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To our patients, who inspire us each and every day.
To our students, who gave us motivation and purpose for this endeavor.
To our teachers, who helped shape us.
None of whom we could have done this without.
CONTENTS
Preface | xiii
Acknowledgments | xv
Abbreviations | xvii
1. Pregnancy Basics | 1
Pregnancy Timeline and Dating | 1
Pregnancies Are Counted in Weeks | 2
Gestational Age Versus Embryonic Age | 2
Normal Pregnancy Timeline and Duration | 2
Methods for Dating | 4
Guidelines and Recommendations for Determining Dating | 6
Tools Available for Calculating Gestational Age | 7
Pregnancy Care | 10
Types of Prenatal Providers | 10
Routine Prenatal Visits | 10
Prenatal Panel | 11
Complete Blood Count | 11
Blood Type and Antibody Testing | 11
HbA1c for Diabetes | 13
Fetal Imaging | 13
Complicated Pregnancies | 16
Documenting a Pregnancy History | 17
Gravida and Para | 17
Calculating Gravidity and Parity (G’s and P’s) | 17
2. The Perinatal Genetic Counseling Appointment and Family History | 21
The Perinatal Genetic Counseling Session | 21
Obtaining a Pregnancy History | 25
Obtaining a Family History | 26
Interpreting a Family History | 27
Mendelian Conditions | 27
Multifactorial Conditions | 28
Consanguinity | 29
Birth Defects | 29
Intellectual Disability and Autism | 29
Pregnancy Loss and Infertility | 30
Unknown Etiologies | 31
Accuracy | 31
Other Conditions (Referrals) | 32
Unique Situations in the Perinatal Family History | 32
Gamete Donation | 33
Same- Sex Couples | 33
Surrogacy | 34
Adoption | 35
Ethnicity | 36
3. Prenatal Screening | 39
Evaluation of a Screen | 39
Sensitivity | 41
Specificity | 41
Positive Predictive Value | 43
Negative Predictive Value | 43
Personal Utility | 45
Prenatal Screening Options | 45
Maternal Serum Screening | 45
Cell-Free DNA Testing | 57
4. Prenatal Diagnosis | 77
Techniques | 77
Chorionic Villus Sampling | 78
Amniocentesis | 82
Testing Options | 85
Karyotype | 85
Fluorescence in Situ Hybridization (FISH) | 86
Microarray | 90
Molecular Testing | 92
AFP and AChE | 93
Other Testing | 93
Indications for Diagnostic Testing | 94
5. Common Indications | 101
Age-Related Risks | 101
Maternal Age | 101
Paternal Age | 106
Personal and Family History | 107
Single- Gene Conditions | 107
Aneuploidy | 108
Multifactorial Conditions | 109
Birth Defects | 110
Intellectual Disability, Developmental Delay, and Autism | 112
Consanguinity | 113
Ultrasound Anomalies | 114
Counseling for Ultrasound Anomalies | 115
Classification of Ultrasound Findings | 115
Estimating Risks | 116
Ultrasound Findings in Pregnancies with Aneuploidy | 116
Common Ultrasound Findings | 123
Hallmark Ultrasound Findings Associated with Genetic Conditions | 123
Open Neural Tube Defects | 123
Teratogens | 134
Recurrent Pregnancy Loss, Stillbirth, and Infertility | 139
Evaluation of Pregnancy Loss and Stillbirth | 143
Evaluation of Infertility | 145
Preconception Counseling | 147
6. Carrier Screening | 161
Background | 161
Who Should Be Offered Carrier Testing? | 161
Carrier Screening for Gamete Donors | 162
Timing of Screening | 162
Evaluating Risks | 163
Positive Test Results | 164
Negative Results and Residual Risks | 165
Other Types of Results | 165
Application of a High-Risk Result | 165
Repeat Testing | 166
Newborn Screening | 166
Condition-Directed or Ethnicity-Based Testing | 166
Cystic Fibrosis | 167
Spinal Muscular Atrophy | 169
FMR1-Related Disorders | 173
Ashkenazi Jewish and French Canadian/Cajun Ethnicity | 178
Hemoglobinopathies | 178
Family History | 184
Expanded Carrier Testing | 186
7. Pregnancy Management | 193
Reproductive Options | 193
Continuation of Pregnancy | 194
Adoption | 194
Termination | 195
Pregnancy Management Referrals | 199
Maternal–Fetal Medicine Specialist | 200
Specialized Imaging | 200
Cardiology | 202
Neonatology | 202
Fetal Surgery or Intervention | 203
Pediatric Surgery | 203
Pediatric Specialists | 204
Pathology and Autopsy | 204
Palliative Care or Hospice | 206
Support Referrals and Bereavement | 206
8. Assisted Reproductive Technology and Reproductive Options for the At-Risk Couple | 215
Reproductive Options for At-Risk Couples | 215
Assisted Reproductive Techniques | 216
Preimplantation Genetic Testing | 217
Preimplantation Genetic Screening | 218
Preimplantation Genetic Diagnosis | 220
9. Common Perinatal Genetic Counseling Situations | 229
Pregnancy Termination | 229
Misinterpreted Intent | 230
Patient–Provider Conflict | 230
Incidental Findings | 231
Misattributed Paternity | 231
Discovery of Consanguinity | 232
Identification of an Incidental Condition | 232
Privacy and Confidentiality | 233
Genetics Is a Family Affair | 233
Secret Information | 234
Working with Couples | 235
Couples in Conflict | 235
“It’s Not My Body” | 236
Dealing with Uncertainty | 236
Fetal Diagnosis and Prognosis | 236
Family History | 237
Complex Conditions | 238
Variants of Uncertain Significance | 238
Fetal Sex Disclosure | 239
Patient’s Desire to Know or Not | 239
Testing May Reveal Sex Chromosome Abnormalities | 239
Disorders Affecting a Specific Sex | 240
Testing Only for Sex | 240
Fetal Sex May Be “Difficult News” | 240
Patient Questions | 241
“What Would You Do?” | 241
When You Don’t Know the Answer | 242
Testing a Fetus for Adult- Onset Conditions | 242
Barriers for Consent | 243
Patient Understanding | 244
Voluntary Participation | 244
Rapidly Evolving Technologies | 245
APPENDIX A | 249
APPENDIX B | 251
INDEX | 259
PREFACE
This book all started as an idea inspired by years of being genetic counselors and instructors of perinatal genetics. The inspiration was, “Why is there no single resource to learn the basic concepts of perinatal genetics?.” The idea was “Why don’t we write one ourselves?” After several conversations with other genetic counselors and educators, the idea became a dream: to make a resource that assisted in educating genetic counselors. The dream has now become a reality thanks to the support and collaboration of others.
Although this text is primarily designed for genetic counseling students, those teaching perinatal genetics, and the genetic counselor who is starting a perinatal position for the first time or after years in a different subspecialty, any health care provider interested in learning these concepts will benefit from the material presented in this book. Essential concepts and information needed to practice perinatal genetic counseling are discussed, including information about pregnancy, the components of a perinatal session, testing options and procedures, common indications, pregnancy management options, and ethical and unique situations encountered in the perinatal setting.
Foundations of Perinatal Genetic Counseling is just that: the foundation on which to build upon. Although many topics are reviewed, this book is meant to be a starting place and is not designed to be
a standalone resource. Students and educators are encouraged to utilize the abundant resources and publications available as well as to take advantage of their individual experience and the collective knowledge of peers, other health care providers, and educators to complement what is learned in this text.
Ultimately, we couldn’t be more excited to share this text for teaching and learning the foundations of perinatal genetics. We are confident that our ultimate goal of supporting the development of qualified, educated, and professional genetic counselors will be that much easier to achieve.
Amber Mathiesen, MS, LCGC Kali Roy, MS, LCGC
ACKNOWLEDGMENTS
We would like to give a special thank-you to Bonnie Baty and to Oxford University Press for providing us with the opportunity to write this book. Without them, the idea for this book would have remained just that— an idea. We would also like to thank ARUP Laboratories for graciously providing us with several images for this text.
And, as always, thank you to our partners and families for always supporting and encouraging us to do what we love.
ABBREVIATIONS
AB Abortion
AC Abdominal circumference
ACOG American Congress of Obstetricians and Gynecologists
ACMG American College of Medical Genetics and Genomics
AFI Amniotic fluid index
ADO Allele dropout
AMA Advanced maternal age
Amnio Amniocentesis
APA Advanced paternal age
ART Assisted reproductive technologies
ASHG American Society of Human Genetics
BMI Body Mass index
BP Blood pressure
BPD Biparietal diameter
CBC Complete blood count
cfDNA Cell-free DNA
CMA Chromosome microarray analysis
CRL Crown–rump length
CVS Chorionic villus sampling
ECT Ectopic pregnancy
| Abbreviations
EDC/ EDD Expected date of confinement/expected due date
DM Diabetes mellitus
FL Femur length
FOB Father of the baby
G Gravida
GA Gestational age
GDM Gestational diabetes mellitus
HbA1c Hemoglobin A1c
HC Head circumference
HTN Hypertension
Hx History
ICSI Intracytoplasmic sperm injection
IOL Induction of labor
ISPD International Society of Prenatal Diagnosis
IUD Intrauterine device
IUFD Intrauterine fetal demise
IUGR Intrauterine growth restriction
IUP Intrauterine pregnancy
IVF In vitro fertilization
L&D Labor and delivery
LMP Last menstrual period
MCA Multiple congenital anomalies
MSS Maternal serum screening
NICU Newborn intensive care unit
NIPT/ NIPS Noninvasive prenatal testing or screening
NPV Negative predictive value
NST Non- stress test
NSGC National Society of Genetic Counselors
NSVD Normal spontaneous vaginal delivery
NT Nuchal translucency
ONTD Open neural tube defect
P Para
PGD/ PGS Preimplantation genetic diagnosis or screening
PCR Polymerase chain reaction
PPV Positive predictive value
Abbreviations
POC Products of conception
RBC Red blood cell
RPL Recurrent pregnancy loss
SAB Spontaneous abortion (miscarriage)
SB Stillbirth
SMFM Society for Maternal–Fetal Medicine
TOC Transfer of care
TOP Termination of pregnancy
VBAC Vaginal birth after cesarean
VUS Variant of uncertain significance
1 Pregnancy Basics
Perinatal genetic counselors have the privilege of working with people during one of the most significant experiences of their lives. Patients have many expectations, hopes, and dreams as well as fears, anxieties, and worries. Although a patient’s provider (e.g., midwife, obstetrician, perinatologist) will manage her pregnancy and delivery, perinatal genetic counselors need to be aware of basic pregnancy concepts. This chapter provides background information on the components of routine prenatal care and testing as well as descriptions and instruction on how to document an obstetric history, establish a gestational age and due date, and use a pregnancy wheel and other similar tools.
Pregnancy Timeline and Dating
In addition to the patient wanting to know what to expect at certain points in pregnancy and when her baby will be arriving, knowing the timeline and having correct dating of a pregnancy is critically important for pregnancy management from the beginning to delivery. Accurate gestational dating is critical for the application and interpretation of certain tests (e.g., maternal serum screening) and for understanding risks from teratogen exposures, as well as obstetrical management of problems such as intrauterine growth restriction, preterm labor, and post-term pregnancy. This section will review the basic timeline of pregnancy as well as current guidelines and tools used for estimating due dates.
Pregnancies are counted in Weeks
Although many patients and the public in general use months to describe where they are in their pregnancy, in health care we use weeks and days as our measurement. For example, it is more accurate to describe a pregnant patient as being at 20 weeks than to say 5 months, which may be 20 weeks plus or minus a few weeks. The days of pregnancy are also included. For example, our patient who is in her 20th week may be 20 weeks and 0 days up to 20 weeks and 6 days. This is commonly written as 20w6d or 20 6/7 weeks.
Gestational age Versus embryonic age
Gestational age and embryonic age (also referred to as fetal age or development age) are estimations of the age of the fetus in weeks. Typically in obstetric care, gestational age is utilized; however, embryonic age is important when considering embryonic development and timing of teratogenic exposures.
The use of gestational age is often confusing for patients and providers alike because it includes the 2 weeks before the patient’s pregnancy was conceived. Gestational age is calculated from the patient’s first day of her last menstrual period (LMP), whereas embryonic age starts at the date when the sperm fertilized the egg (also known as the date of conception and corresponds to the date of ovulation). Most women have 28- day menstrual cycles, counting from the first day of one menstrual period to the first day of the next menstrual period. Ovulation typically occurs at day 14 (2 weeks after a woman’s LMP). Because of this, the gestational age is the embryonic age plus 2 weeks and the embryonic age is the gestational age minus 2 weeks. For example, a fetus that is at 12 weeks’ gestation is 10 weeks by embryonic development.
normal Pregnancy timeline and duration
Commonly used terms to describe what stage a woman is in regarding her pregnancy are antepartum, intrapartum , and
peripartum . Antepartum is defined as the prenatal period or the time during pregnancy before birth. Intrapartum refers to the time during labor and delivery. Peripartum is the time during the last month of gestation and the first few months after delivery.
Based on gestational age, a pregnancy consists of 40w0d (280 days); however, pregnancy lengths between 38w0d and 42w0d are considered normal. Pregnancy consists of three trimesters. The first trimester is between 0w1d and 13w6d, the second trimester is 14w0d to 27w6d, and the third trimester is from 28w0d to the end of the pregnancy.
Pregnancy is also divided into three periods called the germinal period, embryonic period, and the fetal period. The germinal period begins at the time of conception with the formation of the zygote, the single cell formed from the union of the egg and sperm cells. The zygote begins actively dividing and moving down the fallopian tube to the uterus. The zygote eventually forms a structure called the blastocyst, which possesses an inner cell mass and an outer layer called the trophoblast. The inner cell mass will give rise to the fetus, and the trophoblast will become the placenta. Once the developing blastocyst reaches the uterus (typically 6– 8 days after conception), it will begin to implant into the wall of the uterus. The germinal period ends when the blastocyst is fully implanted into uterine tissue (by the end of week 2 by embryonic age or end of week 4 by gestational age). Please see Figure 1.1.
The embryonic stage begins at the third week of development (5w0d gestation) and will continue until the end of the eighth week (end of 10 weeks gestation). The zygote is now termed the embryo. The most characteristic event occurring during this time is gastrulation, the process that establishes the three germ layers called the ectoderm (outer), mesoderm (middle), and endoderm (inner). Each germ layer will differentiate into different structures. Neurulation also takes place during this time, giving rise to the neural tube. This is a critical time for development as it is during the embryonic period when most of the organ systems are established (Moore, Persaud, 1998).
DAY 2 (2 cell stage)
DAY 1 (zygote)
DAY 0 (fertilization)
Ovulation (Oocyte)
Ovulation to implantation.
DAY 3–4
(4 cell stage) (8 cell stage)
DAY 5 (early blastocyst)
DAY 6–7 (late blastocyst)
DAY 8–9 (Implantation)
The fetal period begins at 9 weeks embryonic age (11 weeks gestational age) to the end of the pregnancy. During the fetal period, the organs that formed during the embryonic period grow and differentiate into unique structures (organogenesis) (Moore, Persaud, 1998).
Methods for dating
Pregnancy dating uses three methods: determining the first day of the patient’s LMP or known conception date, ultrasound, and a physical exam. Often a combination of the three methods is used for proper dating and establishing the patient’s expected due date (EDD).
Typically, determining the LMP is the first step in establishing an EDD. The date of the LMP corresponds to day 1 of the pregnancy. The EDD is 280 days from the LMP, or 40 weeks. It is important
FIGURE 1.1
to note that women’s menstrual cycles are of different length and can vary from 14 and 35 days. Ovulation can also be variable and may occur between 11 and 21 days after the LMP. The LMP method assumes ovulation and conception (fertilization) on day 14 and therefore does not account for irregularities in cycle length or variability in the timing of ovulation. Additionally, it has been found that only about one-half of women accurately recall their LMP date (Wegienka, Baird, 2005).
The date of conception can also be used when known. For example, many patients will utilize assisted reproductive technologies (ART) such as in vitro fertilization (IVF) or insemination. IVF involves manually combining eggs and sperm outside of the body and then later transferring an embryo into the uterus. (Please see Chapter 8 for more information on ART.) For patients undergoing IVF, the provider must consider the date of transfer into the uterus and the age of the embryo at that time. Typically, an embryo is transferred on day 3 or 5 after fertilization. The date of fertilization is considered week 2 of the pregnancy, and therefore transferring a 3- day embryo would correspond to 2w3d and a 5- day embryo would be a 2w5d. If the patient has completed an insemination, this would be considered the date of conception, and therefore the date of insemination is week 2 of the pregnancy.
Ultrasound is also used to date a pregnancy and is especially useful when the LMP is unknown or uncertain. The best time to use ultrasound for dating is in the first trimester (up to and including 13w6d). Dating from a first-trimester ultrasound is based on the mean of three separate measurements of the crown–rump length (CRL). The CRL is the measurement of the length of the embryo or fetus from the top of its head to bottom of its torso. Measurements of the CRL are more accurate the earlier in the first trimester that ultrasonography is performed. CRL measurements taken at or after 14w0d weeks (84 mm) decrease in accuracy. A later ultrasound (after 14w0d) can be used to date the pregnancy as well. In a later ultrasound, rather than using the CRL, other measurements including the biparietal diameter (BPD), head circumference (HC), femur length (FL), and abdominal circumference (AC) are used.
