Hacker & Moore's Essentials of Obstetrics and Gynecology: With STUDENT CONSULT Online Access,5th ed.

Chapter 7

Antepartum Care

PRECONCEPTION AND PRENATAL CARE, GENETIC EVALUATION AND TERATOLOGY, AND ANTENATAL FETAL ASSESSMENT

Michael C. Lu, John Williams, III, Calvin J. Hobel

image Preconception Care

Ideally, prenatal care should begin before pregnancy. Organogenesis begins early in pregnancy, and placental development starts with implantation at 7 days postconception. Poor placental development has been linked to such pregnancy complications as preeclampsia, preterm birth, and intrauterine growth restriction and may play a role in fetal programming of chronic diseases in later life. By the time most pregnant women have their first prenatal visit, it is often too late to prevent some birth defects or defective placental development.

More importantly, early prenatal care is often too late to restore allostasis. Allostasis refers to the body’s ability to maintain stability through change. Examples include feedback inhibition on the hypothalamic-pituitary-adrenal (HPA) axis to keep the body’s stress response in check, or modulation of the body’s inflammatory response by the HPA axis. In the face of chronic and repeated stress (psychological or biologic), however, these systems can wear out. If a woman enters pregnancy with worn-out allostatic systems (e.g., dysregulated stress or inflammatory response), she may be more vulnerable to a number of pregnancy complications, including preterm birth.

The growing recognition of the limits of prenatal care and the importance of women’s health before pregnancy has drawn increasing attention to preconception care. As defined by the U.S. Centers for Disease Control and Prevention, preconception care is a set of interventions that aim to identify and modify biomedical, behavioral, and social risks to a woman’s health or pregnancy outcome through prevention and management. The American College of Obstetricians and Gynecologists (ACOG) recommends that a routine visit by any woman who may, at some time, become pregnant presents an opportunity to promote preconception health, whether or not she is planning on getting pregnant. Men should also get preconception care, though the content of preconception care for men is less well defined.

Several models of preconception care have been developed. Major components of preconception care include risk assessment, health promotion, and medical and psychosocial interventions and follow-up, as summarized in Table 7-1. There is currently no consensus on the timing of preconception care, probably because there are different ideas about what preconception care should be or do. For some, preconception care means a single prepregnancy checkup a few months before couples attempt to conceive. A single visit, however, may be too little too late to address some problems (e.g., promoting smoking cessation or healthy weight) and will miss those pregnancies that are unintended at the time of conception (about half of all pregnancies in the United States). For others, preconception care means all well-woman care, from prepubescence to menopause. In practice, however, asking providers to squeeze more into an already hurried routine visit may not be feasible, and some components (e.g., genetic screening or laboratory testing) may not be indicated for every woman at every visit.

TABLE 7-1 ELEMENTS OF PRECONCEPTION COUNSELING AND CARE

Major Components of Preconception Care

Risk Assessment

Reproductive life plan

Ask your patient if she plans to have any (more) children and how long she plans to wait until she (next) becomes pregnant. Help her develop a plan to achieve those goals.

Past reproductive history

Review prior adverse pregnancy outcomes, such as fetal loss, birth defects, low birth weight, and preterm birth, and assess ongoing biobehavioral risks that could lead to recurrence in a subsequent pregnancy.

Past medical history

Ask about past medical history such as rheumatic heart disease, thromboembolism, or autoimmune diseases that could affect future pregnancy. Screen for ongoing chronic conditions such as hypertension and diabetes.

Medications

Review current medication use. Avoid category X drugs and most category D drugs unless potential maternal benefits outweigh fetal risks (see Box 7-1). Review use of over-the-counter medications, herbs, and supplements.

Infections and immunizations

Screen for periodontal, urogenital, and sexually transmitted infections as indicated. Discuss TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes) infections and update immunization for hepatitis B, rubella, varicella, Tdap (combined tetanus, diphtheria, and pertussis), human papillomavirus, and influenza vaccines as needed.

Genetic screening and family history

Assess risk for chromosomal or genetic disorders based on family history, ethnic background, and age. Offer cystic fibrosis screening. Discuss management of known genetic disorders (e.g., phenylketonuria, thrombophilia) before and during pregnancy.

Nutritional assessment

Assess anthropometric (body mass index), biochemical (e.g., anemia), clinical, and dietary risks.

Substance abuse

Ask about smoking, alcohol, drug use. Use T-ACE (tolerance, annoyed, cut down, eye opener) or CAGE (cut-down, annoyed, guilty, eye-opener) questions to screen for alcohol and substance abuse.

Toxins and teratogens

Review exposures at home, neighborhood, and work. Review Material Safety Data Sheet and consult local Teratogen Information Service as needed.

Psychosocial concerns

Screen for depression, anxiety, intimate-partner violence, and major psychosocial stressors.

Physical examination

Focus on periodontal, thyroid, heart, breasts, and pelvic examination.

Laboratory tests

Check complete blood count, urinalysis, type and screen, rubella, syphilis, hepatitis B, HIV, cervical cytology; screen for gonorrhea, chlamydia, and diabetes in selected populations. Consider thyroid-stimulating hormone.

Major Components of Preconception Care

Health promotion

Family planning

Promote family planning based on a woman’s reproductive life plan. For women who are not planning on getting pregnant, promote effective contraceptive use and discuss emergency contraception.

Healthy weight and nutrition

Promote healthy prepregnancy weight through exercise and nutrition. Discuss macronutrients and micronutrients, including 5-a-day and daily intake of multivitamin containing folic acid.

Health behaviors

Promote such health behaviors as nutrition, exercise, safe sex, effective use of contraception, dental flossing, and use of preventive health services. Discourage risk behaviors such as douching, nonuse of seat belt, smoking, and alcohol and substance abuse.

Stress resilience

Promote healthy nutrition, exercise, sleep, and relaxation techniques; address ongoing stressors such as intimate partner violence; identify resources to help patient develop problem-solving and conflict resolution skills, positive mental health, and relational resilience.

Healthy environments

Discuss household, neighborhood, and occupational exposures to metals, organic solvents, pesticides, endocrine disruptors, and allergens. Give practical tips such as how to reduce exposures during commuting or picking up dry cleaning.

Preconception care is probably more than a single prepregnancy visit and less than all well-woman care. A good place to start is to ask every woman at every visit about her reproductive life plan. A reproductive life plan is a set of personal goals about having or not having children based on personal values and resources, and a plan to achieve those goals. The provider should ask the woman if she plans to have any (more) children, and how long she plans to wait until she (next) becomes pregnant. If it is within the next 1 or 2 years, the provider should bring her and her partner back for a full assessment and counseling. The schedule of follow-up visits should be individualized according to identified risks. If she does not plan on becoming pregnant in the next 1 to 2 years or ever, the provider should continue to provide well-woman care but make sure she has effective contraception if needed and update her reproductive life plan at every routine visit. Because about half of all pregnancies in the United States are unplanned, preconception counseling is recommended for every woman of reproductive age.

One example of how preconception care can improve obstetric outcomes is the opportunity to counsel and appropriately change dietary behavior. Women in the reproductive age group should be instructed to take multivitamins containing folic acid and in addition omega-3 fatty acids. Women who are underweight (body mass index [BMI] <19) have a greater risk for having a low-birth-weight or premature infant, and women who are obese (BMI >29) are at significantly greater risk for obstetric complications, including pregnancy-induced hypertension, diabetes mellitus, and fetal macrosomia. It is important that nutrition be balanced for at least 3 months before conception. Attempts at weight loss too soon before conception may have deleterious effects on fetal development.

image Prenatal Care

The three basic components of prenatal care are (1) early and continuing risk assessment, (2) health promotion, and (3) medical and psychosocial interventions and follow-up. Risk assessment includes a complete history, a physical examination, laboratory tests, and assessment of fetal growth and well-being. Health promotion consists of providing information on proposed care, enhancing general knowledge of pregnancy and parenting, and promoting and supporting healthful behaviors. Interventions include treatment of any existing illness, provision of social and financial resources, and referral to and consultation with other specialized providers.

THE FIRST PRENATAL VISIT

The first prenatal visit provides an opportunity to assess or review medical, reproductive, family, genetic, nutritional, and psychosocial histories. Women whose health may be seriously jeopardized by the pregnancy, such as those with Eisenmenger’s syndrome or a history of peripartum cardiomyopathy, should be counseled about the option of terminating the pregnancy. Such reproductive histories as preterm birth, low birth weight, preeclampsia, stillbirth, congenital anomalies, and gestational diabetes are important to obtain because of the substantial risk for recurrence. Women with prior cesarean delivery should be asked about the circumstances of the delivery, and discussion about options for the mode of delivery for the current pregnancy should be initiated. Additionally, the importance of screening women for domestic violence cannot be overemphasized. As many as 20% of women are physically abused during pregnancy (most studies report a prevalence that clusters around 4% to 8%), making abuse more common than preeclampsia, diabetes, and other conditions that are routinely screened for during prenatal care.

Standardized forms have been developed to facilitate overall prenatal risk assessment. One such system is the Problem Oriented Prenatal Risk Assessment System, or POPRAS (www.POPRAS.com).

A complete physical examination should be performed. Clinicians should be familiar with physical findings associated with normal pregnancy, such as systolic murmurs, exaggerated splitting, and S3 during cardiac auscultation, or spider angiomas, palmar erythema, linea nigra, and striae gravidarum on inspection of the skin. During the breast examination, clinicians should initiate discussion about breastfeeding. A pelvic examination should be performed and Pap smear status documented or obtained.

Prenatal laboratory testing should be undertaken as outlined in Table 7-1, if not done during preconception care. Screening for and treating asymptomatic bacteriuria significantly reduces the risk for pyelonephritis and preterm delivery.

Women who are Rh negative should receive RhO(D) immune globulin (RhO-GAM) at 28 weeks of gestation and postpartum and at any time when sensitization may occur (e.g., threatened abortion or invasive procedures such as amniocentesis and chorionic villus sampling). Rubella vaccination is contraindicated during pregnancy, and pregnant women who are found to be seronegative should be vaccinated immediately postpartum. Syphilis testingis mandated by law in virtually all states. Early diagnosis and treatment of syphilis can reduce perinatal morbidity. Women who test negative for hepatitis B surface antigen and are at high risk for hepatitis B infection (e.g., health-care workers) are candidates for vaccination before and during pregnancy. Infants born to women who test positive for hepatitis B surface antigen should receive both hepatitis B immune globulin (HBIG) and hepatitis B vaccine within 12 hours of birth, followed by two more injections of hepatitis B vaccine in the first 6 months of life.

Voluntary and confidential HIV counseling and testing should be offered and documented in the medical record. Diagnosis and treatment significantly reduce the risk for vertical transmission. Other tests, such as screening for sexually transmitted infections like gonorrhea and chlamydia, are generally considered routine. All pregnant women at high risk for tuberculosis should be screened with a purified protein derivative (PPD) skin test when they begin prenatal care.

Additionally, the clinician should use the first prenatal visit to confirm pregnancy and determine viability, estimate gestational age and due date, diagnose and deal with early pregnancy loss, provide genetic counseling and information about teratology, and provide advice on alleviating unpleasant symptoms during pregnancy. Information about nutrition, behavioral changes to expect, and the benefits of breastfeeding should be provided as prenatal care progresses. Clinical pelvimetry should be performed sometime before labor begins.

image Confirming Pregnancy and Determining Viability

Women most commonly present to the clinician after missed menses. About 30% to 40% of all pregnant women will have some bleeding during early pregnancy (e.g., implantation bleeding), which may be mistaken for a period. Therefore, a pregnancy test should be performed in all women of reproductive age who present with abnormal vaginal bleeding.

The pregnancy test detects human chorionic gonadotropin (hCG) in the serum or the urine. The most widely used standard is the First International Reference Preparation (1st IRP). The hCG molecule is first detectable in serum 6 to 8 days after ovulation. A titer of less than 5 IU/L is considered negative, and a level above 25 IU/L is a positive result. Values between 6 and 24 IU/L are considered equivocal, and the test should be repeated in 2 days. A concentration of about 100 IU/L is reached about the date of expected menses. Most qualitative urine pregnancy tests can detect hCG above 25 IU/L.

It is important to differentiate a normal pregnancy from a nonviable or ectopic gestation. In the first 30 days of a normal gestation, the level of hCG doubles every 2.2 days. In patients whose pregnancies are destined to abort, the level of hCG rises more slowly, plateaus, or declines.

The use of transvaginal ultrasonography has improved the accuracy of predicting viability in early pregnancies. Using transvaginal ultrasonography, the gestational sac should be seen at 5 weeks of gestation or a mean hCG level of about 1500 IU/L (1st IRP). The fetal pole should be seen at 6 weeks or a mean hCG level of about 5200 IU/L. Fetal cardiac motion should be seen at 7 weeks or a mean hCG level of about 17,500 IU/L. The presence of a gestational sac of 8 mm (mean sac diameter) without a demonstrable yolk sac, 16 mm without a demonstrable embryo, or the absence of fetal cardiac motion in an embryo with a crown-rump length of greater than 5 mm indicates probable embryonic demise. When there is any doubt about these measurements, it is best to repeat the evaluation in 1 week before terminating the pregnancy.

INCIDENCE OF EARLY PREGNANCY LOSS

Because the incidence of conception is unknown, the incidence of spontaneous abortion (miscarriage) cannot be determined with certainty. Spontaneous abortion occurs in 10% to 15% of clinically recognizable pregnancies.The term biochemical pregnancy refers to the presence of hCG in the blood of a woman 7 to 10 days after ovulation but in whom menstruation occurs when expected. In other words, conception has occurred, but spontaneous loss of the gestation takes place without prolongation of the menstrual cycle. When both clinical and biochemical pregnancies are considered, evidence would suggest that more than 50% of all conceptions are lost, the majority in the 14 days following conception.

Real-time ultrasonography has been extensively used to monitor the intrauterine events of the first trimester of pregnancy. If a live, appropriately grown fetus is present at 8 weeks’ gestation, the fetal loss rate over the next 20 weeks (up to 28 weeks) is on the order of 3%.

TYPES OF SPONTANEOUS ABORTION

The terms and definitions in the remainder of this chapter refer only to clinically recognizable pregnancies.

Threatened Abortion

The term threatened abortion is used when a pregnancy is complicated by vaginal bleeding before the 20th week. Pain may not be a prominent feature of threatened abortion, although a lower abdominal dull ache sometimes accompanies the bleeding. Vaginal examination at this stage usually reveals a closed cervix. About one third of pregnant women have some degree of vaginal bleeding during the first trimester, and 25% to 50% of threatened abortions eventually result in loss of the pregnancy.

Inevitable Abortion

In a case of inevitable abortion, a clinical pregnancy is complicated by both vaginal bleeding and cramp-like lower abdominal pain. The cervix is frequently partially dilated, contributing to the inevitability of the process.

Incomplete Abortion

In addition to vaginal bleeding, cramp-like pain, and cervical dilation, an incomplete abortion involves the passage of products of conception, often described by the woman as looking like pieces of skin or liver.

Complete Abortion

In complete abortion, after passage of all the products of conception, the uterine contractions and bleeding abate, the cervix closes, and the uterus is smaller than the period of amenorrhea would suggest. In addition, the symptoms of pregnancy are no longer present, and the pregnancy test becomes negative.

Missed Abortion

The term missed abortion is used when the fetus has died but is retained in the uterus, usually for more than 6 weeks. Because coagulation problems may develop, fibrinogen levels should be checked weekly until the fetus and placenta are expelled (spontaneously) or removed surgically.

Recurrent Abortion

Three successive spontaneous abortions usually occur before a patient is considered as a recurrent aborter. Many clinicians feel that two successive first-trimester losses or a single second-trimester spontaneous abortion is justification for an evaluation of a couple for the causes of the pregnancy losses (see page 77, “Patients Who Require Genetic Counseling”).

ETIOLOGY

Although many factors may result in the loss of a single pregnancy, relatively few factors are present consistently in couples who abort recurrently. Cause-and-effect relationships in individual patients are frequently difficult to determine.

General Maternal Factors

Infection with Mycoplasma, Listeria, or Toxoplasma should be specifically sought in women with recurrent abortions because despite being found infrequently, they are all treatable with antibiotics. Maternal smoking and alcohol consumption are associated with an increased incidence of chromosomally normal abortions. Women who smoke 20 or more cigarettes daily and consume more than seven standard alcoholic drinks per week have a fourfold increased risk for spontaneous abortion. There is a doubling of the risk for spontaneous abortion with as few as two drinks a week.

There is very little evidence that a sudden physical or emotional shock can cause pregnancy loss, but psychodynamic factors may contribute to recurrent abortion in a few cases.

Three medical disorders are commonly linked to spontaneous abortion: (1) diabetes mellitus, (2) hypothyroidism, and (3) systemic lupus erythematosus (SLE). The evidence linking diabetes mellitus with spontaneous abortion is not conclusive, and severe hypothyroidism is more often associated with disordered ovulation than spontaneous abortion. Up to 40% of clinical pregnancies are lost in women with SLE, and such patients have an increased risk for pregnancy loss before developing the clinical stigmata of the disease (see Chapter 16).

The risk for abortion increases with maternal age (Table 7-2). If a live fetus is demonstrated by ultrasonography at 8 weeks’ gestational age, however, fewer than 2% will abort spontaneously when the mother is younger than 30 years of age. If she is older than 40 years, the risk exceeds 10%, and it may be as high as 50% at age 45 years. The probable explanation is the increased incidence of chromosomally abnormal conceptus in older women.

TABLE 7-2 NUMBER OF PREGNANCIES, SPONTANEOUS ABORTIONS, AND SPONTANEOUS ABORTION RATES BY MATERNAL AGE AT FIRST PREGNANCY

image

Local Maternal Factors

No prospective study has been able to demonstrate unequivocally that a normal pregnancy can be lost as a result of abnormal hormone production by either the corpus luteum or the placenta. In addition to this, no controlled trial of exogenous hormones has been able to demonstrate any benefit, and there is some evidence that exogenous sex steroids may indeed be teratogenic.

Uterine abnormalities, including cervical incompetence, congenital abnormalities of the uterine fundus (as may result from gestational exposure to diethylstilbestrol), and acquired abnormalities of the uterine fundus are known to be associated with pregnancy loss.

Cervical incompetence occurs under a number of circumstances. The incompetence is usually the result of trauma. This occurs most frequently from mechanical dilation of the cervix at the time of termination of pregnancy, but it may also occur at the time of curettage. The diagnosis of cervical incompetence is usually made when a mid-trimester pregnancy is lost with a clinical picture of sudden unexpected rupture of the membranes, followed by painless expulsion of the products of conception.

There continues to be controversy surrounding cervical incompetence, with some experts suggesting that cervical incompetence is, in most instances, a variant of preterm delivery, occurring at a time when there is an associated finding of asymptomatic ascending infection.

When cervical incompetence is suspected during pregnancy (e.g., history of cervical incompetence in a previous pregnancy or of cone biopsy of the cervix), sequential ultrasonography of the cervix and lower uterine segment may identify the problem before a pregnancy loss occurs.

congenitally abnormal uterus may be associated with pregnancy loss in both the first and second trimesters. Surgical correction of the abnormality, particularly with a history of second-trimester loss, is frequently successful. The diagnosis of these abnormalities is made by either hysterography or hysteroscopy. Complete evaluation of the congenitally abnormal uterus usually requires laparoscopic, hysteroscopic, and hysterographic examination before any management plan can be made.

The most commonly acquired abnormalities of the uterus with the potential to affect fecundity are submucous fibroids. Although these tend to occur more frequently in women in their late 30s, they should be considered when investigating pregnancy loss in all women. Removal of submucous fibroids and large (>6 cm) intramural ones is associated with improved fecundity, especially when they distort the endometrial cavity. Subserous fibroids do not appear to affect fecundity.

Intrauterine adhesions result from trauma to the basal layer of the endometrium from previous surgery or infection. When most of the uterine cavity has been obliterated (Asherman’s syndrome), amenorrhea results; but much more frequently, fewer intrauterine adhesions (synechiae) are present with reasonably normal menses, and these lesions are not even suspected until a pregnancy is attempted and lost. Surgical correction of these intrauterine adhesions is recommended to improve fecundity.

Fetal Factors

The most common cause of spontaneous abortion is a significant genetic abnormality of the conceptus. In spontaneous first-trimester abortions, about two thirds of fetuses have significant chromosomal anomalies, with about half of these being autosomal trisomies and most of the remainder being triploid, tetraploid, or 45 X monosomies. Fortunately, most of these are not inherited from either mother or father and are single nonrecurring events. When seen on ultrasonography before spontaneous abortion occurs, many such pregnancies appear to consist of an empty gestational sac. When a fetus is present in many late first-trimester and early second-trimester abortions, it is often significantly abnormal, either genetically or morphologically. It seems that nature has a way of identifying some of its major mistakes and causing them to abort.

Chromosomal Factors

Occasionally, fetal chromosomal abnormalities occur as a result of a chromosomal rearrangement (balanced translocation, inversion) in either parent. Therefore, karyotyping is important for evaluation of couples suffering from recurrent abortion.

Immunologic Factors

A successful pregnancy depends on a number of immunologic factors that allow the host (mother) to retain an antigenically foreign product (fetus) without rejection taking place (see Chapter 6). The precise mechanism of this immunologic anomaly is not fully understood, but the immunologic functioning of some women, particularly those who abort recurrently, is different from that of women who carry pregnancies to term. The immunologic relationship between male and female in such a couple may be regarded as abnormal, and in some instances, treatment of this condition may result in a successful pregnancy.

MANAGEMENT

Threatened Abortion

A threatened abortion is best managed by an ultrasonic examination to determine whether the fetus is present and, if so, whether it is alive. Of those in whom a live fetus is present, 94% will produce a live baby, although the incidence of preterm delivery in these cases may be somewhat higher than in those who do not bleed in the first trimester. Once a live fetus has been demonstrated to the couple on ultrasonography, management consists essentially of reassurance; however, they should be encouraged to undergo first trimester screening for chromosome abnormalities such as trisomy 13, 18, or 21. There is no need for admission to hospital nor is there any evidence that bed rest improves the prognosis.

Incomplete Abortion

Until bleeding has stopped or is minimal, it is best to insert an intravenous line and take blood for grouping and crossmatching because shock may occur from hemorrhage or sepsis. Once the patient’s condition is stable, the remaining products of conception should be evacuated from the uterus under appropriate pain control. These tissues should be sent for pathologic evaluation. An incomplete abortion that is infected must be managed vigorously. Delay in treatment may result in overwhelming sepsis that may lead to renal and hepatic failure, disseminated intravascular coagulation (DIC), and even death.

Missed Abortion

Suspected missed abortion should be confirmed by ultrasound. Once the diagnosis has been made, it is appropriate to evacuate the retained products of conception surgically to minimize the risk for sepsis and DIC and to reduce the extent of hemorrhage and the degree of pain that accompanies the spontaneous expulsive process.

General Management Considerations

When the patient is Rh negative and does not have Rh (anti-D) antibodies, prophylactic Rho(D) immune globulin (Rho-GAM) should be administered. All couples who have had a pregnancy loss should be seen and counseled some weeks after the event. At this time, questions that the couple may have can be answered, the findings of any pathologic studies discussed, and reassurance given about their chances of reproductive success in the future.

Recurrent Abortion

As far as the mother is concerned, it is appropriate to rule out the presence of systemic disorders such as diabetes mellitus, SLE, and thyroid disease, and it is also necessary to test for the presence of a lupus anticoagulant. Paternal and maternal chromosomes should be evaluated, and hysteroscopy or hysterography should be performed to evaluate the uterine cavity. Given the possibility of the pregnancy losses being caused by infectious agents, it is also appropriate to rule out the presence of Mycoplasma, Listeria, Toxoplasma, Treponema, cytomegalovirus, and Brucella.

More than half of couples with recurrent losses will have normal findings during an evaluation. When a specific etiologic factor is found, appropriate management often leads to reproductive success. Many of the congenital abnormalities of the uterus can now be diagnosed using pelvic ultrasonography and may no longer require laparotomy for repair. Cervical incompetence is managed by the placement of a cervical suture (cerclage) at the level of the internal os, and this suture is best placed in the first trimester, after a live fetus has been demonstrated on ultrasonography. The effectiveness of prophylactic cervical cerclage (seeChapters 17 and19in preventing recurrent loss from cervical incompetence has not been conclusively established.

image Estimating Gestational Age and Date of Confinement

Gestational age should be determined during the first prenatal visit. Accurate determination of gestational age may become important later in pregnancy for the management of obstetric conditions such as preterm labor, intrauterine growth restriction, and postdate pregnancy. Clinical assessment to determine gestational age is usually appropriate for the woman with regular menstrual cycles and a known last menstrual period that was confirmed by an early examination. Estimated date of confinement (EDC) or “due date” may be determined by adding 9 months and 7 days to the first day of the last menstrual period.

Ultrasonography may also be used to estimate gestational age. Measurement of fetal crown-rump length between 6 and 11 weeks of gestation can define gestational age to within 7 days. At 12 to 20 weeks, gestational age can be determined within 10 days by the average of multiple measurements (e.g., biparietal diameter, femur length, abdominal and head circumferences). Thereafter, measurements become less reliable with advancing gestation (±3 weeks in the third trimester).

image Patients Who Require Genetic Counseling

Ideally, couples should receive preconception counseling before they decide to have children, so that genetic disease in the couple or their families may be identified before pregnancy. The major reason couples are referred for prenatal diagnosis is advanced maternal age. Women older than 34 years have an increased risk for having children with chromosomal abnormalities. Other indications for genetic counseling and prenatal diagnosis are listed in Box 7-2.

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BOX 7-2 Indications for Genetic Counseling and Prenatal Diagnosis Other than Age

1. A previous child with or a family history of birth defects, chromosomal abnormality, or known genetic disorder

2. A previous child with undiagnosed mental retardation

3. A previous baby who died in the neonatal period

4. Multiple fetal losses

5. Abnormal serum marker screening results

6. Consanguinity

7. Maternal conditions predisposing the fetus to congenital abnormalities

8. A current pregnancy history of teratogenic exposure

9. A fetus with suspected abnormal ultrasonic findings

10. A parent who is a known carrier of a genetic disorder

image

CONGENITAL AND HEREDITARY DISORDERS

Chromosomal Disorders

Chromosomal abnormalities occur in 0.5% of live births, but the incidence associated with spontaneous abortions is much higher and is estimated to be about 50%. The most common chromosomal abnormalities among liveborn infants are sex chromosomal aneuploidy (e.g., Turner syndrome [45 XO], Klinefelter syndrome [47 XXY]), balanced Robertsonian translocations (translocations within group D or between groups D and G), and autosomal trisomies (e.g., Down syndrome; Figure 7-1).

image

FIGURE 7-1 Karyotype of a patient with Down syndrome (47 XX + 21).

Women older than 34 years are at increased risk for giving birth to children with autosomal trisomies (e.g., trisomy 21, 13, or 18) or sex chromosomal abnormalities (e.g., triple X syndrome, Klinefelter syndrome). The overall risk for Down syndrome (trisomy 21) is 1 per 800 live births. It increases to about 1 per 300 live births for women who are 35 to 39 years of age and to about 1 in 80 for those 40 to 45 years of age (Table 7-3). The incidence of Down syndrome diagnosed at the time of chorionic villus sampling (CVS) or amniocentesis is considerably higher. In women 35 to 39 years of age, the rate is about 1 in 125; in those 40 to 45, it is about 1 in 20. The discrepancy between the rate of occurrence at delivery and that at prenatal diagnosis is believed to be due in part to fetal loss in the second and third trimester.

TABLE 7-3 RISK TABLE FOR CHROMOSOMAL ABNORMALITIES BY MATERNAL AGE AT TERM

Age at Term (yr)

Risk for Trisomy 21

Risk for Any Chromosomal Abnormality,

15

1:1578

1:454

16

1:1572

1:475

17

1:1565

1:499

18

1:1556

1:525

19

1:1544

1:555

20

1:1528

1:525

21

1:1507

1:525

22

1:1481

1:499

23

1:1447

1:499

24

1:1404

1:475

25

1:1351

1:475

26

1:1286

1:475

27

1:1208

1:454

28

1:1119

1:434

29

1:1018

1:416

30

1:909

1:384

31

1:796

1:384

32

1:683

1:322

33

1:574

1:285

34

1:474

1:243

35

1:384

1:178

36

1:307

1:148

37

1:242

1:122

38

1:189

1:104

39

1:146

1:80

40

1:112

1:62

41

1:85

1:48

42

1:65

1:38

43

1:49

1:30

44

1:37

1:23

45

1:28

1:18

46

1:21

1:14

47

1:15

1:10

48

1:11

1:8

49

1:8

1:6

50

1:6

Data not available

 Data from Chuckle HA, Wald NJ, Thompson SC: Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level. Br J Obstet Gynaecol 94:387, 1987.

 Adapted from Hook EB: Rates of chromosomal abnormalities at different maternal ages. Obstet Gynecol 58:282-285, 1981.

 Risk for any chromosomal abnormality includes the risk for trisomy 21 and 18 in addition to trisomy 13, 47 XXY, 47 XYY, Turner syndrome genotype, and other clinically significant abnormalities. 47 XXX is not included.

Ninety-five percent of cases of Down syndrome are due to meiotic nondisjunctional events leading to 47 chromosomes with an extra copy of chromosome number 21, whereas 4% are due to an unbalanced translocation. Parents of a child with translocation Down syndrome have rearrangements between chromosome 21 and chromosomes 14, 15, 21, or 22. The remaining 1% of individuals with Down syndrome have the mosaic type, which consists of two populations of cells, one with 46 and one with 47 chromosomes.

A couple who has previously had a child with trisomy 21 (Down syndrome) or with a meiotic nondisjunctional type of chromosomal abnormality is believed to be at a small but definite increased risk (about 1%) of giving birth to another child with a chromosomal abnormality and should be referred for prenatal diagnosis.

Approximately 1 in 500 individuals carries a balanced structural chromosomal rearrangement such as a translocation or inversion. Blood chromosomal studies should be performed on a couple after three or more spontaneous abortions because in about 3% to 5% of such couples, one member is a carrier of a balanced rearrangement. The recurrence risk for spontaneous abortions, abnormal offspring, or both is greatly increased among translocation carriers, and it can be estimated according to the type of translocation and which parent carries the translocation. For example, if the mother carries a balanced 14;21 robertsonian translocation, the risk for a child with an unbalanced translocation resulting in Down syndrome is 10% to 15%. However, if the father carries the translocation, the risk for an affected child is 2% to 3%. These couples should be alerted to the advisability of prenatal diagnosis because of their increased risk for having liveborn children with unbalanced translocations.

Using fluorescent in situ hybridization (FISH), a labeled chromosome-specific DNA segment or probe is hybridized to metaphase, prophase, or interphase chromosomes and visualized with fluorescent microscopy. FISH analysis has led to the identification of a number of genetic syndromes that could not previously be detected because the chromosomal deletion in these syndromes is beyond the resolution of banded chromosomal analysis. Syndromes identified by FISH analysis include Prader-Willi, Angelman, DiGeorge, and Williams syndromes. Trisomies can also be identified in interphase cells with FISH probes.

Single Gene Disorders

Single gene disorders are relatively uncommon. They follow the laws of mendelian inheritance and may be passed from generation to generation, as with autosomal dominant disorders, or affect siblings without a family history of other affected family members, as in autosomal recessive disorders. Males may be affected with healthy females transmitting the abnormal gene, as in X-linked recessive disorders.

Autosomal Dominant Disorders

In autosomal dominant disorders, only one abnormal gene is necessary for disease manifestation. The affected individual has a 50% chance of passing the gene and the disorder on to offspring. The unaffected offspring cannot pass on the gene or the disorder. The occurrence and transmission of the genes are not influenced by gender. A spontaneous mutation of genetic material in the germ cells of clinically normal parents can also result in an affected offspring.

The hallmark of autosomal dominant disease is the variable expressivity. It is important to determine whether a child is affected by a spontaneous mutation or is the product of a parent with minimal expression of the same gene. A careful history and physical examination of family members, in addition to biochemical, radiologic, or histologic testing, may be necessary to determine the parents’ genetic status.

Some of the common autosomal dominant disorders include tuberous sclerosis, neurofibromatosis, achondroplasia, craniofacial synostosis, adult-onset polycystic kidney disease, and several types of muscular dystrophy.

image Autosomal Recessive Disorders

With autosomal recessive disorders, two affected genes must be present for manifestation of the disease. Usually there is no family history, but if a family history exists, siblings of either sex are equally likely to be affected. Consanguineous couples are at an increased risk for having a child who is homozygous for a deleterious recessive gene, with subsequent pregnancies being at 25% risk for producing a similarly affected child.

Many autosomal recessive disorders may be diagnosed prenatally. Biochemical genetic disorders (e.g., Tay-Sachs disease) can be diagnosed by enzymatic assay, whereas others (e.g., sickle cell disorders, β-thalassemia, and cystic fibrosis) can be diagnosed by DNA analysis from amniocytes or chorionic villi.

GENETIC SCREENING FOR AUTOSOMAL RECESSIVE DISORDERS

Carrier screening programs for autosomal recessive disorders have traditionally focused on high-risk populations, in which the frequency of heterozygotes is greater than in the general population. Screening for Tay-Sachs disease among Eastern European Jewish and French Canadian populations has proved to be particularly successful in the recognition of couples at 25% risk for having offspring affected with this fatal disease. Table 7-4 lists selected autosomal recessive disorders for which genetic screening has been initiated.

TABLE 7-4 SELECTED AUTOSOMAL RECESSIVE DISEASES IN DEFINED ETHNIC GROUPS

Disease

Ethnic Group

Carrier Frequency

Sickle cell disease

Blacks

1/10

Cystic fibrosis

Whites

1/25

Tay-Sachs disease

Jews, French Canadians

1/30

Thalassemia

Mediterraneans, Southeast Asians

1/25

The most common gene carried by North American whites is the cystic fibrosis (CF) gene (carrier frequency, 1/25). With the use of recombinant DNA technology, the CF gene has been mapped to chromosome 7, and a gene deletion (AF508) has been found in about 70% of carriers. More than 400 mutations have been identified in the CF gene. Genetic counseling is essential in offering CF carrier detection because 15% of carriers (and maybe more depending on ethnic group) remain undetected, and the limitations of the testing must be explained. At present, carrier detection is offered to individuals with a family history of CF, partners of identified CF carriers, parents of a fetus with ultrasonic findings of an echogenic bowel, those who donate sperm, and any parent who requests carrier testing.

image Sex-Linked Disorders

Sex-linked disorders, caused by recessive genes located on the X chromosome, primarily affect males, whereas unaffected (or mildly affected) females carry the deleterious gene. There is no male-to-male transmission of X-linked disorders. Using gene mapping technology, many sex-linked disorders such as Duchenne muscular dystrophy (DMD) or fragile X syndrome can now be diagnosed by CVS or amniocentesis. X-linked disorders can occur because of new mutations of genetic material as a sporadic event or from the inheritance of the X-linked recessive gene from the carrier mother.

Fragile X syndrome is an X-linked disorder that is the second most common form of mental retardation after Down syndrome, and the most common form of inherited mental retardation. It has an incidence of 1 per 1500 males and 1 per 2500 females. Mental impairment is variable in heterozygous females. The fragile X syndrome is caused by triplet repeat expansion in the long arm of the X chromosome. Using molecular genetic techniques, the number of triplet repeats can be measured in affected individuals to confirm a suspected diagnosis of fragile X or fragile X carrier status. In women who have a family history of mental retardation, genetic counseling is recommended for consideration of fragile X testing in the patient or family member.

image Multifactorial Disorders

Many birth defects are inherited in a multifactorial fashion, which means that both genes and the environment play a role. Common multifactorial disorders include cleft lip or palate, neural tube defects (spina bifida or anencephaly), congenital heart defects, and pyloric stenosis.

Neural tube defects occur in about 1 per 1000 births in the United States. In Northern Ireland, Wales, and Scotland, the incidence of neural tube defects is 6 to 8 per 1000 births. Both anencephaly (congenital absence of the forebrain) and spina bifida (open spine) are believed to occur before 30 days’ gestation because of failure of the neural tube to close. Newborns with anencephaly are stillborn or die within the first few days of life. Newborns with spina bifida have a variable course, depending on the site of the lesion and whether it is a meningocele (herniation of the meninges through an open spinal defect with cord remaining in its usual position) or a myelocele (herniation of the spinal cord). Folic acid has been shown to lower the risk for neural tube defects, and women who have had an infant with a neural tube defect should take vitamins plus 4 mg of folic acid daily before conception. Because neural tube closure is complete by 28 days postconception, initiating folic acid after the first 28 days has no prophylactic value.

With multifactorial disorders in general, and with neural tube defects in particular, a couple who has had one affected child has an increased risk of about 3% for having another similarly affected child.

image Maternal Ultrasonic and Serum Marker Screening

There are multiple approaches available for maternal screening for fetal aneuploidy. Traditionally, second-trimester screening has been the standard approach. First-trimester screening was introduced in the late 1990s.

FIRST-TRIMESTER SCREENING

A combination of maternal age, fetal nuchal translucency (NT) thickness, and maternal serum-free β-human chorionic gonadotrophin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) are included in the first-trimester screen. Maternal age alone has only a 30% detection rate. In the early 1990s, an association was reported between fetal chromosomal abnormalities and the finding of an abnormally increased nuchal translucency (an echo-free area at the back of the fetal neck) between 10 and 14 weeks’ gestational age (Figure 7-2). Increased nuchal translucency has been associated with both chromosomal abnormalities and other congenital anomalies. Elevated levels of free β-hCG and low levels of plasma protein-A are associated with an increased risk for Down syndrome. A multicenter study in the United States reported that combining first-trimester maternal serum screening markers with nuchal translucency and maternal age showed a detection rate for Down syndrome of 79% with a positive screening rate of 5%. Anatomic and radiographic studies have shown absence or hypoplasia of the nasal bones in fetuses with Down syndrome. Visualization of the nasal bone on first-trimester ultrasound has been shown to reduce the risk for Down syndrome (see Figure 7-1), whereas nonvisualization (absence) has been associated with increased risk. The addition of nasal bone assessment to nuchal lucency measurement and serum biochemistry can increase the Down syndrome detection rate to 93% with a screen positive rate of 5%.

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FIGURE 7-2 Ultrasound image of fetal head at 12 weeks and 0 days showing a lucent area at the posterior aspect of the fetal neck that can be measured. Normal values for this measurement and the risk associated with abnormal measurements are based on gestational age as determined by crown-rump length.

SECOND-TRIMESTER SCREENING

Traditionally, a woman was offered the serum triple screening test that measures alpha fetoprotein (AFP)hCG, and unconjugated estriol (UE3) at 16 to 20 weeks of gestation. Amniotic fluid alpha-fetoprotein (AFP) levels are frequently elevated in blood samples of women carrying fetuses affected with neural tube defects. Approximately 80% to 85% of all open neural tube defects can be detected by maternal serum AFP (MSAFP). In addition to open neural tube defects, ventral wall defects (gastroschisis or omphalocele) can cause elevations of MSAFP.

If the MSAFP level is elevated, an ultrasound is done to rule out multiple gestation, fetal demise, or inaccurate gestational age (all of which can give false-positive results). If none of these factors are present, amniocentesis is recommended to determine the amniotic fluid AFP level and to measure acetylcholinesterase (AChE). Acetylcholinesterase is a protein that is present only if there is an open neural tube defect.

An association between low maternal serum AFP and Down syndrome has been noted. The combination of low MSAFP, elevated hCG, and low UE3 levels (triple screen) has a detection rate for Down syndrome of about 70%, with a positive screen result in about 5% of all pregnancies.

Low MSAFP, low hCG, and low UE3 levels can also be used to screen for trisomy 18. With the addition of inhibin A, the quadruple screen increases the Down syndrome detection rate to 81%, with a positive screen result in 5% of pregnancies.

COMBINED FIRST- AND SECOND-TRIMESTER SCREENING

In an attempt to improve the detection rate and minimize the screen positive rate and the number of invasive procedures, a few studies have been conducted to evaluate the concept of combining first- and second-trimester screening. The approaches that have been proposed include integrated screening and sequential screening.

With integrated screening, the first- and second-trimester results are combined into a single risk calculation and are not reported until after the second-trimester results are available. This approach has been found to have the highest sensitivity and to be the most cost effective. Sequential screening involves performance of both first- and second-trimester screening with disclosure of the first-trimester results for clinical management.

It is not uncommon for one or more of the biomarkers to be abnormal in the presence of a chromosomally normal fetus. An elevated level of β-hCG or AFP and low levels of PAPP-A or UE3 are associated with complications of pregnancy such as preterm birth, intrauterine growth restriction, and preeclampsia. Thus, these pregnancies require close follow-up.

Genetic counseling is an essential component of screening programs. It provides education and alleviates anxiety in patients with abnormal test results. Patients must be informed of the differences between screening results and diagnostic testing.

image Diagnostic Procedures

Recombinant DNA technology, coupled with first-trimester fetal tissue sampling, has enhanced the growth and development of prenatal diagnosis. Obstetric procedures, such as ultrasonography, amniocentesis, chorionic villus sampling, and cordocentesis (percutaneous umbilical blood sampling [PUBS]) are currently used during prenatal diagnosis. These procedures are described and discussed in Chapter 17.

image Teratology

A teratogen is any agent or factor that can cause abnormalities of form or function (birth defects) in an exposed fetus. Such abnormalities include fetal wastage and intrauterine fetal growth restriction, malformations due to abnormal growth and morphogenesis, fetal endocrine disruption, and abnormal central nervous system performance.

It was not until the teratogenic effects of rubella infection were demonstrated in 1941 that any notable consideration was given to environmental factors and their potentially deleterious effects on human pregnancy. In the succeeding decades, the susceptibility of the fetus to many environmental factors has been appreciated.

Probably the best known teratogen is thalidomide, which was shown to cause phocomelia and other malformations in the offspring of mothers who had been given the drug during pregnancy. It is the only example of a teratogen that, when introduced to the pregnant population, led to a dramatic epidemic of a specific malformation; withdrawal of the drug led to a virtual disappearance of the malformation.

Although drugs are the most obvious source for teratogenic exposure, chemical waste disposals, alcohol, tobacco, cosmetics, and occupational agents contain substances that individuals are exposed to such as fertilizers and insecticides. Some of these agents are known teratogens, whereas the fetal effects of others are not known.

EXPOSURE

Results of the Collaborative Perinatal Project indicate that more than 900 different drugs are taken by pregnant women in the United States and that 40% of women take medication during the first trimester, when organogenesis occurs. During the first trimester alone, as many as 32% of pregnant women are exposed to analgesics (mostly aspirin), 18% to immunizing agents, 16% to antimicrobial and antiparasitic agents, and 6% to sedatives, tranquilizers, and antidepressants.

PRINCIPLES OF TERATOLOGY

Fetal Susceptibility

The efficacy of a particular teratogen is, in part, dependent on the genetic makeup of both mother and fetus, as well as on a number of factors related to the maternal-fetal environment. For instance, many congenital abnormalities, such as oral clefts, congenital heart disease, and neural tube defects, are inherited through multifactorial inheritance.

Dose

Depending on the particular teratogen, there may be (1) no apparent effect at a low dose, (2) an organ-specific malformation at an intermediate dose, or (3) a spontaneous abortion at a high dose. Additionally, smaller doses administered over several days may produce a different effect from a single large dose.

Timing

Three stages of teratogenic susceptibility may be identified on the basis of gestational age. Before implantation (1 week postovulation in humans), there is no demonstrable teratogenic insult. The most vulnerable stage is from day 17 to day 56 postconception (or day 31 to day 71 by gestational age), during the period of organogenesis. The timing determines which organ system or systems are affected. Unfortunately, most women do not realize they are pregnant until this critical period of development is well under way. From about the 4th month of pregnancy to the end of gestation, embryonic development consists primarily of increasing organ size. With the exception of a limited number of tissues (brain and gonads), teratogenic exposure after the 4th month usually causes decreased growth without malformation.

Nature of Teratogenic Agents

Although few agents are known to cause serious malformations in a large proportion of exposed individuals, there are probably hundreds of potentially teratogenic agents, given the right set of circumstances (susceptible fetus, embryologically vulnerable period, large teratogenic dose). Furthermore, certain drugs combined with other drugs may be capable of producing malformations, although neither agent would be teratogenic when taken alone.

TERATOGENIC AGENTS

Teratogens may be assigned to three broad categories: (1) drugs and chemical agents, (2) infectious agents, and (3) radiation. The list that follows is far from exhaustive. Pharmaceutical agents have their fetal risk classification (as of 2008; see Box 7-1) in parentheses following the drug name.

image

BOX 7-1 FDA Fetal Drug Risk Classification (approximate percent of drugs in each category)

Category A (<5%)

Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester.

Category B (50%)

Animal-reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women.

Category C (40%)

Studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other), and there are no controlled studies in women.

Category D (<5%)

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk.

Category X (<5%)

Studies in animals or human beings have demonstrated fetal abnormalities, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

In 2008 the U.S. FDA proposed an overhaul of how pregnancy and breastfeeding information should be included on provider labeling for prescription drugs. The proposed new labeling would eliminate the current lettering system (above), which is not required to be updated as new information becomes available and, according to experts, can be misleading. The proposed new system would provide brief bulleted information instead of a letter designation on the potential benefits and risks for the mother and the fetus and how these risks may change the course of pregnancy. The proposed new system would require drug labels to be updated as new data emerge. The U.S. FDA website (www.fda.gov) should be consulted for the latest information on the new system and on drug risk during pregnancy and breastfeeding.

 Food and Drug Administration.

image

Alcohol

The adverse effects of ethanol (D) on fetal development were not fully realized until the 1970s. The frequency of the fetal alcohol syndrome runs as high as 0.2%, whereas an additional 0.4% of newborns show less severe features of the disorder (Box 7-3).

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BOX 7-3 Clinical Features of Fetal Alcohol Syndrome

Craniofacial

Eyes: Short palpebral fissures, ptosis, strabismus, epicanthic folds, myopia, microphthalmia

Ears: Poorly formed concha, posterior rotation

Nose: Short, hypoplastic philtrum

Mouth: Prominent lateral palatine ridges, micrognathia, cleft lip or palate, faulty enamel

Maxilla: Hypoplastic

Cardiac

Murmurs, atrial septal defect, ventricular septal defect, tetralogy of Fallot

Central Nervous System

Mild to moderate mental retardation, microcephaly, poor coordination, hypotonia

Growth

Prenatal-onset growth deficiency

Muscular

Hernias of diaphragm, umbilicus, or groin

Skeletal

Pectus excavatum, abnormal palmar creases, nail hypoplasia, scoliosis

image

Antianxiety Agents

Antianxiety agents are currently used by a significant number of pregnant women. Data regarding their teratogenicity are conflicting, although exposure to meprobamate (D) or chlordiazepoxide (D) has been associated with a greater than fourfold increase in severe congenital anomalies. Fluoxetine (B) is now the drug of choice for anxiety and depression during pregnancy and is considered safe to continue even in women who breastfeed. The risk for recurrence of significant depression during pregnancy is too great to routinely discontinue treatment during pregnancy.

Antineoplastic Agents

Aminopterin (X) and methotrexate (D), both of which are folic acid antagonists, have been clearly established as teratogens. Exposure before 40 days’ gestation is lethal to the embryo; later exposure during the first trimester produces fetal effects, including intrauterine growth restriction, craniofacial anomalies, abnormal positioning of extremities, mental retardation, early miscarriage, stillbirth, and neonatal death.

Alkylating agents, including busulfan (D), chlorambucil (D), cyclophosphamide (D), and nitrogen mustard (D), have been associated with fetal anomalies such as severe intrauterine growth restriction, fetal death, cleft palate, microphthalmia, limb reduction anomalies, and poorly developed external genitalia. During the first trimester, the teratogenic risks may be as high as 30%.

Anticoagulants

COUMARIN DERIVATIVES

Use of warfarin (Coumadin [D]) during the first trimester is associated with an increased risk for spontaneous abortion, intrauterine growth restriction, central nervous system defects (including mental retardation), stillbirth, and a characteristic syndrome of craniofacial features known as the fetal warfarin syndrome. Embryologically, the most vulnerable time appears to be between 6 and 9 weeks after conception. As many as 30% of exposed fetuses suffer serious teratogenic consequences, or loss of the pregnancy occurs. Warfarin easily crosses the placenta, causing bleeding problems in the fetus, and is excreted in breast milk.

HEPARIN

Heparin (B) has major advantages over coumarin anticoagulants during pregnancy because it does not cross the placenta. Reported risks include prematurity and fetal demise. Because no specific malformation syndrome has been described, these abnormalities may be more closely related to the maternal disease necessitating the heparin use.

Anticonvulsants

About 1 in 200 pregnant women is epileptic. Box 7-4 lists the etiologic factors that may play a role in the congenital abnormalities associated with in utero exposure to anticonvulsants. The complexity in providing genetic counseling for pregnant epileptic women is underscored when considering the interactive effects of these factors, the effect of combined anticonvulsant treatment, and the genetic aspects of the disease itself. The goals of counseling include providing the patient with the teratogenic risks of her medication, the risk for seizures during pregnancy, the effect of pregnancy on seizures, and the risk for development of epilepsy in her offspring. From a medication standpoint, the benefits of seizure prevention need to be weighed against the teratogenicity of the drug.

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BOX 7-4 Etiologic Factors that May Play a Role in Anticonvulsant Teratogenicity

Antiepileptic Drugs

Dose, serum levels, metabolism, teratogenicity, metabolic interactions

Genetic Predisposition

Maternal, paternal, and fetal metabolism

Maternal Disease

Teratogenicity, underlying disease, seizures

image

DIPHENYLHYDANTOIN (DILANTIN [D])

A specific syndrome, known as the fetal hydantoin syndrome, has been described, the clinical features of which include craniofacial abnormalities, limb reduction defects, prenatal-onset growth restriction, mental deficiency, and cardiovascular anomalies. About 10% of exposed fetuses demonstrate fetal hydantoin syndrome, whereas an additional 30% may have isolated features of the syndrome. Hydantoins may also have a prenatal carcinogenic effect because several exposed infants with signs of fetal hydantoin syndrome have subsequently developed neuroblastomas.

ANTICONVULSANTS

Trimethadione (Tridione [D]) and paramethadione (Paradione [D]), used to treat petit mal epilepsy, have been associated with a characteristic malformation syndrome in exposed fetuses. The clinical features include craniofacial abnormalities, prenatal-onset growth restriction, an increased frequency of mental retardation, and cardiovascular abnormalities. Because of this serious teratogenic potential and because petit mal epilepsy is rare during reproductive years, oxazolidinedione anticonvulsants are contraindicated during pregnancy.

VALPROIC ACID

Valproic acid (D) use during pregnancy is associated with a 1% to 2% risk for open spina bifida. Other findings reported to be associated with valproic acid exposure include cardiac defects, skeletal defects, and craniofacial malformations.

CARBAMAZEPINE

As with valproic acid, carbamazepine (Tegretol [C]) exposure during pregnancy is associated with an increased risk for fetal spina bifida and is an indication for amniotic fluid AFP analysis. Some studies have reported a specific malformation pattern that includes minor craniofacial defects, fingernail hypoplasia, and developmental delay, which are features that would be unlikely to be detected prenatally.

PHENOBARBITAL

The true teratogenicity of phenobarbital (D) is difficult to assess because other drugs are usually taken in combination with this agent, but the risk appears to be very low. Potential complications of phenobarbital include neonatal withdrawal symptoms and neonatal hemorrhage.

Hormones

ESTROGEN-PROGESTIN COMBINATIONS

A large number of pregnant women are exposed to progestins or estrogen-progestin combinations because they continue taking birth control pills, unaware that they are pregnant. Recent analyses have failed to confirm any teratogenicity, and the U.S. Food and Drug Administration has removed the product insert warnings. The main abnormality associated with the use of strongly androgenic progestins during pregnancy is masculinization of the external genitalia in female fetuses, with a risk of up to 2%.

DIETHYLSTILBESTROL

Diethylstilbestrol (DES [X]), which in the past was widely used in the treatment of “threatened abortion,” has clearly been established as a fetal teratogen and carcinogen when used in human pregnancy. DES exposure poses an increased risk for cervical abnormalities and uterine malformations (see Figure 19-2as well as for vaginal clear cell adenocarcinomas in female offspring. Exposed males may be at increased risk for testicular abnormalities, infertility, and testicular malignancy.

Miscellaneous Agents

RETINOIDS

Isotretinoin (Accutane [X]) is prescribed for cystic acne or for acne that has not responded to other forms of treatment. Exposure during pregnancy is clearly associated with a specific malformation pattern that includes central nervous system, cardiovascular, and craniofacial defects (especially ear abnormalities). The central nervous system findings include hydrocephaly, facial nerve palsies, and cortical blindness. Microcephaly with severe ear anomalies, microtia, and cleft palate are common findings. The risk for spontaneous abortion or congenital malformations is greater than 50% in patients who take isotretinoin throughout the first trimester.

Etretinate (X), used for severe psoriasis, has been similarly associated with a characteristic malformation pattern. However, unlike isotretinoin, which has a half-life of less than 1 day, etretinate has a half-life of months, leading to a longer risk period even after the agent has been discontinued.

TOBACCO SMOKING

Maternal tobacco smoking interferes with prenatal growth, including birth weight, birth length, and head circumference. The teratogenic effects are related to the extent of maternal exposure to tobacco and include an increased risk for spontaneous abortion, fetal death, neonatal death, and prematurity. Pregnant women should be strongly encouraged to avoid smoking (or secondhand smoke). They should continue to abstain after delivery because secondhand smoke exposure is associated with an increased risk for respiratory diseases in infants and children.

ILLICIT DRUGS

Prenatal cocaine exposure, particularly among chronic abusers, has been associated with fetal malformations, particularly genitourinary tract anomalies; behavioral abnormalities have also been documented in such fetuses.

INFECTIOUS AGENTS

The exact frequency of significant infection during pregnancy is not known, but it is probably between 15% and 25%. Viruses, bacteria, and parasites may have serious effects on the fetus, including fetal death, growth delay, congenital malformations, and mental deficiency. In more recent years, the AIDS epidemic has had a significant impact on pregnancy management.

RADIATION

Prenatal ionizing radiation exposure occurs frequently as a result of therapeutic or diagnostic medical and dental procedures. The medical effects of ionizing radiation are dose dependent and include teratogenesis, mutagenesis, and carcinogenesis. The most critical period appears to be from about 2 to 6 weeks after conception. Exposures before 2 weeks produce either a lethal effect or no effect at all. Teratogenicity is still a possibility after 5 weeks, but the risk for deleterious consequences is relatively small.

Theoretically, any dose of ionizing radiation at a critical time could cause fetal damage. In most circumstances, diagnostic levels of radiation do not produce a teratogenic risk in the developing fetus.

image Advice during Pregnancy

One of the most important functions of prenatal care is to provide information and support to the woman for self-care. The Cochrane pregnancy and childbirth database (www.cochrane.org) has compiled systematic reviews on the effectiveness of advice and interventions during pregnancy and can be a useful source of information for prenatal care providers. The following sections examine advice given on alleviating unpleasant symptoms, nutrition, lifestyle, and breastfeeding.

ALLEVIATING UNPLEASANT SYMPTOMS DURING PREGNANCY

Nausea and vomiting complicate up to 70% of pregnancies. Eating small, frequent meals and avoiding greasy or spicy foods may help. Also, having protein snacks at night, saltine crackers at the bedside, and room-temperature sodas is a nonpharmacologic approach that may provide some relief. When medication is deemed necessary, antihistamines appear to be the drug of choice, although no single product has been satisfactorily tested for efficacy and safety. Vitamin B6 (pyridoxine) and acupressure (“sea sickness arm bands”) may be effective. Patients with dehydration and electrolyte abnormalities from vomiting (hyperemesis gravidarum) should be evaluated for possible secondary causes, and they may need hospitalization for rehydration and antiemetic therapy.

Heartburn affects about two thirds of women at some stage of pregnancy, resulting from progesterone-induced relaxation of the esophageal sphincter. Avoiding lying down immediately after meals and elevating the head of the bed may help reduce heartburn. When these simple measures fail, antacids, such as calcium carbonate, should be used.

Constipation is a troublesome problem for many women in pregnancy, secondary to decreased colonic motility. Dietary modification, including increased fiber and water intake, can help lessen this problem. Stool softeners may be used in combination with bulking agents. Irritant laxatives should be reserved for short-term use in refractory cases.

Hemorrhoids are caused by increased venous pressure in the rectum. Increased rest, with elevation of the legs, and avoidance of constipation are recommended.

Leg cramps are experienced by almost half of all pregnant women, particularly at night and in the later months of pregnancy. Massage and stretching may afford some relief during an attack. Both calcium and sodium chloride appear to help reduce leg cramps in pregnancy.

Backaches are common during pregnancy and are lessened by avoiding excessive weight gain. Additionally, exercise, sensible shoes, and specially shaped pillows can offer relief. In cases of muscle spasm or strain, analgesics (such as acetaminophen), rest, and heat may lessen the symptoms.

NUTRITIONAL COUNSELING

Although the nutritional care plan should be individualized, every woman can benefit from nutritional education that includes counseling on weight gain, dietary guidelines, physical activity, avoidance of harmful substances and unsafe foods, and breastfeeding. The appropriate weight gain during pregnancy is listed in Table 7-5. Recommended rates of weight gain per week during the second and third trimesters are 1.1 pound, 0.9 pound, and 0.66 pound for pregnant women who are underweight, normal weight, and overweight, respectively. Inadequate weight gain has been associated with low birth weight, whereas excessive weight gain has been associated with fetal macrosomia and maternal obesity, because of the difficulty of the mother returning to her prepregnancy body weight. Women should avoid fasting (>13 hours without food) or skipping meals. This behavior is associated with accelerated ketosis and a greater risk for preterm delivery. They should have five feedings per day (breakfast, lunch, afternoon snack, dinner, and bedtime snack). Pregnant women should never skip breakfast.

TABLE 7-5 APPROPRIATE WEIGHT GAIN IN PREGNANCY

 

BMI

Recommended Weight Gain (pounds)

Underweight

<19

28–40

Normal

19–25

25–35

Overweight

>25

15–25

Weight gain is an important consideration during pregnancy, and the clinician should emphasize the right amount of nutrition over the right amount of weight gain. Normal pregnancy requires an increase in daily caloric intake of 300 kcal.

LIFESTYLE ADVICE

Women should be advised to rest when tired and should be reassured that the fatigue usually abates by the 4th month of pregnancy. Normal prepregnancy activity levels are usually acceptable. Advice regarding work should be individualized to the nature of the work, the health status of the woman, and the condition of the pregnancy. Work that requires prolonged standing, shift or night work, and high cumulative occupational fatigue has been associated with an increased risk for low birth weight and prematurity. When working conditions involve occupational fatigue or stress, a change in work during pregnancy should be recommended by the prenatal care provider.

Women should be advised to continue to exercise during pregnancy, unless there is pregnancy-induced hypertension, preterm labor or rupture of membranes, intrauterine growth restriction, incompetent cervix, persistent second- or third-trimester bleeding, or medical conditions that severely restrict physiologic adaptations to exercise during pregnancy. They should avoid exercise in the supine position after the first trimester and should be encouraged to modify the intensity of their exercise according to maternal symptoms. Any type of exercise involving the potential for loss of balance or even mild abdominal trauma should be avoided.

Travel is acceptable under most circumstances. Prolonged sitting increases the risk for thrombus formation and thromboembolism. Pregnant women should be encouraged to ambulate periodically when taking a long flight or car ride. Support stockings may help reduce lower limb edema and varicose veins. International travel that places the patient at a high risk for infectious disease (such as travel to areas with a high rate of transmission of malaria or typhoid fever) should be avoided, whenever possible. When such travel cannot be avoided, appropriate vaccinations should be administered. For specific recommendations go to www.cdc.gov and select “Traveler’s Health.” Live attenuated virus vaccinations are generally contraindicated in pregnancy, but inactivated virus vaccines may be acceptable.

Women should be reassured that increased, unchanged, and decreased levels of sexual activity can all be normal during pregnancy. Abstinence or condom use may be advisable if there is an increased risk for preterm labor or repeated pregnancy loss, or in women with a history of persistent second- or third-trimester bleeding.

BREASTFEEDING

Breastfeeding has been shown to significantly reduce morbidity and improve cognitive development during infancy and childhood. Providers should initiate discussion with the pregnant woman and her family regarding breastfeeding during the first visit, including possible barriers to breastfeeding, such as prior poor experiences, misinformation, or nonsupportive work environment. Partners, peers, and other family members or friends may also exert an important influence on a woman’s decision to breastfeed. Referral to a childbirth preparation class or a lactation consultant may provide additional encouragement to breastfeeding.

FOLLOW-UP VISITS

Additional prenatal visits are routinely scheduled every 4 weeks until 28 weeks’ gestation, every 2 to 3 weeks until 36 weeks’ gestation, and then weekly until delivery. The schedule of these follow-up visits, however, should be tailored to the needs of individual patients. The regularity of scheduled prenatal visits should be sufficient to allow the clinician to monitor the progression of the pregnancy, provide education and recommended screening and interventions, assess the well-being of the fetus and mother, reassure the mother, and detect and treat medical and psychosocial complications.

During each regularly scheduled visit, the clinician should evaluate blood pressure, weight, urine protein and glucose, uterine size for progressive growth, and fetal heart rate. After the woman reports quickening (first sensation of fetal movement, on average at 20 weeks’ gestation) and at each subsequent visit, she should be asked about fetal movements. Between 24 and 34 weeks, women should be taught warning symptoms of preterm labor (uterine contractions, leakage of fluid, vaginal bleeding, low pelvic pressure, or low back pain). Patients at risk may require additional visits to assess signs and symptoms of preterm labor. Beginning in the late second trimester, they should also be taught to recognize the warning symptoms of preeclampsia (frontal headache, visual changes, hand or facial swelling, epigastric or right upper quadrant pain). Near term, they should be instructed on the symptoms of labor.

Beginning at 28 weeks, systematic examination of the abdomen is carried out at each prenatal visit to identify the lie (e.g., longitudinal, transverse, oblique), presentation (e.g., vertex, breech, shoulder), and position (e.g., flexion, extension, or rotation of the occiput) of the fetus. This can be accomplished by the maneuvers of Leopold. The first maneuver involves palpating the fundus to determine which part of the fetus occupies the fundus. The head is round and hard, whereas the breech is irregular and soft. The second maneuver involves palpating either side of the abdomen to determine on which side the fetal back lies. The fetal back is linear and firm, whereas the extremities have multiple parts. The third maneuver involves grasping the presenting part between the thumb and third finger just above the pubic symphysis to determine the presenting part. The fourth maneuver involves palpating for the brow and the occiput of the fetus to determine fetal head position when the fetus is in a vertex presentation. This is best accomplished with the examiner facing the patient’s feet and placing both hands on either side of the lower abdomen just above the inlet. By exerting pressure in the direction of the pelvic inlet, the hand running along the back will bump into the occiput if the head is extended, whereas the hand on the same side of the small parts will bump into the brow if the head is flexed. If there is a question about the presentation of the fetus, a real-time ultrasound may be performed.

Depending on the practice setting and population, either universal or selective screening for gestational diabetes should be performed between 24 and 28 weeks of gestation. Risk factors for selective screening include family history of diabetes; previous birth of a macrosomic, malformed, or stillborn baby; hypertension; glycosuria; maternal age of 30 years or older; or previous gestational diabetes. Repeat measurements of hemoglobin or hematocrit levels early in the third trimester have been recommended. Tests for sexually transmitted infections (e.g., syphilis) may also be repeated at 32 to 36 weeks of gestation if the woman has specific risk factors for these diseases. The Centers for Disease Control and Prevention recommend universal screening for maternal colonization of group B streptococcus at 35 to 37 weeks of gestation. The value of selective ultrasound for specific indications has been clearly established; the value of routine ultrasound in low-risk pregnancies remains undetermined. Ultrasonic examination during pregnancy is not harmful, but controlled trials have failed to demonstrate that routine ultrasonic examinations for dating in early pregnancy, anatomic survey in mid-pregnancy, or assessment of fetal growth in late pregnancy improve perinatal outcome.

image Assessment of Fetal Well-Being

During the past 20 years, electronic advances have provided new technology that has made the fetus more accessible and has allowed visualization of the fetus and recording of intrauterine fetal events. A combination of the nonstress test, contraction stress test, and real-time ultrasonic assessment is used to assess fetal well-being. Figure 7-3 presents an algorithm that may be used to follow a high-risk pregnancy.

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FIGURE 7-3 Algorithm for the antenatal evaluation of a high-risk pregnancy.

MATERNAL SELF-ASSESSMENT OF FETAL WELL-BEING

A simple technique (kick counting) may be used to assess fetal well-being. The mother assesses fetal movement (kick counts) each evening on her left side. She should recognize 10 movements in 1 hour, and if she does not, she should retest in 1 hour. If she still does not have 10 fetal movements in 1 hour, she should contact her doctor or present for fetal assessment of well-being.

NONSTRESS TEST ASSESSMENT

The first step in the assessment of fetal well-being is the nonstress test. With the mother resting in the left lateral supine position, a continuous fetal heart rate tracing is obtained using external Doppler equipment. The mother reports each fetal movement, and the effects of the fetal movements on heart rate are determined. A normal fetus responds to fetal movement with an acceleration in fetal heart rate of 15 beats/minute or more above the baseline for at least 15 seconds (Figure 7-4). If at least two such accelerations occur in a 20-minute interval, the fetus is regarded as being healthy, and the test is said to be reactive. A nonreactive nonstress test is shown in Figure 7-5.

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FIGURE 7-4 Reactive nonstress test. Note the fetal heart rate (FHR) accelerations with most fetal movements, denoted by spikes above 75 mm Hg in lower panel. bpm, Beats per minute.

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FIGURE 7-5 Nonreactive nonstress test. Note the lack of beat-to-beat variability and the lack of acceleration of the fetal heart rate (FHR) with fetal movements (arrows). bpm, Beats per minute.

ULTRASONIC ASSESSMENT

The next step in prenatal assessment is to determine the adequacy of amniotic fluid volume by real-time ultrasonography. Reduced fluid (oligohydramnios) suggests fetal compromise. Oligohydramnios can be defined as an amniotic fluid index (AFI) of less than 5 cm. The AFI represents the sum of the linear measurements (in centimeters) of the largest amniotic fluid pockets noted on ultrasonic inspection of each of the four quadrants of the gestational sac. When amniotic fluid is reduced, the fetus is more likely to become compromised as a result of umbilical cord compression. Excessive amniotic fluid (polyhydramnios; AFI > 23 cm) can be a sign of poor control in a diabetic pregnancy or an indication that the fetus may have an anomaly. Fetal breathing (chest wall movements) and fetal movements (stretching and rotational movements) are also used to assess the fetus. A fetus who has at least 30 breathing movements in 10 minutes or 3 body movements in 10 minutes is considered healthy. A combination of a reactive nonstress test, adequate amniotic fluid, adequate fetal breathing, adequate fetal movements, and adequate tone is frequently referred to as a normal biophysical profile. Each parameter is given a score of 2. A normal profile equals 10. Table 7-6 lists the recommended frequency for biophysical profile testing based on the high-risk condition.

TABLE 7-6 RECOMMENDED FREQUENCY FOR BIOPHYSICAL PROFILE TESTING

High-Risk Condition

Frequency

IUGR

 

Mild

Weekly

Moderate

Twice weekly

DIABETES MELLITUS

 

Class A

Weekly, 37 to 40 wk

 

Twice weekly, beyond 40 wk

Class B and worse

Twice weekly, beginning at 34 wk

POST-TERM PREGNANCY

Twice weekly, beginning at 42 wk

Decreased fetal movements

Weekly

Other high-risk conditions

Weekly

Maternal or physician concern

Weekly

IUGR, intrauterine growth restriction.

 For severe IUGR, delivery is usually indicated.

UMBILICAL ARTERY DOPPLER ASSESSMENT

During the ultrasonic assessment, it is easy to assess fetal umbilical artery vascular resistance as an index of fetal health performing pulse wave Doppler assessment. A normal systolic-to-diastolic (S/D) ratio (Figure 7-6) suggests normal flow when the S/D ratio is low, indicating low fetal-placental vascular resistance. When flow becomes abnormal, there is complete loss of flow in the umbilical artery during diastole from the fetus to the placenta (Figure 7-7). When the fetus is very ill, there can be reversed flow during diastole, whereby the deflection during diastole is negative (downward, –cm/second) and blood in the umbilical artery flows backward from the placenta to the fetus in the umbilical artery. Under the latter condition, the fetus should be delivered expeditiously.

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FIGURE 7-6 Fetal umbilical artery Doppler assessment at 31 weeks and 3 days showing a series of Doppler waveforms with systolic (upper) peaks marked with X (+37 cm/sec) and lower X marking diastole at (+21 cm/sec). The systolic-to-diastolic ratio is calculated as 2.14 (upper right corner), and normal for this gestational age is <3.2.

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FIGURE 7-7 Fetal umbilical artery Doppler assessment at 26 weeks and 5 days in a case with reduced amniotic fluid (small lucent pocket left of midline with Doppler assessment of cord artery). The systolic-to-diastolic ratio cannot be calculated as in Figure 7-6 because of absent diastolic flow. Only systolic flow can be measured (+30 cm/sec).

CONTRACTION STRESS TEST

The contraction stress test is a test for uteroplacental dysfunction, a condition that may occur in a high-risk pregnancy. A dilute infusion of oxytocin is given to establish at least three uterine contractions in 10 minutes. If late decelerations are observed with each contraction, the test is positive (abnormal). If only one deceleration is observed, the test is suspicious. When the test is positive, the baby should usually be delivered.

PREVENTIVE HEALTH CARE

Management before and during pregnancy presents an opportunity for patient education and the practice of preventive medicine. Childbirth preparation classes for both the patient and her husband are very educational, particularly during the first pregnancy. The presence and encouragement of the baby’s father can be most helpful during labor and delivery. These classes provide an important opportunity for both parents to enhance bonding to the infant before birth.

Although preconception, prenatal, and obstetric information is of primary importance, other topics that may have lifelong relevance can be introduced and emphasized during antepartum care. The pregnancy itself is frequently a strong motivator for women to eliminate potentially harmful habits or dietary patterns and to become more aware of their general health. Therefore, a systematic approach to the dissemination of preventive health-care information is generally well received by the pregnant woman.

SUGGESTED READING

American Academy of Pediatrics, the American College of Obstetricians, Gynecologists. Guidelines for Perinatal Care, 4th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1997.

Invasive prenatal testing for fetal aneuploidy. ACOG Committee Opinion No. 88. Obstet Gynecol. 2007;110:1449-1457.

Liston R., Sawchuck D., Young D. Fetal health surveillance: Antepartum and intrapartum consensus guideline. Society of Obstetricians and Gynecologists of Canada. British Columbia Prenatal Health Program. [Erratum in J Obstet Gynaecol Can 29:909, 2007.]. J Obstet Gynaecol Can. 2007;29:S3-S56.

Mennuti M.T. Genetic screening in reproductive health care. Clin Obstet Gynecol. 2008;51:3-33.

Rayburn W.F. What you need to know about medication safety in pregnancy. OBG Management. 2007;19(11):66-82.