Approximately 3% to 4% of newborns are born with a major birth defect and will require genetic evaluation. These birth defects or malformations can be sporadic or associated with other anomalies. Some children may have physical features consistent with a well-known syndrome, while others may have anomalies detected prenatally or postnatally. Other neonatal presentations include some inborn errors of metabolism (acidosis), unexplained seizures, extreme hypotonia, or feeding difficulties. Infants with ambiguous genitalia require a multidisciplinary evaluation involving clinicians from genetics, endocrinology, urology, pediatrics or neonatology, and psychology. A thorough clinical evaluation requires a detailed prenatal history, a family history, and a comprehensive clinical exam, often including anthropometric measurements.
Congenital anomalies can be divided into major or minor.
Major malformations are structural abnormalities that have medical and cosmetic consequence. They may require surgical intervention. Examples include cleft palate and congenital heart disease such as tetralogy of Fallot.
Minor malformations are anomalies with no medical or cosmetic significance. They may aid in the diagnosis or recognition of a specific syndrome. Most of the minor abnormalities are limited to the head and neck region. Infants with three or more minor malformations are at a high risk for having a major malformation (20%—25%) and/or a syndrome.
Major and minor malformations are often part of patterns.
A syndrome consists of a group of anomalies that are associated due to single or similar etiologies, with known or unknown cause, such as Down syndrome due to trisomy 21.
Associations are clusters of malformations that occur together more frequently than occur sporadically, such as VACTERL association (vertebral, anal, cardiac, tracheoesophageal fistula, renal, and limbs anomalies, in particular radial ray defects) where at least three anomalies are required for the diagnosis.
A developmental field defect consists of a group of anomalies resulting from defective development of a related group of cells (developmental field). In this case, the involved embryonic regions are usually spatially related but may not be contiguous in the infant. Holoprosencephaly, affecting the forebrain and face, is an example.
Disruptions are extrinsic events that occur during normal development. These events can compromise the fetal circulation and result in a major birth defect.
An example of a disruption is amniotic bands that may result in amputation of digits or limbs.
Deformations can occur when physical forces act upon previously formed structures. Examples of deformations include uterine crowding or oligohydramnios that results in plagiocephaly or clubfeet.
A comprehensive history is an important step in evaluating an infant with a birth defect.
Prenatal
Chronic maternal illnesses and associated treatment medications, including diabetes (insulin and non-insulin dependent), seizures, hypertension, myotonic dystrophy, phenylketonuria, Graves’ disease (see Table 10.1 for prenatal exposures and effects).
Drug exposures should include prescribed drugs, such as antihypertensives (angiotensin-converting-enzyme inhibitors), seizure medications, antineoplastic agents (methotrexate), and illicit drugs (e.g., cocaine). Other drugs that may result in birth defects include misoprostol (to induce abortions). Timing of the exposure is important. Teratogenic agents tend to have their maximum effect during the embryonal period, from the beginning of the fourth to the end of the seventh week postfertilization, with exception of severe forms of holoprosencephaly when exposure may occur around or before 23 days (see Appendix B).
Infections and immunizations.
Social history.
Other exposures may include alcohol; physical agents, such as x-ray and high temperature; chemical agents; and tobacco (see Table 10.1).
Nutritional status.
Fertility issues and use of reproductive assistance (e.g., history of multiple miscarriages, in vitro fertilization [IVF], medications to stimulate ovulation). Genetic disorders, such as Beckwith-Wiedemann syndrome, Russell-Silver syndrome, and Angelman syndrome that can be caused by imprinting defects (epigenetic mutations) have been seen in children conceived by assisted reproductive technology using intracytoplasmic sperm injection (ICSI).
Multiple gestations (see Chap. 11).
Results of prenatal studies should be obtained, including ultrasonographic and magnetic resonance imaging (MRI), and chromosome or microarray studies done on samples obtained by amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical blood sampling.
Table 10.1 Well-Recognized Human Teratogens
Exposure Type
Fetal Effect
Drugs
Aminopterin/methotrexate
Growth restriction, clefting, syndactyly, skeletal defects, craniosynostosis, dysmorphic features
Retinoic acid
CNS defects, microtia, ID, conotruncal defects: VSD, ASD, TOF
Lithium
Ebstein anomaly
Propylthiouracil, iodine
Hypothyroidism
Warfarin
Skeletal anomalies, stippled epiphyses, nasal hypoplasia
ACE inhibitors
Skull defects, renal hypoplasia/agenesis
Alcohol
Fetal alcohol syndrome or alcohol-related neurodevelopmental disorders
Thalidomide
Limb reduction defects
Valproic acid
Neural tube defects
Phenytoin
Dysmorphic features, nail hypoplasia, cleft lip and palate, ID, growth restriction
Diethylbestrol
Clear cell cervical cancer in female progeny
Cocaine
Vascular disruptions, CNS anomalies
Misoprostol (Cytotec)
Limb malformations, absent digits
Statins (HMG-CoA reductase inhibitor)
Limb defects, CNS abnormalities, congenital heart disease
Maternal conditions
Maternal phenylketonuria
Microcephaly, intellectual disability
Myasthenia gravis
Neonatal myasthenia
Systemic lupus erythematosus
Cardiac conduction abnormalities
Diabetes
Neural tube defects, sacral agenesis, congenital heart disease, renal anomalies
Exposure Type
Fetal Effect
Other exposures
Radiation
Miscarriage, growth restriction
Prolonged heat exposure
Microcephaly
Smoking
Growth restriction
Lead
Low birth weight, neurobehavioral and neurologic deficits
Mercury
CNS anomalies, neurobehavioral and neurologic deficits
Infections
Varicella
Limb scars
Cytomegalovirus
Microcephaly, chorioretinitis, ID
Toxoplasmosis
Microcephaly, brain calcifications, ID
Rubella
Microcephaly, deafness, congenital heart disease, ID
ID = intellectual disability; VSD = ventricular septal defect;
ASD = atrial septal defect; TOF = tetralogy of Fallot;
CNS = central nervous system; ACE = angiotensin converting enzyme
Results of first- and second-trimester screening, including triple and quad screens, should be obtained. First-trimester screening combines the use of nuchal translucency with serum levels of pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG) measured as free beta subunit (beta hCG) or total hCG. The second-trimester screening includes alpha-fetoprotein (AFP), unconjugated estriol (uE3), free β-hCG for the triple screen, plus inhibin A as part of the quad screen. A low maternal serum AFP (MSAFP) level can be seen in trisomies 21, 18, and 13. A high MSAFP may be a sign of multiple gestation, open neural tube defect, abdominal wall defect, impending fetal death, congenital nephrosis, or epidermolysis bullosa. A high hCG can be seen with trisomy 21, while low hCG may occur with trisomies 18 and 13.
Quality and frequency of fetal movements should be documented. Rapid and intense movements could be due to fetal seizures, while decreased
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