December 2, 2005 |title=Chemicals Listed Effective December 2, 2005 as Known to the State of California to Cause Reproductive Toxicity |url=https://oehha.ca.gov/proposition-65/crnr/chemicals-listed-effective-december-2-2005-known-state-california-cause-reproductive-toxicity#:~:text=Related%20Notices%20*%20Notice%20of%20Intent%20to,Information%20on%20Five%20Chemicals.%20May%2028%2C%202004. |access-date=25 April 2025 |website=State of California OEHHA}}

Maternal stress has been associated with an increased risk of various birth defects, though a direct causal relationship has not been conclusively established. Studies suggest that the exposure to significant psychological stress or traumatic events during pregnancy may correlate with a higher incidence of congenital anomalies, such as oral facial cleft (cleft lip and palate), neural tube defects and conotruncal heart defects.{{Cite journal |last1=Carmichael |first1=Suzan L. |last2=Shaw |first2=Gary M. |last3=Yang |first3=Wei |last4=Abrams |first4=Barbara |last5=Lammer |first5=Edward J. |date=May 2007 |title=Maternal Stressful Life Events and Risks of Birth Defects |journal=Epidemiology |volume=18 |issue=3 |pages=356–361 |doi=10.1097/01.ede.0000259986.85239.87 |pmc=2094125 |pmid=17435445}} One proposed mechanisms involves the dysregulation of maternal stress hormones, particularly glucocorticoids, which include cortisol and other corticosteroids. These hormones, often referred to as "stress hormones", are capable of crossing the placental barrier, but their effects on the fetus depends on the timing, duration, and intensity of exposure.{{Cite web |title=Stress and the Placenta |url=https://www.ohsu.edu/school-of-medicine/moore-institute/stress-and-placenta |access-date=2025-03-20 |website=www.ohsu.edu |language=en}} The placenta expresses various enzymes, which metabolizes active cortisol into its inactive form, protecting the fetus. However extreme physiological responses or chronic stress could overwhelm this protective factor. Additionally, stress-induced changes in maternal physiology, such as reduced uteroplacental blood flow, inflammation, and oxidative stress, may further contribute to developmental disruptions.{{Cite journal |last1=Seckl |first1=Jonathan R. |last2=Holmes |first2=Megan C. |date=June 2007 |title=Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology |journal=Nature Clinical Practice. Endocrinology & Metabolism |volume=3 |issue=6 |pages=479–488 |doi=10.1038/ncpendmet0515 |pmid=17515892}} Sometimes, corticosteroids are used therapeutically to promote fetal lung maturation in preterm labor, excessive or prolonged exposure has been linked to intrauterine growth restriction and altered fetal programming.{{cite journal |last1=DiPietro |first1=Janet A. |last2=Costigan |first2=Kathleen A. |last3=Gurewitsch |first3=Edith D. |date=April 2005 |title=Maternal psychophysiological change during the second half of gestation |journal=Biological Psychology |volume=69 |issue=1 |pages=23–38 |doi=10.1016/j.biopsycho.2004.11.003 |pmid=15740823}} Further research is needed to clarify the exact role of maternal stress in teratogenesis and to determine the potential long-term impacts on offspring health.

Micronutrient deficiencies during pregnancy can contribute to teratogenesis by disrupting essential developmental processes. Deficiencies in folate, iodine, vitamin A, and other key nutrients have been linked to congenital anomalies, miscarriage, and impaired fetal growth. These deficiencies impair cellular differentiation, gene expression, and organogenesis, making proper maternal nutrition crucial for fetal development. Prevention strategies include dietary supplementation and food fortification programs to reduce the incidence of birth defects worldwide.{{Cite journal |last1=Gernand |first1=Alison D. |last2=Schulze |first2=Kerry J. |last3=Stewart |first3=Christine P. |last4=West |first4=Keith P. |last5=Christian |first5=Parul |date=May 2016 |title=Micronutrient deficiencies in pregnancy worldwide: health effects and prevention |journal=Nature Reviews. Endocrinology |volume=12 |issue=5 |pages=274–289 |doi=10.1038/nrendo.2016.37 |pmc=4927329 |pmid=27032981}}

Folate deficiency increases the risk of neural tube defects. It has been shown that supplementation of folate before, during, and after conception is able to reduce the risk of a fetus developing neural tube defects, cardiovascular malformations, cleft lip and palate, urogenital abnormalities, and reduced limb size.{{Cite journal |last1=Safi |first1=J. |last2=Joyeux |first2=L. |last3=Chalouhi |first3=G. E. |date=2012 |title=Periconceptional Folate Deficiency and Implications in Neural Tube Defects |journal=Journal of Pregnancy |language=en |volume=2012 |issue=1 |pages=295083 |doi=10.1155/2012/295083 |doi-access=free |issn=2090-2735 |pmc=3415073 |pmid=22900183}}

In mothers, an iodine deficiency can lead to hypothyroidism, increasing the chances for miscarriage to occur.{{Citation |title=Iodine |date=1994 |work=Mother To Baby {{!}} Fact Sheets |url=https://www.ncbi.nlm.nih.gov/books/NBK582771/ |access-date=2025-04-23 |place=Brentwood (TN) |publisher=Organization of Teratology Information Specialists (OTIS) |pmid=35952044}} Hypothyroidism can also potentially cause growth problems in the baby, increasing the chances for preterm delivery. If the iodine deficiency is severe, the likelihood of stillbirth is increased as well as the child having the potential for increased hearing problems. Iodine deficiency has been associated with craniofacial and heart defects. The most severe cases of iodine deficiency caused hypothyroidism can result in cretinism.{{Cite journal |last=Zimmermann |first=Michael B. |date=July 2012 |title=The Effects of Iodine Deficiency in Pregnancy and Infancy |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-3016.2012.01275.x |journal=Paediatric and Perinatal Epidemiology |language=en |volume=26 |issue=s1 |pages=108–117 |doi=10.1111/j.1365-3016.2012.01275.x |pmid=22742605 |issn=0269-5022}}

Zinc deficiency can result in fetal death, intrauterine growth retardation, and teratogenesis.{{Cite journal |last1=Uriu-Adams |first1=Janet Y. |last2=Keen |first2=Carl L. |date=2010 |title=Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development |url=https://onlinelibrary.wiley.com/doi/10.1002/bdrb.20264 |journal=Birth Defects Research Part B: Developmental and Reproductive Toxicology |language=en |volume=89 |issue=4 |pages=313–325 |doi=10.1002/bdrb.20264 |pmid=20803691 |issn=1542-9741}} It can also have postnatal effects, such as behavioral abnormalities, elevated risk of high blood pressure, or impaired cognitive abilities.

{{Further|Paleopathology}}

Evidence for congenital deformities found in the fossil record is studied by paleopathologists, specialists in ancient disease and injury. Fossils bearing evidence of congenital deformity are scientifically significant because they can help scientists infer the evolutionary history of life's developmental processes. For instance, because a Tyrannosaurus rex specimen has been discovered with a block vertebra, it means that vertebrae have been developing the same basic way since at least the most recent common ancestor of dinosaurs and mammals. Other notable fossil deformities include a hatchling specimen of the bird-like dinosaur, Troodon, the tip of whose jaw was twisted.{{cite book |last1=Molnar |first1=R. E. |chapter=Theropod paleopathology: a literature survey |pages=337–363 |editor1-last=Tanke |editor1-first=Darren H |editor2-last=Carpenter |editor2-first=Kenneth |title=Mesozoic Vertebrate Life |date=2001 |publisher=Indiana University Press |isbn=978-0-253-33907-2 }} Another notably deformed fossil was a specimen of the Choristodera Hyphalosaurus, which had two heads- the oldest known example of polycephaly.{{cite journal | vauthors = Ji Q, Wu XC, Cheng YN | title = Cretaceous choristoderan reptiles gave birth to live young | journal = Die Naturwissenschaften | volume = 97 | issue = 4 | pages = 423–428 | date = April 2010 | pmid = 20179895 | doi = 10.1007/s00114-010-0654-2 | bibcode = 2010NW.....97..423J }}

Thalidomide is a teratogen known to be significantly detrimental to organ and limb development during embryogenesis.{{cite journal | vauthors = Vargesson N | title = Thalidomide-induced teratogenesis: history and mechanisms | journal = Birth Defects Research. Part C, Embryo Today | volume = 105 | issue = 2 | pages = 140–156 | date = June 2015 | pmid = 26043938 | pmc = 4737249 | doi = 10.1002/bdrc.21096 | doi-access = free }} It has been observed in chick embryos that exposure to thalidomide can induce limb outgrowth deformities, due to increased oxidative stress interfering with the Wnt signaling pathway, increasing apoptosis, and damaging immature blood vessels in developing limb buds.{{cite journal | vauthors = Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N | title = Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 21 | pages = 8573–8578 | date = May 2009 | pmid = 19433787 | pmc = 2688998 | doi = 10.1073/pnas.0901505106 | doi-access = free | bibcode = 2009PNAS..106.8573T }}{{cite journal | vauthors = Knobloch J, Shaughnessy JD, Rüther U | title = Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway | journal = FASEB Journal | volume = 21 | issue = 7 | pages = 1410–1421 | date = May 2007 | pmid = 17283219 | doi = 10.1096/fj.06-7603com | doi-access = free }}

Retinoic acid (RA) is significant in embryonic development. It induces the function of limb patterning of a developing embryo in species such as mice and other vertebrate limbs.{{cite journal | vauthors = Yashiro K, Zhao X, Uehara M, Yamashita K, Nishijima M, Nishino J, Saijoh Y, Sakai Y, Hamada H | title = Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb | journal = Developmental Cell | volume = 6 | issue = 3 | pages = 411–422 | date = March 2004 | pmid = 15030763 | doi = 10.1016/S1534-5807(04)00062-0 | doi-access = free }} For example, during the process of regenerating a newt limb an increased amount of RA moves the limb more proximal to the distal blastoma and the extent of the proximalization of the limb increases with the amount of RA present during the regeneration process. A study looked at the RA activity intracellularly in mice in relation to human regulating CYP26 enzymes which play a critical role in metabolizing RA. This study also helps to reveal that RA is significant in various aspects of limb development in an embryo, however irregular control or excess amounts of RA can have teratogenic impacts causing malformations of limb development. They looked specifically at CYP26B1 which is highly expressed in regions of limb development in mice. The lack of CYP26B1 was shown to cause a spread of RA signal towards the distal section of the limb causing proximo-distal patterning irregularities of the limb. Not only did it show spreading of RA but a deficiency in the CYP26B1 also showed an induced apoptosis effect in the developing mouse limb but delayed chondrocyte maturation, which are cells that secrete a cartilage matrix which is significant for limb structure. They also looked at what happened to development of the limbs in wild type mice, that are mice with no CYP26B1 deficiencies, but which had an excess amount of RA present in the embryo. The results showed a similar impact to limb patterning if the mice did have the CYP26B1 deficiency meaning that there was still a proximal distal patterning deficiency observed when excess RA was present. This then concludes that RA plays the role of a morphogen to identify proximal distal patterning of limb development in mice embryos and that CYP26B1 is significant to prevent apoptosis of those limb tissues to further proper development of mice limbs in vivo.{{citation needed|date=January 2025}}

There has been evidence of teratogenic effects of lead in rats as well. An experiment was conducted where pregnant rats were given drinking water, before and during pregnancy, that contained lead. Many detrimental effects, and signs of teratogenesis were found, such as negative impacts on the formation of the cerebellum, fetal mortality, and developmental issues for various parts of the body.{{cite journal | vauthors = Mousa AM, Al-Fadhli AS, Rao MS, Kilarkaje N | title = Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats | journal = Drug and Chemical Toxicology | volume = 38 | issue = 1 | pages = 73–83 | date = January 2015 | pmid = 24724870 | doi = 10.3109/01480545.2014.907578 }}

In botany, teratology investigates the theoretical implications of abnormal specimens. For example, the discovery of abnormal flowers—for example, flowers with leaves instead of petals, or flowers with staminoid pistils—furnished important evidence for the "foliar theory", the theory that all flower parts are highly specialised leaves.{{cite book |doi=10.1093/acprof:oso/9780199661596.003.0002 |chapter=Historical interpretations of flower induction and flower development |title=Understanding Flowers and Flowering, Second Edition |date=2014 |pages=16–26 |isbn=978-0-19-966159-6 | vauthors = Glover B }} In plants, such specimens are denoted as 'lusus naturae' ('sports of nature', abbreviated as 'lus.'); and occasionally as 'ter.', 'monst.', or 'monstr.'.{{cite journal |last1=Vázquez |first1=Francisco María |title=(023–024) Proposals to add a new Article and some Examples under Article 5 |journal=Taxon |date=October 2014 |volume=63 |issue=5 |pages=1142 |doi=10.12705/635.21 |bibcode=2014Taxon..63.1142V }}

Plants can have mutations that leads to different types of deformations such as:{{citation needed|date=January 2025}}

• Fasciation: Development of the apex (growing tip) in a flat plane perpendicular to the axis of elongation
• Variegation: Degeneration of genes, manifesting itself among other things by anomalous pigmentation
• Virescence: Anomalous development of a green pigmentation in unexpected parts of the plant
• Phyllody: Floral organs or fruits transformed into leaves
• Witch's broom: Unusually high multiplication of branches in the upper part of the plant, mainly in a tree
• Pelorism: Zygomorphic flower regress to their ancestral actinomorphic symmetry
• Proliferation: Repetitive growth of an entire organ, such as a flower

Studies designed to test the teratogenic potential of environmental agents use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early teratologists exposed pregnant animals to environmental agents and observed the fetuses for gross visceral and skeletal abnormalities. While this is still part of the teratological evaluation procedures today, the field of Teratology is moving to a more molecular level, seeking the mechanism(s) of action by which these agents act. One example of this is the use of mammalian animal models to evaluate the molecular role of teratogens in the development of embryonic populations, such as the neural crest,{{cite journal | vauthors = Cerrizuela S, Vega-Lopez GA, Aybar MJ | title = The role of teratogens in neural crest development | journal = Birth Defects Research | volume = 112 | issue = 8 | pages = 584–632 | date = May 2020 | pmid = 31926062 | doi = 10.1002/bdr2.1644 }} which can lead to the development of neurocristopathies. Genetically modified mice are commonly used for this purpose. In addition, pregnancy registries are large, prospective studies that monitor exposures women receive during their pregnancies and record the outcome of their births. These studies provide information about possible risks of medications or other exposures in human pregnancies. Prenatal alcohol exposure (PAE) can produce craniofacial malformations, a phenotype that is visible in Fetal Alcohol Syndrome. Current evidence suggests that craniofacial malformations occur via: apoptosis of neural crest cells,{{cite journal | vauthors = Sulik KK, Cook CS, Webster WS | title = Teratogens and craniofacial malformations: relationships to cell death | journal = Development | volume = 103 | issue = Suppl | pages = 213–231 | date = 1988 | pmid = 3074910 | doi = 10.1242/dev.103.Supplement.213 | url = https://cdr.lib.unc.edu/downloads/f7623n81g }} interference with neural crest cell migration,{{cite journal | vauthors = Shi Y, Li J, Chen C, Gong M, Chen Y, Liu Y, Chen J, Li T, Song W | title = 5-Mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities | journal = Molecular Brain | volume = 7 | issue = 67 | pages = 67 | date = September 2014 | doi = 10.1186/s13041-014-0067-9 | doi-access = free | pmid = 25223405 | pmc = 4172781 }}{{cite journal | vauthors = Cartwright MM, Smith SM | title = Stage-dependent effects of ethanol on cranial neural crest cell development: partial basis for the phenotypic variations observed in fetal alcohol syndrome | journal = Alcoholism: Clinical and Experimental Research | volume = 19 | issue = 6 | pages = 1454–1462 | date = December 1995 | pmid = 8749810 | doi = 10.1111/j.1530-0277.1995.tb01007.x }} as well as the disruption of sonic hedgehog (shh) signaling.{{cite journal |last1=Boschen |first1=Karen E. |last2=Fish |first2=Eric W. |last3=Parnell |first3=Scott E. |title=Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube |journal=Reproductive Toxicology |date=October 2021 |volume=105 |pages=136–147 |doi=10.1016/j.reprotox.2021.09.002 |pmid=34492310 |pmc=8529623 |bibcode=2021RepTx.105..136B }}

Understanding how a teratogen causes its effect is not only important in preventing congenital abnormalities but also has the potential for developing new therapeutic drugs safe for use with pregnant women.{{citation needed|date=January 2025}}

{{portal|Biology|Medicine}}

• Carcinogen
• Congenital abnormalities
• Mutagen
• Polydactyly
• Retinoic acid
• Teratoma
• Thalidomide

{{Reflist}}

• {{cite book |last1=Gilbert |first1=Scott F. |title=Ecological Developmental Biology |date=2015 |publisher=Sinauer |isbn=978-1-60535-344-9 }}

{{Commons category}}

• [http://www.teratology.org/ Society of Teratology]
• [http://www.etsoc.com/ European Teratology Society] {{Webarchive|url=https://web.archive.org/web/20100405220820/http://www.etsoc.com/ |date=5 April 2010 }}
• [http://www.otispregnancy.org/ Organization of Teratology Information Specialists]
• [http://www.marchofdimes.org/ March of Dimes Foundation]
• [https://web.archive.org/web/20131212054644/http://www.nyam.org/library/rare-book-room/exhibits/telling-of-wonders/ A Telling of Wonders: Teratology in Western Medicine through 1800 (New York Academy of Medicine Historical Collections)]
• [http://www.reprotox.org/ The Reproductive Toxicology Center Database]

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