Genetics for Nurses in Obstetric Disciplines

Genetics for Nurses in Obstetric Disciplines A guide to recognition and referral of congenital and genetic disorders AUTHORS: Golder N. Wilson MD PhD,1 Vijay Tonk PhD,2 REVIEWERS Shirley Karr BSN RN,3 Joanna K. Spahis BSN CNS,4 Shirley Myers,5 RNC, MSN, FNP, and Sherry Letalian RN6 1Clinical Professor of Pediatrics, Texas Tech University Health Science Center at Lubbock and Private Practitioner, KinderGenome Genetics, Dallas Texas; 2Professor of Pediatrics and Obstetrics-Gynecology; Director, Cytogenetics Laboratory, Texas Tech University Health Science Center at Lubbock;3Genetics Coordinator, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at Amarillo;4Pediatric Clinical Nurse Specialist in Genetics and Coordinator of the Down Syndrome Clinic, Department of Genetics, Children’s Medical Center of Dallas5Women’s Health Nurse Practitioner, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at Amarillo;6Pediatric Clinic Coordinator, Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock Acknowledgement: This presentation was designed as part of the GEN-ARM (Genetics Education Network for Nursing Assessment, Recognition, and Management) for the Mountain States Region Genetics Collaborative (MSRGCC); contact www.mostgene.org or Ms. Joyce Hooker at joycehooker@mostgene.org

Genetic Disorders are Common Genetic diseases affect 5-10% of children Nurses can recognize and refer genetic disorders without need for esoteric genetic knowledge We will now present cases where your nursing skills and alertness (REYDAR=Recognize, EYDentify, Assess, Refer) can greatly benefit children with genetic diseases. These cases will introduce you to simple principles of genetics that will give you confidence in recognizing these patients and foster a medical home These cases and principles are geared to the nursing genetics primer and resources on the GENARM CD

Think genetics when something is unusual or extreme • Case example 1: A term AGA newborn product of a pregnancy with little prenatal care has an enlarged and distorted head, blue-gray sclerae (whites of the eyes), and deformed limbs. X-rays show multiple fractures, and the mother blames this on an auto accident at 7 months gestation. Do you agree? Newborn with large head and deformed bones with fractures by x-ray

This unusual presentation should prompt REYDAR for a genetic disease • More detailed family history would be useful, although many genetic disorders occur as new changes (new mutations) • The symptoms of blue sclerae and multiple fractures could be searched on the website Online Mendelian Inheritance in Man (go to http://www.ncbi.nlm.nih.gov/entrez/ or enter OMIM in search engine). They point to a disorder called osteogenesis imperfecta (166210). • OMIM contains >6000 diseases that can be searched by symptom, name, or number; associated databases contain genetic education, medical literature (PubMed), and even the complete human genome sequence/gene map. • Also useful is the companion database www.genetests.org that lists testing (when available) for the particular genetic disease (go to the clinical laboratory section and search by disease name

The family history indicated that the mother and other relatives had mild features of osteogenesis imperfecta or brittle bone disease (see Chapter 2) Suspicion of genetic disease underlying this unusual infant led to referral and genetic counseling for this autosomal dominant disease—mother’s guilt about her accident was assuaged and she learned she had a 50% chance each of her future children would have OI Family history Pedigree

Note that simple recognition and assessment of possible genetic disease, not sophisticated knowledge, optimized nursing care of this family. • Nurses with additional interest in genetics can learn to construct pedigrees, interpret inheritance mechanisms, and provide recurrence risks for the parents (genetic counseling) • Nurses are ideally positioned to be genetic counselors with their hands-on contact, emphasis on education, and focus on prevention • Read chapters 2-4 in the primer to acquire the skills for genetic counseling

Genetic disease can be defined by abnormal genes, tissues, or chromosomes (genetic testing) Categories of genetic disease relate to the steps from gene to family (genetic hierarchy) • A family has people with unusual symptoms • A person has abnormal form or function (disease) • A tissue (cell to organ) has abnormal structure (metabolic disorders) • A chromosome is extra or missing (chromosome disorders) • Several genes (plus environment) are abnormal (multifactorial disorders or susceptibilities) • A gene (DNA to RNA to protein) is abnormal (Mendelian disorders

Categories of genetic or congenital disease

Mendelian diseases like osteogenesis imperfecta have distinctive family patterns • The pattern of affected relatives is caused by transmission of single genes, each with a unique position (locus) on the chromosome. • The paired chromosomes 1-22 and XX in females imply paired genes except for X and Y genes in the male • Dominant or recessive diseases result when one or both gene partners (alleles) are abnormal. • Abnormal alleles can be predicted (genetic risks) and sometimes diagnosed through their abnormal DNA sequence or RNA/protein expression.

Sickle cell anemia is recessive, requiring both β-globin alleles to be abnormal (SS versus AS trait or AA normal). Sickle cell anemia can be predicted (25% risk for next child) and tested (abnormal S protein or gene) Other inherited anemias can be related to different abnormal globin alleles (C, D, E, thassemias). A or S

OI is caused by one abnormal allele at a collagen gene (genotype Oo) • Different phenotypes of OI relate to different collagen alleles • The >6000 Mendelian diseases thus relate to a similar number of different genes and abnormal alleles. • Characterization of abnormal alleles provides DNA testing—few of the >1600 characterized disease genes are available to the clinic. • Simultaneous analysis of multiple genes (DNA chips, arrays) is not yet practical in the way that karyotypes define any abnormal chromosomes

Know categories, not rare diseases • Single genes altering development cause birth defects and syndromes • Single genes altering enzyme pathways cause inborn errors of metabolism • Single genes altering organ function(s) produce extreme or early–onset • examples of common disease (e.g., neonatal diabetes) Mendelian diseases reflect transmission of single genes (abnormal alleles) = DNA diagnosis Multifactorial diseases reflect multiple abnormal genes plus environment = DNA/HLA markers Many genes altering development cause isolated birth defects like cleft palate Many genes altering enzyme pathways cause common metabolic diseases (e.g., adult-onset diabetes, hyperlipidemia) Many genes altering organ function(s) produce adult diseases (e.g., schizophrenia) Chromosomal diseases imbalance multiple genes and cause multiple birth defects = Karyotype

REYDAR of common obstetric presentations Recognition → Category → Referral ↔ Medical home • Case 9P—adolescent female with unplanned pregnancy • Case 10P—Diabetic woman who is 10 weeks pregnant • Case 11P—A pregnant couple and cystic fibrosis screening • Case 12P—A pregnant couple with infertility and two miscarriages • Case 13P—Couple with maternal history of mental retardation (see Chapter 1)

Case 9P. Adolescent female with unplanned pregnancyA 16-year-old female was referred to obstetric clinic from the emergency room after a diagnosis of malnutrition and a positive pregnancy test. She had been brought in by the police for vagrancy and alcoholism, exhibiting poor hygiene and nutrition on examination. Fetal ultrasound revealed a fetus of about 3 months gestation with very small head circumference, abnormal head shape, and intrauterine growth retardation. Her obstetric RN recognized two likely diagnoses, and referred her to maternal-fetal medicine for evaluation including level II ultrasound. REYDAR of common obstetric presentations Recognition  category  referral and management

Poor breast-feeding may signal syndromes or congenital disorders Case 9P (cont): The intrauterine growth retardation and small head circumference would be consistent with fetal alcohol syndrome. However, the unusual head shape and severe microcephaly by ultrasound raised the possibility that the fetus had anencephaly (OMIM #206500, others). Had this young female remained in pediatric care, she could have benefited from counseling regarding the importance of preconception/prenatal care. Preconceptional supplementation of folic acid can reduce the incidence of neural tube defects like anencephaly or spina bifida by 2/3. It is likely that this young woman had poor nutrition with low folic acid as part of her street lifestyle and alcoholism.. Recognition of her social history was the key to REYDAR, not knowledge of a rare disease.

Case 10P. Diabetic woman who is 10 weeks pregnant • A 25-year-old woman with juvenile diabetes presents to her obstetrician at approximately 10 weeks of pregnancy. She has had several hospitalizations for diabetic control and states that her blood sugars have been high for the past few weeks. The obstetric nurse discusses the risks of hypoglycemia, respiratory distress, and polycythemia for infants of poorly controlled diabetic mothers, but does not mention another risk for the fetus, which is?

Women with poorly controlleddiabetes have a 3-5 fold increased risk for congenital anomalies in their fetus that can be remembered by 3Cs—cranial, cardiac, and caudal anomalies. Cranial defects can include anencephaly as in case 9P or holoprosencephaly (photo at right); caudal defects underdevelopment of the sacrum/lower limbs (caudal regression) or spina bifida. Anomaly patterns like the VATER association (192350) or Goldenhar syndrome (164210) also occur at higher frequency in infants of diabetic mothers.

Preconception counsel • Stringent diabetic control in later pregnancy can eliminate neonatal physiologic changes like hypoglycemia, hypocalcemia, polycythemia, and respiratory problems. Lowering the risks of diabetic pregnancy illustrates the potential collaboration of pediatric and obstetric nurses in preconception counsel.

Case 11P: A pregnant couple and cystic fibrosis screening A 26-year-old Caucasian woman with no chronic illnesses presents to an obstetric nurse practitioner for her initial prenatal visit. Her last menstrual period was three weeks ago and a home pregnancy test was positive. She has no prior miscarriages or infertility and her family history is normal. Her husband is also age 26, Caucasian, and in good health with a normal family history. What general risks and tests should the nurse consider for this pregnancy and what precautions should be mentioned regarding significance of the test results?

Case 11P: Discussion • The couple’s general risk for birth defects will be 2-3%--that for an average pregnancy with no risk factors from family illness, maternal age, or chronic maternal disease. The nurse must discuss screening tests that are available, including those for chromosome or single gene disorders. Screening has classically been performed when an early diagnosis would make a difference in disease treatment or cure, but new genetic and reproductive monitoring technologies bring new options for pregnant couples. Ultrasound combined with fetal markers in maternal blood (triple test, quad screen) now detects 87% of fetuses with Down syndrome when applied in the first trimester.

Case 11P: Discussion (cont) • Fetal chromosome testing by chorionic villus sampling (8-10 weeks) and amniocentesis (15-18 weeks) can recognize over 200 chromosome disorders, but risks for miscarriage and costs have restricted these tests to women with increased risk (age over 35, prior miscarriages).

Routine chromosome analysis (karyotype) can be performed on cells fromblood (white blood cells) obtained from individuals or fetuses (by fetoscopy), chorionic villus sampling (dividing villus cells) or amniotic fluid (amniotic fibroblasts). This testing requires at least 5-7 days for results.

13 18 21 X Y Cloned DNA segment from target chromosome FISH probes Fluorescent label 13, X, Y No culture or need for metaphase spreads 18 21 Male with trisomy 13 Now a rapid FISH test is available that does not require stimulation of cell division and gives results within 2-4 hours. Rapid FISH highlights chromosomes commonly involved in disorders—e.g., 13 (Patau syndrome), 18 (Edwards syndrome), or 21 (Down syndrome), showing three versus the normal two FISH signals in each cell nucleus (X and Y probes also show Turner syndrome ordocument sex in cases of ambiguous genitalia)

Case 11P: Discussion • The nurse should mention early ultrasound and quad screening as options, but point out that screening tests can miss abnormal fetuses or raise anxiety through abnormal results with normal fetuses. Furthermore, abnormal quad screens require clarification by amniocentesis, an invasive procedure where abnormal results give options for pregnancy termination rather than any fetal treatment. The nurse should make sure that the couple understands the mental disability associated with many chromosome disorders, the positive aspects of rearing children with disabilities, and the couple’s tolerance for ambiguous reslts or options like pregnancy termination.

Case 11P: Discussion Complementing chromosome analysis is DNA technology that allows screening for common mutations in certain ethnic groups—e. g., cystic fibrosis (OMIM #219700) for Caucasians, hemoglobinopathies (e.g., sickle cell anemia-- OMIM #603903) for Africans or Asians, Tay-Sachs disease (OMIM #272800) for Jews. Cystic fibrosis has an incidence of about 1 in 1600 Caucasion infants, with a 1 in 20 chance that the average Caucasian parent will be a carrier. The nurse can inform her Caucasian patient of cystic fibrosis screening but also discuss the consequences of a positive result—testing the husband to see if he too is a carrier, then considering amniocentesis to test fetal DNA for the 1 in 4 chance the fetus will have cystic fibrosis. Although DNA testing is highly accurate, rare cystic fibrosis mutations that confer mild disease and composite mutations (compound heterozygotes) can limit predictions of putative disease severity in the fetus. Women should also be informed that DNA analysis may reveal non-paternity.

Case 11P: Discussion • The nurse should also emphasize that DNA testing is not comprehensive in the sense that a routine chromosome study (karyotype) can find over 200 different chromosome disorders. DNA testing must be directed at the disease of interest. Costs and volume considerations have limited DNA testing by commercial laboratories (Quest, LabCorp) to the more common conditions like cystic fibrosis or sickle cell anemia.. Available DNA tests and the laboratories performing them can be reviewed by accessing the website www.genetests.org, going to the clinical laboratories section, and entering the disease of interest. Until DNA chips are developed that screen for hundreds of diseases, couples should know that the 2-3% risk for birth defects/genetic diseases in the average pregnancy remains even after specific DNA testing.

Rules from Chapter 1 • RULE 7: Pregnancy planning and preconception counsel are important priorities because recognition of pregnancy by a missed period (3-4 weeks embryonic age) may be too late for preventive measures • RULE 8: Pregnant couples should be advised of increasing options for gene/chromosome screening as well as the limitations (e.g., false positives/negatives) and consequences (e.g., amniocentesis, elective abortion) that may ensue.

Chromosome disorders • Miscarriages (50-60%), liveborn children (0.5%), cancer tissue (many have diagnostic changes)--over 200 chromosomal diseases due to extra or missing chromosome or parts of chromosomes (p small or q long arms) • Hallmarks are multiple major or minor anomalies (unusual appearance) with mental disability • Most recognized by a routine karyotype, but FISH is required to detect submicroscopic deletions (e.g., DiGeorge) or the 3% of suspect children who have changes on subtelomere FISH after normal karyotypes • Individual submicroscopic deletions are found in Williams (7q), hereditary retinoblastoma (13q), Prader-Willi (15q), Shprintzen-DiGeorge spectrum (22q), and ~15 others. • Consider chromosomes in any child with unexplained mental disability and/or multiple birth defects, couples with >2 miscarriages, prenatal diagnosis for women over age 35 • Prenatal diagnosis of chromosome disorders can be performed by preimplantation diagnosis (first week), chorionic villus sampling (10-12 weeks), or amniocentesis (15-18 weeks). See Chapter 7 for more information

Case 4N: Sudden deterioration and unusual odor in a newborn after 24 hours of feeding. • Case 12P: Pregnant couple with infertility and two miscarriages • A couple present to an obstetric nurse early in pregnancy. They are each 28 years old and have been trying for a successful pregnancy for 4 years. They have had two early miscarriages at 7 and 9 weeks, neither showing abnormalities by gross inspection. Both are in good health without chronic illnesses, and neither has any family history of birth defects or miscarriages. What concerns should the nurse address?

Inborn errors of metabolism • Case 12P: Discussion • A history of recurrent abortion, particularly when coupled with infertility, should raise concern about chromosome aberrations. Couples with three or more miscarriages will have an approximate 3% chance to carry a chromosome aberration. Most likely are balanced translocations where two chromosomes have joined together and result in no extra or missing chromosome material. However, the joined or balanced chromosomes may not segregate appropriately during meiotic formation of gametes, producing a conceptus with unbalanced chromosomes. The chromosome imbalance may have severe consequences as a miscarriage or survive to be born as a child with mental disability and birth defects.

Case 12P: Discussion • The nurse should offer chromosome testing to couples with two or more miscarriages, explaining the implications for explaining their infertility/pregnancy loss or for chromosome aberrations in their current pregnancy. Additional considerations would be maternal causes of pregnancy loss like chronic disease or clotting abnormalities that can lead to antiphospholipid syndrome and maternal illness. Couples with infertility and/or multiple miscarriages should also be referred to maternal-fetal medicine or reproductive endocrinologists for examination of hormone deficiencies (e.g., premature ovarian failure), clotting abnormalities (e.g., certain prothrombin mutations detectable by DNA analysis), or antiphospholipid antibodies (e.g., lupus anticoagulant) that can cause lethal HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets-- OMIM #189800) in pregnant women.

Inborn errors of metabolism • Over 300 disorders with overall frequency 1 in 600. • Nearly all are Mendelian autosomal or X-linked recessive—the abnormal alleles cause their encoded enzyme to be defective with build-up of chemicals before the block and deficiency of those after the block • Children with inborn errors usually have a normal appearance with abnormal blood chemistries (low glucose, anion gap, high ammonia, high lactic acid) • Early recognition is key before organ damage occurs from acidosis, seizures, or chemical build-up; dietary treatment is often available

. Case 13P: Couple with maternal history of mental retardation Bob and June present to a nurse practitioner for prenatal care at an estimated 6 weeks of pregnancy. Bob is 26, June 24, and they had a normal daughter Karen two years ago with no pregnancy or delivery problems. Both are healthy and of Caucasian ancestry, and Bob’s family history is normal The nurse finds that June is an only child, but that her mother Gail has two brothers who have mental retardation. In addition, Gail has a sister Joan with with two boys and a girl, and one boy Eric has mental retardation thought due to birth injury. Gail’s other sister Jill has three boys and two girls, and her eldest son Jim has mental retardation of unknown cause. One of Jill’s daughters has also had learning problems that caused her to drop out of high school, and she has a preschool son Bert with speech delay. What concerns should the nurse address?

Gail Joan Jill June Case 13P: Discussion Besides the usual options for genetic and fetal screening (ultrasound, quad screen, cystic fibrosis screening), the nurse should recognize the positive family history and recommend genetic evaluation. The presence of several relatives with the same condition (mental disability) brings up the possibility of Mendelian disease, and sketching of the family pedigree (below) would suggest an X-linked disorder associated with mental retardation. Genetic evaluation would inform June that her mother Gail has a 50% chance and she a 25% chance to be a carrier for the X-linked disease.

Case 13P: Discussion The X-linked fragile X syndrome (OMIM #300624) is the most common genetic cause of mental disability with an estimated incidence of 1 in 2000 males. Since June is early in her pregnancy, a fragile X DNA test could be performed on one of her male relatives to confirm or exclude this diagnosis. It would be ideal if one of her affected male relatives could be evaluated by a clinical geneticist so that the diagnosis of fragile X syndrome or another of the >20 syndromes associated with X-linked mental disability could be suspected.

If the diagnosis of fragile X were confirmed in a male relative, June could have fragile X DNA testing to determine if she was a carrier. If her relatives were not available, or if their evaluation could not be accomplished in a time frame to accomplish June’s testing and options for prenatal diagnosis, then June could have the fragile X DNA test but realize that a negative result would not exclude other X-linked mental retardation syndromes. Preconception knowledge of fragile X syndrome in her family with recognition of her carrier status would have allowed Jill and Bob to consider other options such as surrogate egg donor or in vitro fertilization with preimplantation genetic diagnosis (PGD) and implantation of an unaffected embryo. Their case emphasizes the value of recognizing suspect family histories as early as possible in order to provide genetic counseling and reproductive options.

Rules from Chapter 1 • RULE : Early screening of pregnant couples for positive family histories (miscarriages, infertility, multiple affected relatives) allows timely evaluation of family members and appropriate preconception/prenatal testing. • RULE : Common conditions like mild mental disability often exhibit multifactorial determination with lower recurrence risks (2-3%) than the more extreme and unusual Mendelian conditions.

Common disorders (like mild mental or learning disabilities often exhibit multifactorial determination • Case 13P: Discussion • If Jill or Bob had only one relative with mental disability with no obvious pedigree pattern, then multifactorial determination of the mental disability would be most likely. The odds of multifactorial disability would be increased if the affected person was mild and did not have an unusual appearance or biochemical abnormalities. Multifactorial disorders confer a 2-3% risk for primary relatives—i.e., siblings/parents/children. Since Jill and Bob had normal intellect, their risks from one relative with mental disability would be less than 2-3%.

Multifactorial Disorders Table 4.1. Multifactorial Disorders in the United States *Ranks first for neonatal causes of death; approximate scale: ++++ (100% of predisposition due to genetic factors as for Mendelian disorders) to + (20% of predisposition due to genetic factors)

Multifactorial Disorders • Most isolated birth defects like cleft palate, hypospadias, heart defects, spina bifida • Many common diseases like diabetes mellitus, hypertension, mental illness, mild mental/learning disabilities • Multiple genes involved, giving lower transmission risks (about 3% for offspring of affected parent, sibling to affected child) • Therapeutic goals are to manipulate environment (e.g., folic acid) either generally or for specific high-risk individuals identified by associated DNA markers (more diverse and sensitive than HLA haplotypes

Multifactorial disorders: For some (e.g., coronary artery disease), single genes of major effect (e.g., those regulating cholesterol) are good risk markers) Recognizing at-risk children or adolescent females provides important opportunities for nursing education and prevention (see chapter 4)

Review Questions • 1-2. A 21-year-old female was referred to obstetric clinic from the emergency room after a diagnosis of malnutrition and a positive pregnancy test. She had been brought in by the police for vagrancy and alcoholism, exhibiting poor hygiene and nutrition on examination. She also was affected with cystic fibrosis, having a milder disease course, and a sister had a child with spina bifida. Fetal ultrasound revealed a fetus of about 3 months gestation with very small head circumference, abnormal head shape, and intrauterine growth retardation.

1. The poor malnutrition and unplanned pregnancy caused the young woman to miss the following standards of care: • Amniocentesis because of higher risks for chromosome abnormalities and cystic fibrosis • Triple/Quad screening with ultrasound to screen for fetal chromosome abnormalities • Preconception counsel including provision of vitamins with folic acid • Prosecution because of suspected alcoholism causing damage to the fetus • Preimplantation genetic diagnosis of to avoid the high risk for fetal cystic fibrosis • 2. Which of the following birth defects would be most likely to occur in this situation? • Congenital heart defect • Omphalocele • Anencephaly • Tracheo-esophageal fistula • Anal atresia

Questions 3-4 • 3. A Caucasian couple in the 20s comes in for preconception counseling regarding their first pregnancy. They have had no prior miscarriages or infertility and their family histories are normal. This lack of risk factors means that their risk for fetal abnormalities in this pregnancy is approximately: • 50% • 25% • 10% • 2-3% • <1% • 4. Which of the following genetic screening tests should be considered for this couple? • Alpha-thalassemia • Beta-thalassemia • Tay-Sachs disease • Sickle cell anemia • Cystic fibrosis

Questions 5-6 • 5. A couple present to an obstetric nurse for counseling because they have had three early miscarriages at 6-8 weeks gestation. Both are in good health without chronic illnesses, and neither has any family history of birth defects or miscarriages. Which of the following is an important contributor to miscarriages that can be tested in this couple? • Autosomal dominant disorders • Chromosomal disorders • Multifactorial disorders • Mitochondrial disorders • X-linked recessive disorders • 6. Which of the following results is most plausible for this couple, along with its likelihood given their history? • Trisomy, 1% • Trisomy, 10% • Translocation, 2-3% • Translocation 20-30% • Turner syndrome, 10%

Answers 1-C 2-C • Questions 1-2. • The importance of preconception counsel is recognized by the American College of Obstetrics and Gynecology (ACOG). Provision of folic acid prior to conception (the embryo will be at least 3 weeks along when mother misses her menstrual period) lowers the risk of neural tube defects (spina bifida, anencephaly) by 2/3. Neural tube defects exhibit multifactorial determination (see Chapter 4) with increased risk (0.5-1%) to relatives. The woman is affected with cystic fibrosis (219700--autosomal recessive) and would be a homozygote (genotype cc—see Chapter 3) but the father would be unlikely to be a carrier (at least 19/20 chance) and thus there would be no indication for prenatal diagnosis. A planned pregnancy could have included carrier screening for cystic fibrosis in the father.

Answers 3D 4E • Questions 3-4 • The risk for any type of congenital anomaly or genetic disease is 2-3% for the average pregnancy. This risk becomes 5-6% for disease when children are examined at age 2-3 years (e.g., developmental disabilities). Caucasians have an increased frequency of cystic fibrosis

Answers 5B 6C • Questions 5-6 • Balanced translocations in a parent are a cause for recurrent miscarriages because unbalanced gametes can be produced during meiosis, causing extra or missing chromosomes and developmental abnormalities in the conceptus (see Chapter 7). Couples with three miscarriages have an approximate 2-3% chance that one of them will carry a balanced translocation

Genetics for Nurses in Obstetric Disciplines