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, taking , 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).
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. 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 (IVF) with preimplantation genetic testing of embryos
Preimplantation genetic testing (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
Prenatal testing for congenital anomalies
Pregnancy termination if a genetic disorder is present
Transfer care to tertiary center for delivery with more extensive neonatal services
(See also General Principles of Medical Genetics.)
Risk Factors for Genetic Disorders or Congenital Anomalies
Some risk of genetic abnormality exists in all pregnancies. Among live births, incidence is (1)
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, most congenital heart defects) result from polygenic or multifactorial (ie, also influenced by environmental factors) inheritance.
Risk of having a fetus with a chromosomal disorder 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).
Chromosomal disorders are more likely to be present in the following:
Pregnancies that spontaneously abort during the first trimester (50 to 80%) (3)
Fetuses with a major malformation (30%) (4)
Stillbirths (8 to 16%) (5, 6)
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 Maternal Age and Risk of Having a Baby With a Chromosomal Abnormality.) The risk of common aneuploidies by maternal age is (7)
< 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). Paternal age > 35 to 50 years increases risk of some spontaneous dominant pathogenic gene variants (formerly termed mutations), such as achondroplasia, in offspring (8).
Maternal Age and Risk of Having a Baby With a Chromosomal Abnormality*
Age of Woman | Risk of Any Chromosomal Abnormality | |
|---|---|---|
20 | 0.2% | |
30 | 0.3% | |
35 | 0.6% | |
40 | 1.6% | |
45 | 5.4% | |
49 | 15% | |
* This table includes only chromosomal abnormalities that can be detected by standard chromosomal testing. Risks of having a baby with submicroscopic chromosomal abnormalities (which can be detected only by special testing) are not included. Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol. 1981 Sep;58(3):282–285. | ||
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).
An autosomal dominant 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 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 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
