Fetal warfarin syndrome is a disorder of the embryo which occurs in a child whose mother took the medication

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

(brand name: Coumadin) during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

. Resulting abnormalities include

low birth weight Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an infant of or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal inten ...

, slower growth,

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...

, small head size, and malformed

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s, cartilage, and

joints A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...

.Yurdakök, M. 2012, "Fetal and neonatal effects of anticoagulants used in pregnancy: a review", ''The Turkish journal of pediatrics'', vol. 54, no. 3, pp. 207. Warfarin is an oral anticoagulant drug (blood thinner) used to reduce blood clots,

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...

, and

embolism An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel. The embolus may be a blood clot (thrombus), a fat globule (fat embolism), a bubble of air or other gas ( gas embolism), amniotic fluid (am ...

in people with prosthetic heart valves, atrial fibrillation, or those who have had

ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop funct ...

.Reid, A., Forrester, C. & Shwe, K. 2009, "Warfarin", ''Student BMJ'', vol. 17. Warfarin blocks the action of

vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...

, causing an inhibition of blood

clotting factors Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

and the pro-bone-building

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...

osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein. Because osteocalcin has g ...

. Warfarin is a teratogen which can cross from the mother to the developing

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

. The inhibition of clotting factors can lead to

internal bleeding Internal bleeding (also called internal hemorrhage) is a loss of blood from a blood vessel that collects inside the body. Internal bleeding is usually not visible from the outside. It is a serious medical emergency but the extent of severity dep ...

of the fetus while the inhibition of osteocalcin causes lower bone growth. As well as birth defects, warfarin can induce spontaneous

abortion Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pre ...

or stillbirth.Hou, J. 2004, "Fetal warfarin syndrome", ''Chang Gung medical journal'', vol. 27, no. 9, pp. 691. Because of this, warfarin is

contraindicated In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

during pregnancy.

Signs and symptoms

The key symptoms, visible at birth, vary between individuals exposed to warfarin ''

in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albin ...

''. The severity and occurrence of symptoms is dose dependent with higher doses (>5 mg warfarin daily) more likely to cause immediately noticeable defects.Vitale, N., De Feo, M., De Santo, L.S., Pollice, A., Tedesco, N. & Cotrufo, M. 1999, "Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves", ''Journal of the American College of Cardiology'', vol. 33, no. 6, pp. 1637-1641. The period of pregnancy in which warfarin is administered can affect the category of defects which develop. Warfarin taken in the

first trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

of pregnancy is more likely to result in physical abnormalities while warfarin taken in the second and

third trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but can ...

more commonly causes abnormalities of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. The more extreme symptoms such as severe intellectual disability,

blindness Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...

and deafness occur more often when warfarin is used throughout all three trimesters.

Growth

Babies born with fetal warfarin syndrome may have a below-average birth weight and do continue to grow at a reduced rate.Starling, L.D., Sinha, A., Boyd, D. & Furck, A. 2012, "Fetal warfarin syndrome", ''BMJ case reports'', vol. 2012, no. 1, pp. 1-4

Facial features

Children with fetal warfarin syndrome show many otolaryngological abnormalities consistent with abnormal bone and cartilage growth. Children may present with hypoplasia of the nasal ridge and a deep groove at the midline of the nose, thinned or absent

nasal septum The nasal septum () separates the left and right airways of the nasal cavity, dividing the two nostrils. It is depressed by the depressor septi nasi muscle. Structure The fleshy external end of the nasal septum is called the columella or co ...

,Silveira, D.B., da Rosa, E.B., de Mattos, V.F., Goetze, T.B., Sleifer, P., Santa Maria, F.D., Rosa, R.C.M., Rosa, R.F.M. & Zen, P.R.G. 2015, "Importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome", ''American Journal of Medical Genetics Part A'', vol. 167, no. 6, pp. 1294-1299.

choanal atresia Choanal atresia is a congenital disorder where the back of the nasal passage (choana) is blocked, usually by abnormal bony or soft tissue (membranous) due to failed hole development of the nasal fossae during prenatal development. It causes persi ...

; a narrowing the airway at the posterior

nasal cavity The nasal cavity is a large, air-filled space above and behind the human nose, nose in the middle of the face. The nasal septum divides the cavity into two cavities, also known as fossae. Each cavity is the continuation of one of the two nostrils. ...

cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...

and

laryngomalacia Laryngomalacia (literally, "soft larynx") is the most common cause of chronic stridor in infancy, in which the soft, immature cartilage of the upper larynx collapses inward during inhalation, causing airway obstruction. It can also be seen in o ...

; large soft protrusions into the larynx. These facial defects and narrowing of the airways often lead to

respiratory distress Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

, noisy breathing and later; speech defects. Narrow airways often widen with age and allow for easier breathing. Dental problems are also seen with abnormally large dental buds and late eruption of deciduous teeth. Development of the eyes is also affected by warfarin. Microphthalmia; abnormally small eyes,

telecanthus Telecanthus, or dystopia canthorum, refers to increased distance between the inner corners of the eyelids (medial canthi), while the inter-pupillary distance is normal. This is in contrast to hypertelorism, in which the distance between the w ...

; abnormally far apart eyes and

strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

; misaligned or crossed eyes are common signs of fetal warfarin syndrome. The appearance of an ectopic lacrimal duct, where the tear duct protrudes laterally onto the eye has also been noted.

Bodily features

Whole body skeletal abnormalities are common in fetal warfarin syndrome. A generalized reduction in bone size causes

rhizomelia Rhizomelia refers to either a disproportion of the length of the proximal limb, such as the shortened limbs of achondroplasia, or some other disorder of the hip or shoulder. According to Stedman's medical dictionary "rhizomelic" means "relating to ...

; disproportionally short limbs,

brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...

; short fingers and toes, a shorter neck, short trunk, scoliosis; abnormal curvature of the spine and stippled epiphyses; malformation of joints. Abnormalities of the chest: either

pectus carinatum Pectus carinatum, also called pigeon chest, is a malformation of the chest characterized by a protrusion of the sternum and ribs. It is distinct from the related malformation pectus excavatum. Signs and symptoms People with pectus carinatum usua ...

; a protruding sternum, or

pectus excavatum Pectus excavatum is a structural deformity of the anterior thoracic wall in which the sternum and rib cage are shaped abnormally. This produces a caved-in or sunken appearance of the chest. It can either be present at birth or develop after pubert ...

; a sunken sternum form an immediately recognizable sign of fetal warfarin syndrome.

Congenital heart defects A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

such as a thinned

atrial septum The interatrial septum is the wall of tissue that separates the right and left atria of the heart. Structure The interatrial septum is a that lies between the left atrium and right atrium of the human heart. The interatrial septum lies at angl ...

coarctation of the aorta Coarctation of the aorta (CoA or CoAo), also called aortic narrowing, is a congenital condition whereby the aorta is narrow, usually in the area where the ductus arteriosus (ligamentum arteriosum after regression) inserts. The word ''coarctation' ...

patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...

; a connection between the pulmonary artery and aorta occur in 8% of fetal warfarin syndrome patients. Situs inversus totalis, the complete left-right mirroring of thoracic organs, has also been observed

CNS

Defects of the central nervous system can lead to profound intellectual disabilities. Fetal warfarin syndrome can lead to

microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...

; an abnormally small head, hydrocephaly; increased ventricle size and CSF volume, and agenesis of the corpus callosum. These defects contribute to the appearance of significant intellectual disability in 31% of fetal warfarin syndrome cases.

Hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

, whole body muscle relaxation, can appear in

newborns An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used t ...

with severe nervous deficits. Atrophy of the

optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual information from the retina to the brain. In humans, the optic nerve is derived fro ...

can also cause blindness in fetal warfarin syndrome.Raghav, S. & Reutens, D. 2006;2007;, "Neurological sequelae of intrauterine warfarin exposure", ''Journal of Clinical Neuroscience'', vol. 14, no. 2, pp. 99-103.

Physiological

Inhibition of coagulation and resultant internal bleeding can cause too few red blood cells to be present in the bloodstream and

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

in newborns with fetal warfarin syndrome. Low

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...

levels can lead to partial oxygen starvation, a high level of

lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as nat ...

in the bloodstream, and

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describes ...

. Prolonged oozing of fluid from the stump of the cut

umbilical cord In placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord is physiologi ...

is common.

Cause

Fetal warfarin syndrome appears in greater than 6% of children whose mothers took warfarin during pregnancy. Warfarin has a low

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

so can pass from the maternal to fetal bloodstream through the tight filter-like junctions of the

placental barrier The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate materna ...

. As the teratogenic effects of warfarin are well known, the medication is rarely prescribed to pregnant women. However, for some patients, the risks associated with discontinuing warfarin use may outweigh the risk of embryopathy. Patients with prosthetic heart valves carry a particularly high risk of thrombus formation due to the inorganic surface and

turbulent In fluid dynamics, turbulence or turbulent flow is fluid motion characterized by chaotic changes in pressure and flow velocity. It is in contrast to a laminar flow, which occurs when a fluid flows in parallel layers, with no disruption between ...

blood flow generated by a mechanical prosthesis. The risk of blood clotting is further increased by generalized

hypercoagulability Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...

as concentrations of clotting factors rise during pregnancy.Maiello, M., Torella, M., Caserta, L., Caserta, R., Sessa, M., Tagliaferri, A., Bernacchi, M., Napolitano, M., Nappo, C., De Lucia, D. & Panariello, S. 2006, "Hypercoagulability during pregnancy: evidences for a thrombophilic state", ''Minerva ginecologica'', vol. 58, no. 5, pp. 417. This increased chance of blood clots leads to an increased risk of potentially fatal pulmonary or systemic emboli cutting off blood flow and oxygen to critical organs. Thus, some patients may continue taking warfarin throughout the pregnancy despite the risks to the developing child.

Mechanism

Warfarin's ability to cause fetal warfarin syndrome ''in utero'' stems from its ability to limit

activation. Warfarin binds to and blocks the enzyme Vitamin K epoxide reductase which is usually responsible for activating vitamin K during vitamin K recycling. Vitamin K, once activated, is able to add a carboxylic acid group to glutamate residues of certain proteins which assists in correct

protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...

.Danziger, J. 2008, "Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification", ''Clinical Journal of the American Society of Nephrology'', vol. 3, no. 5, pp. 1504-1510. Without active vitamin K, a fetus exposed to warfarin is unable to produce large quantities of

clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

and

growth factors. Without vitamin K, clotting factors II, VII, IX and X are unable to be produced. Without these vital parts of the

coagulation cascade Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...

a durable fibrin plug cannot form to block fluid escaping from damaged or permeable

vasculature The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

. Anemia is common in fetuses exposed to warfarin as blood constantly seeps into the

interstitial fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

amniotic cavity The amniotic sac, also called the bag of waters or the membranes, is the sac in which the embryo and later fetus develops in amniotes. It is a thin but tough transparent pair of membranes that hold a developing embryo (and later fetus) until shor ...

. High doses of warfarin and heavy bleeding lead to abortion and stillbirth.

Osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein. Because osteocalcin has g ...

is another protein dependent on vitamin K for correct folding and function. Osteocalcin is normally secreted by osteoblast cells and plays a role in aiding correct bone mineralization and bone maturation.Yamauchi, M., Yamaguchi, T., Nawata, K., Takaoka, S. & Sugimoto, T. 2010, "Relationships between undercarboxylated osteocalcin and vitamin K intakes, bone turnover, and bone mineral density in healthy women", ''Clinical Nutrition'', vol. 29, no. 6, pp. 761-765. In the presence of warfarin and subsequent absence of vitamin K and active osteocalcin, bone mineralization and growth are stunted.

Prevention

Fetal warfarin syndrome is prevented by withholding prescription to pregnant women or those trying to

conceive Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...

. As warfarin can remain in the mother's body for up to five days,Walfisch, A. & Koren, G. 2010, "The "Warfarin Window" in Pregnancy: The Importance of Half-life", ''Journal of obstetrics and gynaecology Canada'', vol. 32, no. 10, pp. 988. warfarin should not be administered in the days leading up to conception. Doctors must take care to ensure women of reproductive age are aware of the risks to the baby should they get pregnant, before prescribing warfarin. For some women, such as those with prosthetic heart valves, anticoagulation medication cannot be suspended during pregnancy as the risk of thrombus and emboli is too high. In such cases an alternate anticoagulant, which cannot pass through the placental barrier to the fetus, is proscribed in place of warfarin. Heparin is one such anticoagulant medication, although its efficacy in patients with prosthetic heart valves is not well established.Loftus, C. (1996). ''Neurosurgical aspects of pregnancy''. Park Ridge, Ill.: American Association of Neurological Surgeons. New anticoagulant medications, which are efficacious and non-teratogenic such as ximelagatran continue to be developed.

Management

Medication

As well as the routine dose of vitamin K given to newborns after birth, babies born with fetal warfarin syndrome are given additional doses intramuscularly to overcome any remaining warfarin in the circulation and prevent further bleeding.

Fresh frozen plasma Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the re ...

is also administered to raise concentrations of active blood clotting factors. If the child is anemic from extensive bleeding ''in-utero'', red blood cell concentrate is given to restore oxygen carrying capacity.

Surgical correction

Surgical interventions can be given to improve functionality and correct cosmetic abnormalities.

Osteotomy An osteotomy is a surgical operation whereby a bone is cut to shorten or lengthen it or to change its alignment. It is sometimes performed to correct a hallux valgus, or to straighten a bone that has healed crookedly following a fracture. It is ...

(bone cutting) and zetaplasty surgeries are used to cut away abnormal tissue growths at the piriform aperture around and

pharynx The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its st ...

to reduce airway obstruction.

Rhinoplasty Rhinoplasty ( grc, ῥίς, rhī́s, nose + grc, πλάσσειν, plássein, to shape), commonly called nose job, medically called nasal reconstruction is a plastic surgery procedure for altering and reconstructing the nose. There are two typ ...

surgery is used to restore normal appearance and function of the nose.

Heart surgery Cardiac surgery, or cardiovascular surgery, is surgery on the heart or great vessels performed by cardiac surgeons. It is often used to treat complications of ischemic heart disease (for example, with coronary artery bypass grafting); to corr ...

may also be required to close a

References

External links

Datagenno - Fetal Warfarin Syndrome
{{Congenital malformation due to exogenous toxicity Congenital malformation due to exogenous toxicity Syndromes