Embryology and Teratology Flashcards
- Which of the following class of medication is MOST likely to be the cause of renal failure and oligohydramnios when used in the second trimester of pregnancy?
A. Alcohol
B. SSRI
C. Antiepileptics
D. Retinoids
E. Angiotensin I converting enzyme (ACE) inhibitors
E. In-utero exposure to angiotensin I converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists during the second or third trimester of pregnancy is associated with an increased risk of fetal hypotension, renal failure, and oligohydramnios. This leads to fetal growth restriction, joint contractures, pulmonary hypoplasia, and stillbirth or neonatal death. Other anomalies such as calvarial hypoplasia have been reported. In children who survive the neonatal period, renal insufficiency often occurs. Exposure to ACE inhibitors in the first trimester has not been well studied but suggests an association with cardiovascular anomalies. Fetal alcohol syndrome (FAS) has been reported in offspring of alcoholic mothers. Features of FAS include prenatal and postnatal growth restriction. The criteria for the diagnosis of FAS is the presence of at least one from each of the following groups of characteristics: (1) Growth retardation before or after birth (2) Facial anomalies, including small palpebral fissures, indistinct or absent philtrum, epicanthal folds, flattened nasal bridge, low-set and unparallel ears, and abnormal midfacial development (3) Central nervous system dysfunction, including microcephaly, varying degrees of mental retardation, or other evidence of abnormal neurobehavioral development, such as ADHD. Full FAS occurs in about 6% of infants exposed infants of heavy alcohol drinkers. Other birth defects can occur in fetuses exposed to alcohol in utero such as genitourinary malformations, IUGR, abnormal neurologic exams, which are found in approximately 70% of fetuses exposed to heavy alcohol use in utero. There is no known safe amount of alcohol use in pregnancy. Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants (including such medications as fluoxetine, paroxetine, sertraline, citalopram, and escitalopram). Several studies have been conducted to evaluate whether or not these drugs are associated with an increased risk of cardiac malformation. However, a recent large cohort study including 950,000 pregnant women suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. Antiepileptic drugs generally fall into two categories: older generation and newer generation. The older generation drugs (such as Valproic acid, phenytoin, and carbamazepine) are associated with an increased risk of congenital malformation, specifically open neural tube defects (ONTDs), and cleft lip/palate. The newer generation antiepileptic drugs are also associated with ONTDs and clefts but to a lesser extent. Vitamin A (Retinol) is known to be teratogenic in animal models; however, the threshold for teratogenic effects in humans is controversial. The current recommended daily allowance for a singleton pregnancy is 2560 IU of vitamin A. Isotretinoin in the first trimester has been associated with CNS malformation, microtia/anotia, micrognathia, cleft palate, cardiac and great vessel defects, thymic abnormalities, eye anomalies, and limb reduction defects. In the second and third trimesters, exposure to isotretinoin has been linked to FGR, low birth weight, fetal arrhythmias, and decreased organ function.
- What is the MOST likely dose of ionizing radiation that would be associated with birth defects such as microcephaly, imparired brain function, and growth deficiency?
A. 0.25 rad
B. 0.5 rad
C. 5 rad
D. 25 rad
E. 50 rad
E. Very early in pregnancy, radiation is thought to have an “all-or-none effect.” The dose could be so high that a miscarriage ensues, or the fetus lives and there is no increased risk of anomalies. However, later in the first trimester/early second trimester (8 to 15 weeks), radiation can cause significant adverse effects including microcephaly, cognitive delay, and FGR. Unfortunately, our knowledge on this topic comes from studying pregnant women who survived the Nagasaki and Hiroshima attacks. Based on those reviews, approximately 50 rads or greater to the uterus is associated with the aforementioned effects. It is not thought that diagnostic procedures involving radiation have the potential to increase the risk to the fetus unless the cumulative dose to the uterus exceeds 10 rads; conservative guidelines suggest that doses should be kept below 5 rad to the uterus during pregnancy if radiation exposure is required. Common radiologic procedures and their approximate radiation doses include: abdominal x-ray - 100 mrad; CT of chest - < 1 rad; CT of abdomen - 3.5 rad.
What is the most likely abnormality in a child brown with micrognathia, deformed ears, and hearing loss?
A. 22q11 microdeletion
B. Abnormality in the 1st and 2nd branchial arches
C. Warfarin exposure
D. FGF3 mutation
. The branchial apparatus, consisting of (1) branchial arches, (2) pharyngeal pouches, (3) branchial grooves, and (4) branchial membranes, contributes to the formation of the head and neck. Most congenital malformations of the head and neck originate during transformation of the branchial apparatus into its adult derivatives. Abnormal development of the components of the first branchial arch results in malformations of the eyes, ears, mandible, and palate that together constitute the first arch syndrome. The two main manifestations of first arch syndrome include Treacher Collins syndrome and Pierre Robin syndrome. 22q11 microdeletion (velocardiofacial syndrome/DiGeorge syndrome) is associated with conotruncal cardiac anomalies, cleft palate, and thymic hypoplasia. Warfarin embryopathy includes abnormalities of the bone and cartilage, specifically, nasal and limb hypoplasia. Fibroblast growth factor receptor 3 (FGFR3) mutations can result in several skeletal dysplasias including isolated craniosynostosis, thanatophoric dysplasia, and some cases of hypochondroplasia.
First arch syndrome
. The two main manifestations of first arch syndrome include Treacher Collins syndrome and Pierre Robin syndrome
The branchial apparatus, consisting of (1) branchial arches, (2) pharyngeal pouches, (3) branchial grooves, and (4) branchial membranes, contributes to the formation of the head and neck. Most congenital malformations of the head and neck originate during transformation of the branchial apparatus into its adult derivatives. Abnormal development of the components of the first branchial arch results in malformations of the eyes, ears, mandible, and palate that together constitute the first arch syndrome.
Warfarin embryopathy
abnormalities of the bone and cartilage, specifically, nasal and limb hypoplasia
FGFR3 mutations
result in several skeletal dysplasias including isolated craniosynostosis, thanatophoric dysplasia, and some cases of hypochondroplasia
Which one of the following statements is FALSE?
A. Midgut herniation is abnormal once the crown-rump length is 40 mm or greater
B. The fetal stomach is visible by 10 weeks gestational age
C. The falx cerebri is present by 10 weeks gestational age
D. The fetal bladder is visualized by 12 weeks gestational age
E. The atria, ventricles, and atrioventricular valves are seen by 11 weeks gestation
A. Physiologic midgut herniation of the bowel into the base of the umbilical cord can be present before the crown-rump length (CRL) is 54 mm. After the CRL reaches 61 mm (approximately 12 completed weeks), persistent midgut herniation is abnormal. Between 54 and 61 mm, the significance of herniation is not clear and may represent a normal variant or early evidence of disease. The remaining answer choices are all accurate as written.
A small for gestational age neonate was noted to have nasal hypoplasia stippled epiphyses on x-ray, hydrocephalus, and cataracts. Exposure to which of the following in the first trimester can cause this constellation of findings?
A. Valproic acid
B. Isotretinoin
C. Ethanol
D. Vitamin K antagonist
E. Methotrexate
. Vitamin K antagonists freely cross the placenta and are known teratogens. Warfarin, the most commonly used vitamin K antagonist, is associated with a well-described pattern of abnormalities when the fetus is exposed at 6 to 12 weeks of gestation. Estimates of the incidence of warfarin embryopathy among fetuses exposed at 6 to 12 weeks vary from 10% to 30%. The risk appears directly correlated with maternal dose (not INR), with daily doses >5 mg posing a higher risk. Among women who stop warfarin before 6 weeks of gestation, embryopathy is extremely rare. In women with mechanical heart valves requiring vitamin K antagonist anticoagulation, switching to unfractionated heparin or LMWH from 6 to 12 weeks of gestation with a resumption of warfarin thereafter can be considered after careful maternal counseling about the relative risks/benefits. Doing so has been associated with a low risk for warfarin embryopathy.
The other answer choices represent known teratogens as well, but the fetal effects of each are different than that of the described neonate. Valproic acid has been associated with facial abnormalities such as midface hypoplasia and broad nasal bridge as well as hyperconvex fingernails. Isotretinoin, an active ingredient in certain acne medications, has been associated with fetal CNS malformations, ear abnormalities, micrognathia, cleft palate, and heart defects. Ethanol is associated with fetal alcohol syndrome (FAS), with its characteristic facies (smooth philtrum, short palpebral fissures, thin vermilion of the upper lip, microcephaly) and behavioral/cognitive deficiencies. Methotrexate exposure has been associated with fetal growth restriction, calvarial ossification abnormalities, micrognathia, and limb abnormalities.
A woman with seizure disorder taking carbamazepine presents for preconception counseling. What is the time period when carbamazepine exposure is most likely to inhibit neural tube closure in the human embryo, in days after conception?
A. 14 to 21 days
B. 21 to 28 days
C. 28 to 35 days
D. 30 to 40 days
B. The time period for an agent to inhibit neural tube closure in the human embryo is approximately 21 to 28 days after conception. Carbamazepine is an anticonvulsant that increases the risks of neural tube defects (NTDs) up to 10-fold. Exposure after the second month of pregnancy can result in NTDs. Carbamazepine has also been associated with other abnormalities such as upslanting palpebral fissures, a long philtrum, nail hypoplasia, microcephaly, and growth restriction.
. Which of the following drugs is not safe while breastfeeding?
A. Enalapril
B. Warfarin
C. Citalopram
D. Iodine
D. It is important to note that many medications that are not safe in pregnancy may be safe during lactation. There are few cellular pumps that are known in human milk drug transfer. The iodine pump in human milk is similar to the pump in the thyroid gland, to ensure that the infant receives iodine. Iodide concentrates in milk because of this pump. Iodides (ionic forms of iodine) should be avoided because the concentrations in milk are very high. High levels of iodine may result in significant thyroid depression in infants. Hale TW, Rowe HE. Medications and Mothers’ Milk. 2014.
The following pattern of anomalies – oral cleft, growth restriction, microcephaly, hypoplasia of digits and nails, short nasal bone, ocular hypertelorism, abnormal ears, prominent upper lip, and urogenital anomalies – is associated with prenatal exposure of ____ occurring in up to ___ fold of the exposed?
A. Valproic acid___3
B. Methorexate ___2
C. SSRIs___3
D. Phenytoin ___2
E. Coriticosteroids___3
D. Phenytoin has been used as an antiepileptic since 1938. Its half-life varies between 20 to 50 hours and it accumulates in fatty tissue. Its plasma concentration is lowered during pregnancy, which in part decreases the seizure threshold. Early reports on the teratogenicity of the drug indicate that up to 10% of infants prenatally exposed to the drug show a pattern of malformations termed fetal hydantoin syndrome. Newer reports show that the effects of the drug likely do not exceed two-fold that of the background risk, especially if used as monotherapy. Unfortunately, the significant impact of maternal epilepsy on embryologic development cannot be excluded from the current studies available. Additionally, newborns exposed in utero to phenytoin can develop clotting problems due to vitamin K deficiency. Phenytoin is not the drug of choice for reproductive-age women starting treatment. However, it can be continued in some instances if risks/ benefits are appropriately discussed. Monotherapy should be the goal with the use of the lowest efficacious dose.
A 36 year old G2P1001 has an ultrasound at 18 weeks of gestation. Ultrasonography demonstrates ventriculomegaly and intracranial calcifications. She denies any history of recent illness. Initial testing returns the following results: low-risk noninvasive prenatal screening (cell-free DNA), CMV IgG positive and IgM negative, and toxoplasmosis IgG positive and IgM positive. Which of the following options would be the most appropriate next step for determining diagnosis?
D. Toxoplasma gondii is a protozoan that is dependent on cats, which are the only host for the oocyst. Mammals can ingest the oocyst, which can be infected by the trophozoite. Human infection can occur when infected meat is ingested or when food is contaminated by cat feces via flies, fingers, etc. Most infections in immunocompetent humans are asymptomatic, but congenital infection can occur if a woman develops acute primary toxoplasmosis during pregnancy. Up to 50% of neonates born to mothers with acute toxoplasmosis show evidence of infection. Ultrasound findings suggestive of congenital toxoplasmosis infection include ventriculomegaly, intracranial calcifications, microcephaly, ascites, hepatosplenomegaly, and growth restriction. The primary method of diagnosis of maternal T. gondii infection is serologic testing. Negative T. gondii IgM and positive IgG suggests remote infection with no concern for fetal transmission in an immunocompetent woman. Negative IgM and IgG can indicate either absence of infection or recent acute infection without sufficient time for seroconversion. Positive IgM and IgG suggests either recent infection or a false-positive result, since serologic assays have high rates of false positives and negatives. In the latter case, if there is a high index of suspicion, serologies can be repeated in 2 to 3 weeks to look for an increase in IgG antibodies indicative of recent infection, and/or serologies can be repeated in an experienced toxoplasmosis reference laboratory. If serologically confirmed, reference laboratories can perform IgG avidity testing to determine when the infection may have occurred. Low avidity suggests recent primary infection within the last 5 months. Diagnosis of fetal infection can be confirmed with PCR of the amniotic fluid after 18 weeks of gestation.
ACOG Practice Bulletin, Number 51, June 2015.
Gabbe Obstetrics, 6th edition, Chapter 51, Maternal and Perinatal Infection–Bacterial.
A daycare worker has a fetus with echogenic bowel and cerebral calcifications on ultrasound, and is concerned about CMV. She was negative when she donated blood 1 year ago. Serum testing reveals positive IgM and IgG with low avitidy. How would you counsel her about the risk of congenital infection after a primary CMV infection in pregnancy?
A. 0-10%
B. 10-30%
C. 30-50%
D. 50-70%
E. 70-90%
C. The correct answer is 30 to 50%. A wide range of likelihoods of congenital infection after a primary maternal infection have been reported, with a range of 30% in the first trimester to a range of 40% to 70% in the third trimester. Rates of subsequent neonatal effects are much lower. In women with primary infection, approximately 18% of their infants will have symptoms at birth, which can include jaundice, petechial rash, hepatosplenomegaly, or even death. In those who are asymptomatic at birth, up to 25% can experience sequelae in the first 2 years of life which can include sensorineural hearing loss or cognitive delays, chorioretinitis, seizures, and death. Severe illness is more likely in fetuses exposed in the first half of pregnancy.
A 21 year old G0 presents to you for preconception consultation regarding her history of Crohns disease for which she takes infliximab, an anti-tumor necrosis factor (TNF) agent. Her disease has been well controlled on infliximab, with her last flare over 6 months ago. How do you counsel her regarding the use of anti-TNF agents for inflammatory bowel disease in pregnancy?
A. She should discontinue infliximab if she plans to breastfeed because this drug is present in high concentrations in breastmilk
B. She should discontinue her infliximab as soon as she attempts pregnancy because there is strong evidence linking infliximab with birth defects
C. If her disease remains in remission on infliximab through the 1st and 2nd trimesters, she could adjust her dosing schedule to give the last dose of the agent during pregnancy at 30-32 weeks gestation to minimize the level of infliximab in the newborn
D. She should continue her infliximab throughout pregnancy and postpartum to avoid a flare of her Crohn’s disease her infant should receive all vaccines on schedule because there are no known effects of anti-TNF agents on developing fetal immune system
E. If she continues infliximab throughout her pregnancy, her infant should not receive any vaccines for the first year of life
C. Anti-TNF medications are being increasingly used for the treatment of inflammatory bowel disease and several other autoimmune diseases. This class of medications includes infliximab, adalimumab, certolizumab pegol, and golimumab. These drugs have been classified as FDA pregnancy category B. Infliximab consists of IgG antibodies that are actively transported across the placenta by the FcRn receptor, with the majority of transfer likely occurring in the third trimester in women taking regular, periodic doses of the drug. Available data on the use of infliximab in pregnancy have shown no increased incidence of birth defects or adverse pregnancy outcomes; however, children of women who used anti-TNF agents during pregnancy have been found to have an increased risk of infection out to 12 months of age. The optimal timing of anti-TNF agent dosing during pregnancy has been extensively debated. In general, the risks of fetal exposure to the drug must be weighed against the risks of disease flare and maternal immunization to the medication that precludes effective use of the drug following pregnancy. Because of the high rate of placental transfer of infliximab in the third trimester, the dosing schedule may be adjusted so that the last infusion given during pregnancy is administered at 30-32 weeks gestation. Infusions are typically dosed every 8 weeks, so this schedule allows the maximum amount of time between drug dosing and delivery. It is generally recommended that women with inflammatory bowel disease that has been well-controlled on an anti-TNF agent continue the medication through the first and second trimester, and resume the medication following delivery. Because women on maintenance therapy with anti-TNF agents have usually been refractory to alternative treatments, they are considered to be at high risk for disease flare if their anti-TNF agent is discontinued. Women may also develop immunization to the drug if the medication is held for too long, which would preclude effective use of the drug following delivery. Infliximab is detected in the breast milk at insignificant concentrations and is considered compatible with breastfeeding. Because infants born to mothers who used anti-TNF agents during pregnancy may have an increased risk of infection following delivery, it is recommended that these infants not receive any live vaccines in the first 6 months of life unless levels of the biologic agent are undetectable. The only live vaccine typically administered within the first 6 months of life in the United States is the Rotavirus vaccine. The available data suggests that inactivated vaccines are relatively safe for infants exposed to anti-TNF agents in utero and that these infants mount detectable serologic responses to vaccination, so inactivated vaccines should be administered on schedule.
Creasy and Resnick’s Maternal-Fetal Medicine: Principles and Practice 8e. Chapter 62: Gastrointestinal disease in pregnancy.
Mahadevan U, Matro R. Care of the pregnant patient with inflammatory bowel disease. Obstet Gynecol. 2015;126(2):401-12
All of the following are true about teratogenicity except
A. Not all exposures deemed as teratogenic are actually teratogenic all the time; the timing and dose of particular exposure during pregnancy often determine the kind and extent of its teratogenic potential
B. The embryonic period, during which organogenesis takes place, occurs between implantation at around 14 days to around 30 days post conception
C. For some teratogens, a level of exposure exists below which probably no demonstrated harmful embryonic effect occurs
D. Abnormal development produced by a teratogenic exposure is manifested as death, malformation(s), growth retardation, or a functional disorder
E. Susceptibility to a teratogenic exposure depends on the fetal and maternal genotype
B. The embryonic period, during which organogenesis takes place, occurs between implantation at around 14 days to around 60 days postconception. This is usually the most sensitive period to teratogenesis when exposure to a teratogenic agent has the greatest likelihood of producing a malformation. The remaining answers are all correct.
Identifying Human Teratogens: An Update. Alwan S, Chambers CD. J Pediatr Genet. 2015 Jun;4(2):39-41. doi: 10.1055/s-0035-1556745
