Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information to potential parents about precautions they can take to help prevent other causes of birth defects (eg, avoiding teratogens Exposure to Teratogens Risk factors for complications during pregnancy include Preexisting maternal disorders Physical and social characteristics (eg, age) Problems in previous pregnancies (eg, a previous history... read more , taking supplemental folic acid Diet and supplements , managing chronic diseases).
Information presented at genetic counseling should be as simple, nondirective, and jargon-free as possible to help anxious potential parents understand it. Frequent repetition may be necessary. Patients should be given time alone to formulate questions. Patients may be told about additional resources (eg, American College of Obstetricians and Gynecologists: Genetic Disorders and Pregnancy) for many common issues that may be related to genetic abnormalities, such as advanced maternal age, recurrent spontaneous abortions, previous children with neural tube defects, and previous children with trisomy (see Risk Factors for Complications During Pregnancy Risk Factors for Complications During Pregnancy Risk factors for complications during pregnancy include Preexisting maternal disorders Physical and social characteristics (eg, age) Problems in previous pregnancies (eg, a previous history... read more ).
Many potential parents (eg, those with known or suspected risk factors) benefit from referral to genetic specialists for presentation of information and testing options. Parents with risk factors for genetic abnormalities are advised about possible outcomes and options for genetic evaluation Preconception or Prenatal Carrier Testing of Parents Carrier testing is part of routine prenatal care and is ideally done before conception. The extent of carrier testing is related to how the woman and her partner weigh factors such as The probability... read more . If testing identifies a disorder, reproductive options are discussed.
Preconception reproductive options for patients with genetic disorders include
Donor sperm if the man is a carrier
Donor oocytes if the woman is a carrier
In vitro fertilization In vitro fertilization (IVF) Assisted reproductive technologies (ARTs) involve manipulation of sperm and ova or embryos in vitro with the goal of producing a pregnancy. For assisted reproductive technologies, oocytes and... read more (IVF) with preimplantation genetic testing of embryos Preimplantation Genetic Testing (PGT) Prenatal procedures that provide a definitive diagnosis of genetic disorders are invasive and involve some fetal risk. Women may choose to have prenatal procedures to know of fetal abnormalities... read more
Preimplantation genetic testing Preimplantation Genetic Testing (PGT) Prenatal procedures that provide a definitive diagnosis of genetic disorders are invasive and involve some fetal risk. Women may choose to have prenatal procedures to know of fetal abnormalities... read more (PGT) is used to identify genetic defects in embryos created through in vitro fertilization before they are implanted. It may be done if either partner has a high risk of certain mendelian disorders or chromosomal abnormalities.
Postconception reproductive options include
Transfer care to tertiary center for delivery with more extensive neonatal services
(See also General Principles of Medical Genetics Overview of Genetics A gene, the basic unit of heredity, is a segment of DNA containing all the information necessary to synthesize a polypeptide (protein) or a functional RNA molecule. Protein synthesis, folding... read more .)
Risk Factors for Genetic Disorders or Congenital Anomalies
Some risk of genetic abnormality exists in all pregnancies. Among live births, incidence is (1 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more )
0.5% for numeric or structural chromosomal disorders
1% for single-gene (mendelian) disorders
1% for multiple-gene (polygenic) disorders
Among spontaneous abortions or stillbirths, rates of abnormalities are higher.
Most malformations involving a single organ system (eg, neural tube defects Overview of Congenital Neurologic Anomalies , most congenital heart defects Overview of Congenital Cardiovascular Anomalies Congenital heart disease is the most common congenital anomaly, occurring in almost 1% of live births ( 1). Among birth defects, congenital heart disease is the leading cause of infant mortality... read more ) result from polygenic or multifactorial (ie, also influenced by environmental factors) inheritance.
Risk of having a fetus with a chromosomal disorder Overview of Chromosomal Abnormalities Chromosomal abnormalities cause various disorders. Abnormalities that affect autosomes (the 22 paired chromosomes that are alike in males and females) are more common than those that affect... read more is increased for most couples who have had a previous fetus or infant with a chromosomal disorder (recognized or missed), except for a few specific types (eg, 45,X; triploidy; de novo chromosomal rearrangements). Couples with a previous child with Down syndrome may be at an increased risk of recurrence, depending on the type of chromosomal abnormality. For nondisjunction trisomy 21, which is the most common form, if the female partner is < 35 years old, the risk of having another fetus with trisomy 21 is 3.5 times higher and for age ≥ 35 years it is 1.7 times higher (2 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more ).
Chromosomal disorders are more likely to be present in the following:
Pregnancies that spontaneously abort Septic Abortion Septic abortion is serious uterine infection during or shortly before or after a spontaneous or an induced abortion. Septic abortion is a gynecologic emergency. Septic abortions usually result... read more during the first trimester (50 to 80%) (3 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more )
Fetuses with a major malformation (30%) (4 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more )
Stillbirths Stillbirth Stillbirth is fetal death (fetal demise) at ≥ 20 weeks gestation (> 28 weeks in some definitions). Management is delivery and postpartum care. Maternal and fetal testing is done to determine... read more (8 to 16%) (5 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more , 6 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more )
A small percentage of parents may have a chromosomal disorder that increases risk of a chromosomal disorder in the fetus. Asymptomatic parental chromosomal disorders (eg, balanced abnormalities) such as certain translocations and inversions (no disruption of a gene and no genetic material lost or added) may not be suspected. A balanced parental chromosomal rearrangement should be suspected if partners have had recurrent spontaneous abortions, infertility, or a child with a congenital abnormality.
The chance of a fetal chromosomal disorder increases as maternal age increases because rates of nondisjunction (failure of chromosomes to separate normally) during meiosis increase. (See table .) The risk of common aneuploidies by maternal age is (7 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more )
< 35 years: Trisomy 21 (1/591), trisomy 18 (1/2862), and trisomy 13 (1/4651)
≥ 35 years: Trisomy 21 (1/100), trisomy 18 (1/454), and trisomy 13 (1/1438)
Most chromosomal disorders due to older maternal age involve an extra chromosome (trisomy), particularly trisomy 21 (Down syndrome Down Syndrome (Trisomy 21) Down syndrome is an abnormality of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies... read more ). Paternal age > 35 to 50 years increases risk of some spontaneous dominant pathogenic gene variants (formerly termed mutations), such as achondroplasia Osteochondrodysplasias (Osteochondrodysplastic Dwarfism) , in offspring (8 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more ).
Some chromosomal disorders are submicroscopic and thus not identified by traditional karyotyping. The submicroscopic chromosomal abnormalities, sometimes called copy number variants, occur independently of the age-related nondisjunction mechanisms. The precise incidence of these abnormalities is unclear, but incidence is higher in fetuses with structural abnormalities. A multicenter study demonstrated a 1% incidence of clinically relevant copy number variants in fetuses with normal karyotypes independent of indication for testing and a 6% incidence in fetuses with structural abnormalities (9 Risk factors for congenital disorders references Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for genetic disorders. In addition, prenatal counseling provides information... read more ).
An autosomal dominant Autosomal Dominant Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more disorder is suspected if there is a family history in more than one generation; autosomal disorders affect males and females equally. If one parent has an autosomal dominant disorder, risk is 50% that the disorder will be transmitted to an offspring.
For an autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more disorder to be expressed, an offspring must receive a pathogenic gene variant for that disorder from both parents. Parents may be heterozygous (carriers) and, if so, are unaffected but carry the abnormal gene (phenotypically normal). On average, if both parents are carriers, offspring (male or female) are at a 25% risk of being homozygous for the pathogenic gene variant and thus affected, 50% are likely to be heterozygous, and 25% are neither affected nor carriers (genotypically normal). If only one parent is a carrier, offspring are at a 50% risk of being heterozygous and a 50% chance of being genotypically normal. If only siblings and no other relatives are affected, an autosomal recessive disorder should be suspected. Likelihood that both parents carry the same autosomal recessive trait is increased if they are consanguineous.
Because females have two X chromosomes and males have only one, X-linked recessive disorders X-Linked Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more are expressed in all males who carry the pathogenic gene variant. Such disorders are usually transmitted through phenotypically normal, heterozygous (carrier) females. Thus, for each son of a carrier female, risk of having the disorder is 50%, and for each daughter, risk of being a carrier is 50%. Affected males do not transmit the gene to their sons, but they transmit it to all their daughters, who thus are carriers. Unaffected males do not transmit the gene.
Risk factors for congenital disorders references
1. Korf BR, Pyeritz RE, Grody WW: 3-Nature and frequency of genetic disease. In Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics, 7th ed. Academic Press, 2019, Pages 47-51,ISBN 9780128125373,https://doi.org/10.1016/B978-0-12-812537-3.00003-2
2. Sheets KB, Crissman BG, Feist CD, et al: Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet Couns 20(5):432-441, 2011. doi:10.1007/s10897-011-9375-8
3. Hardy K, Hardy PJ, Jacobs PA, et al: Temporal changes in chromosome abnormalities in human spontaneous abortions: Results of 40 years of analysis. Am J Med Genet A 170(10):2671-2680, 2016. doi:10.1002/ajmg.a.37795
4. Donnelly JC, Platt LD, Rebarber A, et al: Association of copy number variants with specific ultrasonographically detected fetal anomalies. Obstet Gynecol 124(1):83-90, 2014. doi:10.1097/AOG.0000000000000336
5. Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23):2185-2193, 2012. doi:10.1056/NEJMoa1201569
6. Dalton SE, Workalemahu T, Allshouse AA, et al: Copy number variants and fetal growth in stillbirths. Am J Obstet Gynecol 228(5):579.e1-579.e11, 2023. doi:10.1016/j.ajog.2022.11.1274
7. Forabosco A, Percespe A, Santucci S: Incidence of non-age-dependent chromosomal abnormalities: a population-based study on 88965 amniocenteses. Eur J Hum Genet 17 (7): 897–903, 2009. doi:10.1038/ejhg.2008.265
8. Sharma R, Agarwal A, Rohra VK, et al: Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol 13:35, 2015. Published 2015 Apr 19. doi:10.1186/s12958-015-0028-x
9. Wapner RJ, Martin CL, Levy B: Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 367:2175-2184, 2012. doi:10.1056/NEJMoa1203382
Drugs Mentioned In This Article
Drug Name | Select Trade |
---|---|
folic acid |
Folacin , Folicet, Q-TABS |