Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter III.4. High Risk Pregnancy
Mary Elaine Patrinos, MD
January 2002

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A 26 year old G1P0, O+, VDRL NR, rubella immune, HBsAg negative female at 27 weeks gestation presents to labor and delivery with a 2 day history of headache and facial swelling. Maternal history is remarkable for a single prenatal visit in the first trimester.

Exam: VS T 37, P 75, RR 14, BP 170/100. Her exam is remarkable for facial and pretibial edema and hyperreflexia.

Labs: Urine dipstick positive for 3+ protein. Ultrasound demonstrates decreased amniotic fluid. The fetus is in the breech position and no fetal abnormalities are noted. Estimated fetal weight is 650 grams.

A decision is made to deliver the infant by cesarean section following maternal treatment with betamethasone.


The risk factors identified in the above scenario include poor prenatal care, severe preeclampsia, prematurity, oligohydramnios, and intrauterine growth restriction. For the pediatrician, detailed knowledge of the maternal and pregnancy history is critical to providing timely and comprehensive care to the infant. Therapeutic interventions are planned based on the neonate's anticipated problems. Appropriate steps in preparing for the delivery of the above infant include: 1) mobilization of the high risk delivery team comprised of a physician (typically a neonatologist), neonatal nurse, and respiratory therapist, 2) notification of neonatal intensive care nursery staff, 3) preparation of exogenous surfactant for treatment of anticipated surfactant deficiency or respiratory distress syndrome (RDS), 4) planning for immediate vascular access to meet the infant's fluid and metabolic needs.

A high risk pregnancy can be defined as any pregnancy where maternal and/or fetal conditions may lead to an adverse perinatal outcome. Preterm labor (PTL) and delivery, premature rupture of membranes, multiple gestation, preeclampsia, diabetes, maternal substance abuse, and vaginal bleeding, are common high risk conditions. A pregnancy may be identified as high risk during the antepartum or intrapartum period. Indeed, lack of, limited, or late prenatal care, in and of itself, is a common high risk condition seen in urban perinatal centers. Screening tests for certain high risk problems such as diabetes, genetic conditions, and congenital anomalies are either routinely or selectively performed during the antepartum period for early recognition and intervention. This chapter will focus on a few of the more common pregnancy complications with an emphasis on neonatal outcome.

Preterm labor is defined as the onset of labor prior to 37 weeks gestation. The World Health Organization defines preterm delivery as a delivery that occurs between 20 and 37 weeks gestational age. Preterm labor is responsible for 40-50% of all preterm births. The remainder of preterm births occur from preterm premature rupture of membranes (PPROM) and maternal medical or obstetrical (maternal and/or fetal) complications (1). Most of the major risk factors for preterm delivery are: African-American ethnicity, socioeconomic status, smoking, substance abuse, poor nutrition, absent or inadequate prenatal care, history of preterm labor/delivery, uterine/cervical anomalies, uterine abnormalities (myomata, DES exposure), hypertension/preeclampsia, diabetes, multiple gestation, oligo- or polyhydramnios, vaginal bleeding, and infection.

After reviewing the list above, it is readily apparent that preterm delivery is the common denominator for many high risk conditions of pregnancy. Timely detection of preterm labor and delivery allows for prompt referral of the mother to a facility where more intensive surveillance, monitoring, and care for both mother and newborn can be accomplished (2).

The pathogenesis of spontaneous, isolated PTL is multifactorial; however, many cases appear to result from occult upper genital tract infections with activation of the decidua. Inflammatory cytokines such as interleukin-1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-a (TNFa) have been detected in amniotic fluid in association with intrauterine infection and preterm labor. These cytokines stimulate the production of PGE2 and PGF2a which increase dramatically during labor. Although eliminating or markedly reducing the incidence of PTL seems an impossible goal when considering its multiple causes, ongoing efforts to actively treat PTL remain critical, especially for the patient population less than 32 weeks gestation. Studies assessing prevention methods such as education and surveillance programs and home uterine activity monitoring have demonstrated no benefit in reducing the frequency of preterm birth. Other strategies involved in the treatment of preterm labor are: cervical cerclage, tocolytics (beta sympathomimetics such as terbutaline and ritodrine, magnesium sulfate, prostaglandin synthetase inhibitors such as indomethacin), and antibiotics. Of these, the most frequently used methods at Kapiolani Medical Center for Women and Children are cerclage, terbutaline, magnesium sulfate, and antibiotics. Although it has been difficult to demonstrate the efficacy of tocolytics and antibiotics in clinical trials for preterm labor, these agents may provide a 48 hour latency period during which antenatal corticosteroids can be administered. Maternal and fetal side effects must be considered with the use of any intervention for PTL. Cerclage is generally limited to patients with a history of incompetent cervix. It involves placing a suture circumferentially around the internal cervical os between 12-14 weeks gestation. Maternal risks associated with cerclage placement include the risk of anesthesia, bleeding, infection, rupture of membranes, maternal soft tissue injury, and spontaneous suture displacement. The major risks to the fetus are infection and preterm birth. Terbutaline, the most commonly used beta sympathomimetic, stimulates the beta-2 receptors found in the uterus. Potential fetal side effects of beta-2 agonists include elevation in baseline heart rate, rhythm disturbances, septal hypertrophy, and hypoglycemia. Magnesium sulfate affects uterine activity by decreasing the release of acetylcholine and altering the amount of calcium pumped out of myometrial cells. Respiratory and motor depression can occur in the neonate with high maternal magnesium levels. In general, side effects to the fetus and neonate are minimal when compared to beta sympathomimetics. Given the role of prostaglandins in labor, indomethacin would seem a logical choice for a tocolytic agent. Reported fetal side effects include oligohydramnios secondary to decreased fetal urine output, ductal constriction with the potential for subsequent persistent pulmonary hypertension in the neonate, and necrotizing enterocolitis. The use of indomethacin is restricted to pregnancies at <30-32 weeks gestation and for a treatment period of less than 48 hours. The benefits of antibiotic therapy are best appreciated in relation to PPROM. Ampicillin and erythromycin have been shown to increase the latency period from the time of rupture of membranes to delivery with significant neonatal benefits (1).

The incidence of neonatal mortality and morbidity increases with decreasing gestational age. Although it is outside the scope of this chapter to address the multiple medical, psychosocial, neurodevelopmental and financial problems associated with prematurity, it should be emphasized that the "borderline viable" population of infants (<25 weeks gestational age) remain the greatest challenge. Due to their statistically poor outcomes, the question of whether or not to provide life supportive measures in the delivery room is, ideally, discussed with the prospective parents prior to delivery. The management of these most fragile newborns remains an ongoing area of controversy and debate in neonatal medicine.

Preeclampsia is defined as new onset gestational hypertension with proteinuria, with or without edema. It complicates approximately 8% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality. Uteroplacental ischemia mediated by the renin-angiotensin system is one of the most fundamental abnormalities of this disorder, however, the etiology of preeclampsia is still unknown. Predisposing factors include primiparity, younger and older age extremes, familial/genetic factors, twin gestation, diabetes, and non-immune hydrops fetalis. The oldest and most effective treatment is delivery. Additional and alternative treatment strategies such as antihypertensives and magnesium sulfate for prevention of seizures are commonly employed especially when the degree of fetal immaturity (balanced with maternal status) precludes immediate delivery. The increase in perinatal morbidity and mortality associated with preeclampsia is largely due to prematurity. Uteroplacental insufficiency and abruptio placenta contribute to poor outcomes (3). Fetal intrauterine growth restriction is a frequent and expected by product of uteroplacental ischemia. Interestingly, despite the increase in fetal growth restriction and prematurity, preeclampsia is associated with a decreased risk of cerebral palsy (4).

Diabetes mellitus is classified as type 1 (lack of insulin production or pre-gestational), type 2 (adult onset, insulin resistance). An elaborate and more detailed classification system for diabetes in pregnancy was developed by Priscilla White and later modified where type A1 is described as gestational diabetes treated with diet, and type A2 requires insulin therapy. Gestational diabetes is defined as carbohydrate intolerance first recognized during pregnancy. It accounts for the majority (80-90%) of the 3-5% of pregnancies complicated by diabetes and is caused by a 60% decrease in peripheral insulin sensitivity (a normal phenomenon in pregnancy), for which some women cannot compensate (i.e., there is a concomitant inability of the pancreas to produce adequate insulin in response to a glucose load). Because this condition is often asymptomatic, screening is indicated between 24 and 28 weeks gestation. Glucose management is strict with the recommendation to maintain levels between 60 and 120 mg/dl. It is well established that tight metabolic control is associated with a marked reduction in the fetal and neonatal complications associated with diabetes in pregnancy listed in the table below:

Fetal and Neonatal Complications of Diabetes in Pregnancy:

A. Congenital Anomalies (Type 1 DM only)
. . . . - Caudal dysplasia (sacral agenesis)
. . . . - Neural tube defects
. . . . - Cardiac anomalies (transposition, VSD, hypertrophic cardiomyopathy)

B. Macrosomia (DM Types 1 and 2)
. . . . - Hypoglycemia
. . . . - Birth trauma
. . . . - Perinatal asphyxia

C. Polyhydramnios (DM Types 1 and 2)

D. Hypoxia (DM Types 1 and 2)
. . . . - Polycythemia

E. Delayed lung maturation (DM Types 1 and 2)

Congenital anomalies in infants of mothers with type 1 diabetes occurs in up to 25% of pregnancies (compared to 2-5% for non-diabetic pregnancies) depending upon the status of glucose control during embryogenesis (the first 8 weeks of pregnancy) (5). Macrosomia occurs in 25%-45% of pregnancies complicated by diabetes which is a direct result of fetal hyperglycemia and hyperinsulinemia. Neonatal management of all infants of diabetic mothers includes a thorough evaluation for birth trauma and congenital defects, screening for and management of hypoglycemia, and close scrutiny of the infant for signs of respiratory distress.

Maternal substance abuse occurs in 5-6% of all pregnancies. This condition presents the greatest clinical challenge to the pediatrician because prevention and treatment strategies are either nonexistent or unsatisfactory. Coexisting problems include sexually transmitted diseases (syphilis, HIV), tuberculosis, hepatitis, preterm labor, and both acute and long term consequences to the newborn. Agent specific neonatal outcomes are frequently confounded by polysubstance abuse, poor nutrition, poor health care and unsatisfactory home environments. In Hawaii, the most commonly abused drugs are alcohol, marijuana, amphetamines, and methamphetamines. Additional substances of abuse include cocaine, heroin, and miscellaneous other agents. As a general rule, the severity and frequency of fetal/neonatal side effects associated with maternal substance abuse is related to timing, dose, and duration of use. Heroin has been one of the best studied and well characterized due to its prolonged existence as an illicit drug. Complications of heroin addiction in pregnancy include an increased incidence of stillbirth, preterm birth, and the delivery of infants who are small for gestational age. Neonatal abstinence syndrome (symptoms of withdrawal) occur in 50%-75% of infants and usually begin within 48 hours after birth and consists of a combination of irritability, jitteriness, coarse tremors, high pitched cry, sneezing, yawning, tachypnea, poor feeding, vomiting, diarrhea, sweating, temperature instability, hyperreflexia, and, occasionally, seizures. A scoring system has been devised using the above symptoms to assist with the management of these infants. Pharmacotherapy for severe withdrawal symptoms include tincture of opium, phenobarbital, and methadone. The use of naloxone is strictly contraindicated as it can lead to acute, severe withdrawal and seizures. Methadone withdrawal seen in infants of mothers under treatment for heroin addiction has many similar characteristics to heroin abstinence syndrome. Methadone is associated with both delayed onset and increased severity of withdrawal symptoms, including seizures.

Fetal alcohol syndrome (FAS) has also been extensively addressed in the literature. Alcohol is a physical and behavioral teratogen (6). Exposure during pregnancy may result in a spectrum of symptoms secondary to varying degrees of insult to the central nervous system. Microcephaly, mild to moderate mental retardation, subtle cognitive and behavioral deficits have all been well described. Additional features of FAS include growth deficiency, short palpebral fissures, hypoplastic philtrum, thin upper lip, micrognathia, cardiac defects and a variety of other anomalies. Acute neonatal withdrawal from alcohol is rare.

No consistent or specific complications have been associated with the use of marijuana in pregnancy. Adverse pregnancy outcomes associated with cocaine abuse include higher incidence of stillbirth, asphyxia, prematurity, and babies with low birth weight and smaller heads. Symptoms of withdrawal are subtle and not well characterized. Breastfeeding is contraindicated as cocaine intoxication has been demonstrated in breast fed infants. Abuse of either amphetamine or methamphetamine during pregnancy is associated with a higher incidence of perinatal mortality, prematurity, and growth deficits. Abnormal central nervous system findings including cystic encephalomalacia and hemorrhage have also been described (6). Selective drug screening of mothers and newborns takes place routinely at most perinatal centers. Decisions regarding who to screen is often related to other perinatal risk factors such as inadequate prenatal care, previous history of substance abuse, high risk clinical signs in the mother (inappropriate or unusual behavior), history of prostitution, history of preterm labor, and presence of sexually transmitted disease(s). Documentation of fetal drug exposure by newborn urine or meconium toxicology screening typically results in referral to child protective services. All too often, these infants are placed in foster care pending rehabilitation of the mother or correction of the potentially harmful home situation.

In summary, there are many high risk conditions of pregnancy that can result in adverse neonatal outcomes, especially prematurity. It is important for the pediatrician to be fully aware of maternal risk factors so that he/she may be fully prepared to receive the newborn in the delivery room and provide ongoing care. Timely recognition of certain high-risk conditions during pregnancy often results in the transfer of the mother and fetus to a facility equipped to provide subspecialty care.


Questions

1. True/False: Preterm labor is defined as the onset of labor prior to 34 weeks gestation.

2. An effective and safe measure for treating preterm labor and delaying preterm delivery is:
. . . . a. Antibiotics
. . . . b. Cerclage
. . . . c. Detection of uterine contractions through the use of home uterine activity monitoring
. . . . d. Magnesium sulfate therapy

3. The most widely accepted explanation for the onset of preterm labor is
. . . . a. Adrenal cortical suppression
. . . . b. Decidual activation and inflammatory cytokines
. . . . c. Increased levels of serum oxytocin
. . . . d. Premature, idiopathic activation of the normal labor process

4. True/False: Preeclampsia is a complication of pregnancy associated with hypertension and proteinuria.

5. Which of the following is not a predisposing factor for preeclampsia
. . . . a. Age
. . . . b. Cigarette smoking
. . . . c. Diabetes
. . . . d. Twins

6. True/False: Naloxone is the treatment of choice for drug withdrawal in methadone addicted newborns.


References

1. Ramsey PS, Goldenberg RL. Obstetric Management of Prematurity. In: Fanaroff AA, Martin RJ (eds). Neonatal-Perinatal Medicine Diseases of the Fetus and Infant, 7th edition. 2002, St. Louis, Mo: Mosby, pp. 287-319.

2. Hauth JC, Merenstein GB (eds). Guidelines for Perinatal Care, 4th edition. 1997, American Academy of Pediatrics and The American College of Obstetricians and Gynecologists.

3. Shah DM. Hypertensive Disorders of Pregnancy. In: Fanaroff AA, Martin RJ (eds). Neonatal-Perinatal Medicine Diseases of the Fetus and Infant, 7th edition. 2002, St. Louis, Mo: Mosby, pp. 263-276.

4. O'Shea TM, Dammann O. Antecedents of Cerebral Palsy in Very Low-Birth Weight Infants. Clin Perinatol 2000;27(2):288.

5. Lindsay CA. Pregnancy Complicated by Diabetes Mellitus. In: Fanaroff AA, Martin RJ (eds). Neonatal-Perinatal Medicine Diseases of the Fetus and Infant, 7th edition. 2002, St. Louis, Mo: Mosby, pp. 277-286.

6. Rosen TS, Bateman DA. Infants of Addicted Mothers. In: Fanaroff AA, Martin RJ (eds). Neonatal-Perinatal Medicine Diseases of the Fetus and Infant, 7th edition. 2002, St. Louis, Mo: Mosby, pp. 661-673.


Answers to questions

1.false, 2.d, 3.b, 4.true, 5.b, 6.false


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