Pre-term birth occurs when a neonate is birthed or

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1 Susan L. Rideout, RN-C, BSN Pre-term birth occurs when a neonate is birthed or delivered prior to the completion of the 37th week of pregnancy. It s the leading cause of morbidity and the second leading cause of mortality in the neonate, second only to birth defects. Pre-term births are on the rise: In 1980 the rate of pre-term births was 8.9 percent (March of Dimes Perinatal Data Center, 2002). However, in 2001 pre-term births in the U.S. increased to 11.9 percent, the highest rate in 20 years. Some of this increase may be related to increased birth rates for twins and higher-order multiples, which now compose more than 3 percent of all births in the U.S. (U.S. Department of Health and Human Services, 2002). Then, some pre-term deliveries are intentional because a maternal or fetal condition indicates that birth of the baby is necessary. Pre-term birth also results from premature rupture of membranes, and at least 50 percent of preterm births are classified as idiopathic, where labor begins spontaneously prior to 37 weeks gestation (Freda & Patterson, 2001).

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3 Pre-term birth can cause serious and long-term health problems for neonates, including some of the most common problems: respiratory distress syndrome (RDS) intraventricular hemorrhage (IVH) necrotizing enterocolitis (NEC) Pre-term neonates also are at risk for developing long-term problems, such as (Moos, 2004): developmental delays vision and hearing impairments persistent respiratory disease cerebral palsy The cost of care for these children is staggering, accounting for approximately 10 percent of all health care dollars spent on children in the U.S. The cost of lost productivity and potential for these children is immeasurable (Freda & Patterson, 2001). Identifying Women at Risk There are many risk factors that predispose women for preterm labor and birth (see Table 1). Some of these risk factors aren t changeable, but some can be lessened or eliminated if identified. About one-half of all women who give birth prematurely have no identified risk factors (Moos, 2004). Unfortunately, there is no definitive test to determine which pregnant woman will experience pre-term birth. Thus, it s a general risk of pregnancy, and all pregnant women should be considered at risk for having pre-term labor and birth, not just those with risk factors present. While it s important to identify which women may be at higher risk, all women should be educated about and assessed for signs of pre-term labor during prenatal visits (Freda & Patterson, 2001). For example, there has been an increase in the number of pregnancies conceived through in vitro fertilization (IVF). This has contributed to the increase in the number of multiple gestation pregnancies (Moore, 2003). In women undergoing reproductive technology, such as IVF, fetal fibronectin testing and measurement of cervical length by use of transvaginal ultrasound are currently the most commonly used predictors of pre-term labor (Goldenberg, 2002). Both of these tests have a high-negative predictive value. If either test is positive, there is no predictive value as to when a woman might birth an infant, but a negative result indicates that it s unlikely that she would deliver within the next two weeks. These tests should be reserved for asymptomatic high-risk patients or patients with symptoms of preterm labor, as it would not be cost-effective or necessary to routinely screen all women (Bernhardt & Dorman, 2004). Many women have signs and symptoms of pre-term labor without ever progressing to pre-term delivery, whether treated or not. True pre-term labor is diagnosed only if there is progressive cervical change with regular contractions. Often women with symptoms of pre-term labor are treated before a diagnosis is confirmed because waiting for cervical change may make treatment aimed at delaying delivery less effective (Witcher, 2002). Intervening for Women at Risk Early intervention in pre-term labor reduces neonatal morbidity and mortality by delaying or preventing pre-term delivery. The major treatment goals are to (Goldenberg, 2002): reduce the frequency and/or strength of contractions in order to increase the time to delivery optimize fetal chances for survival if pre-term delivery does occur Several methods are used to decrease or eliminate contractions, including bed rest, hydration, sedation and the use of tocolytic agents. Optimal fetal well-being is the goal of treatment, and this is facilitated by the use of corticosteroids and antibiotics. If necessary, a pregnant woman at risk for preterm birth may be transferred to a facility with a neonatal intensive care unit (NICU). When delivery is delayed for at least 24 to 48 hours after administration, maternal injections of corticosteroids (such as betamethasone or dexamethasone) are helpful to reduce neonatal RDS (Haram, Mortensen, & Wollen, 2003). Tocolytic Therapy To understand how tocolytics work, it s important to understand what causes myometrial contractility. While there are several theories as to what causes labor to begin, there is still no definite conclusion as to exactly how or why it starts. Uterine contractions result from the interaction of myosin and actin through a series of reactions promoted by the enzyme myokinase light-chain kinase (MLCK). Free calcium must be present for MLCK to cause the reaction. Free calcium is found in intracellular fluid by cellular depolarization that causes an influx of calcium through the cell membrane or by release of stored intracellular calcium (Witcher, 2002). Most tocolytics currently in use work by decreasing intracellular calcium, thereby stopping the enzyme reaction that causes the uterus to contract. Several types of tocolytics are used in treating pre-term labor; however, the only drug approved by the Food and Drug Administration (FDA) as a tocolytic is ritodrine hydrochloride (Yutopar). Ritodrine can be used if labor begins between 20 and 36 weeks gestation and if the fetus weighs between 500 and 2,499 grams. However, the tocolytic agents commonly used at most hospitals are magnesium sulfate, terbutaline and nifedipine. 58 AWHONN Lifelines Volume 9 Issue 1

4 Magnesium Sulfate Magnesium sulfate has been used for seizure prophylaxis and to treat seizures in pre-eclamptic and eclamptic patients for almost 100 years. Its first use as a tocolytic was in the 1960s, but it was used in laboratory experiments rather than in clinical tests (Pryde, Besinger, Gianopoulos, & Mittendorf, 2001). While initial clinical observational studies showed that this drug is effective, randomized clinical trials don t show magnesium sulfate to be more effective than saline as a tocolytic agent, and the drug doesn t improve perinatal outcomes (Pryde et al., 2001). Still, this drug is often chosen as the firstline therapy for pre-term labor. The goal of initial treatment for pre-term labor is to prolong delivery, usually by 48 hours or more, to allow for administered corticosteroids to enhance lung maturity in the fetus. If labor is stopped or slowed, often the woman will be treated with another medication such as terbutaline or nifedipine. Table 1. Additional Risk Factors for Pre-term Labor as Described By Moore (2003) Young maternal age (17 or younger) Older maternal age (35 or older) Low pre-pregnancy weight Obesity Hypertension Diabetes mellitus Clotting disorders Anemia Presence of uterine fibroids Socioeconomic status including low income, life stress or unsafe neighborhood Genitourinary infections Periodontal disease Intimate partner violence Maternal employment that requires long hours or long periods of standing Tobacco and other substance abuse Prior delivery of a pre-term infant More recently, an association between magnesium sulfate administration to women in pre-term labor and a reduction in cerebral palsy rates has been reported (Pryde et al., 2001). After promising recent initial studies, several large ongoing randomized clinical trials are now under way to research the effectiveness of maternal administration of magnesium sulfate in the protection against cerebral palsy. While it s not entirely understood how magnesium sulfate decreases contractility, it s thought that it competes with intracellular calcium and may also hyperpolarize the cell membrane, which decreases the amount of calcium allowed into the cell (Jeyabalan & Caritis, 2002). Magnesium sulfate must be given parenterally, usually through an intravenous (IV) catheter, as oral doses have been shown to be ineffective. A bolus or loading dose of 4 to 6 grams is given over 15 to 30 minutes, and then maintained at between 1 and 4 grams per hour. Magnesium sulfate is intended for stabilization and usually only given for 24 to 48 hours at the maintenance dose. A serum level between 5 and 8 mg/dl is considered therapeutic for stopping uterine contractions, but the dosage should be carefully titrated depending on uterine activity and maternal side effects (Witcher, 2002). Maternal side effects need to be carefully assessed with this medication, the most common of which are (Jeyabalan & Caritis, 2002; Witcher, 2002): a feeling of flushing or a warm sensation nausea and vomiting dry mouth lethargy and generalized weakness blurry vision headache A woman undergoing therapy should be informed about the possible side effects prior to magnesium sulfate administration. Because of the smooth muscle relaxant effect of magnesium sulfate, nurses should assess the patient for hypotension by checking blood pressure and heart rate every 15 minutes when therapy is initiated and then every hour for the duration of the therapy. Magnesium sulfate also has central nervous system (CNS) and respiratory depressive effects, so respirations and deep tendon reflexes also need to be assessed with blood pressure. Loss of patellar reflexes occurs when magnesium blood levels reach 9 to 13 mg/dl, and respiratory depression can occur at 14 mg/dl (Witcher, 2002). Calcium gluconate at a dose of 1 gram IV (Jeyabalan & Caritis, 2002) should be kept readily available to be administered as an antidote if a nurse s assessment shows loss of reflexes and/or respiratory depression. Fluid intake and output should be carefully monitored when using this medication. Additional IV fluid is almost always administered with mag- February March 2005 AWHONN Lifelines 59

5 nesium sulfate, as venospasm can occur at the IV site causing pain and possible interruption of the fluid administration. Fluid overload, along with the vasodilating and the respiratory depressive effects of the magnesium, can lead to pulmonary edema. Urine output needs to be monitored, as magnesium sulfate is excreted in the urine and can quickly reach toxic levels if urine output is decreased (Lowe et al., 2002). Once uterine contractions stop and the woman is stabilized, she is usually switched to an oral agent and weaned from the magnesium sulfate. However, some women aren t given any other tocolytics and are monitored for a day or two to see if uterine contractions return. Some women are able to control any recurring pre-term labor through bed rest and hydration. While it has been shown to reduce uterine contractions, there have been no randomized studies on singleton pregnancies to determine the effectiveness of bed rest for pre-term labor treatment (Witcher, 2002). Promoting maternal hydration has become customary to manage pre-term labor, but there s also no evidence in the form of randomized studies to support its use. Terbutaline Terbutaline (Brethine) is a drug commonly given to stop preterm contractions. It s a beta-adrenergic agonist (also referred to as a betamimetic) that acts on beta receptors in smooth muscle. Terbutaline works by decreasing the sensitivity of myosin and actin to the contraction promoting influence of calcium and prostaglandins (Pryde et al., 2001). Terbutaline can be given IV, orally or subcutaneously. A meta-analysis conducted by Tsatsaris, Papatsonis, Goffinet, Dekker, and Carbonne (2001) found that betaadrenergic agonists were effective at delaying birth for 48 hours. Because terbutaline stimulates the beta receptors, it causes uterine smooth muscle, which has beta2 receptors, to relax. But beta receptors are found throughout the body, and terbutaline is not selective for beta2 receptors. It also stimulates beta1 receptors, causing most maternal and fetal cardiac side effects. This beta1 stimulation in the heart causes maternal and fetal tachycardia and can cause cardiac dysrhythmias, such as premature ventricular contractions, premature atrial contractions, atrial fibrillation and supraventricular tachycardia (Witcher, 2002). Women with underlying heart disease or conduction abnormalities should not be given this medication for obvious Susan L. Rideout, RN-C, BSN, is a staff nurse at Eastern Maine Medical Center in Bangor, Maine, and is also a clinical nursing instructor for Husson College in Bangor and the University of Maine in Orono. DOI: / reasons. Tachycardia caused by terbutaline has also been known to cause myocardial ischemia. While the same effects can be seen in the fetus, they are generally rare due the fact that the sympathetic innervation in the fetus is immature (Witcher, 2002). The heart rates of both the woman and fetus need to be monitored prior to the administration of each dose for the cardiac side effects of this drug. Beta-adrenergic agonists such as terbutaline can also have an effect on blood glucose levels. This is caused by stimulation of beta2 receptors in hepatic tissue causing glycogenesis. This in turn causes blood sugar levels to rise (Pryde et al., 2001). Therefore, this medication should be used with caution in women with diabetes, and glucose levels need to be assessed at least four times per day or more often if glucose levels are found to be elevated. Betamimetic tocolytics also cause activation of the renin-angiotensin-aldosterone system, causing the body to retain fluid. This fluid retention, along with the relaxation of smooth muscle, bronchioles and diaphragm, can lead to pulmonary edema (Pryde et al., 2001). Fluid balance and respiratory status should also be monitored closely in a patient receiving tocolytic therapy with terbutaline. Breath sounds should be assessed at least once per shift, and intake and output should be monitored each shift. Stimulation of the CNS is common in those taking terbutaline, manifesting itself as tremors at rest (Pryde et al., 2001). The side effects of betamimetic therapy for tocolysis with such drugs as terbutaline sometimes make its use intolerable. If continued maintenance therapy is planned, medication such as hydroxyzine (Vistaril) is administered for side effects. Hydroxyzine is an antihistamine that is often used as an antianxiety drug or as a sedative (Lowe et al., 2002). Women may feel sleepy while on this medication, but anecdotally many women report that this is more tolerable than the side effects of the terbutaline. Whenever caring for a woman on terbutaline therapy for tocolysis, nurses need to assess for both the effects of the medication and the side effects. Nifedipine Nifedipine is a calcium channel blocker used in treating preterm labor. It works as a potent vasodilator and to selectively relax uterine muscle. It blocks the influx of calcium at the cell membrane, thereby decreasing contractility (Economy & Abuhamad, 2001). The most common side effect seen with nifedipine is hypotension, but it can also cause headache and flushing. Increases in pulse rate as a compensatory reaction to the hypotension are sometimes also noted with use of this medication, but these increases are seldom as pronounced as with terbutaline therapy (Pryde et al., 2001). Calcium channel blockers cause fewer side effects and have been shown to be as effective (in some trials more effective) 60 AWHONN Lifelines Volume 9 Issue 1

6 than other comparative agents such as beta-adrenergic agonists and magnesium sulfate (Economy & Abuhamad, 2001). A meta-analysis by Tsatsaris et al. (2001) also showed nifedipine to be more effective and better tolerated than betaadrenergic agonists. Calcium channel blockers are overall more safe than many of the other medications used to treat pre-term labor. However, more caution should be used if administering a calcium channel blocker and magnesium sulfate simultaneously, as profound hypotension, cardiac toxicity and neuromuscular blockade have been reported in rare cases (Papatsonis, Van Geijn, & Dekker, 2000). When initiating therapy with nifedipine, whether as a firstline treatment for pre-term labor or as secondary maintenance therapy after stabilization with magnesium sulfate, close monitoring of maternal blood pressure and fetal heart rate are warranted, as severe hypotension can cause decreased blood flow to the uterus and cause fetal compromise. In pre-term labor patients with gestational hypertension, the slight drop in blood pressure achieved with the use of nifedipine is welcome, as long as the fetus tolerates the decrease. Overall, the literature suggests that nifedipine may be the best choice for tocolysis unless there is known or suspected cardiac disease. It s preferred to terbutaline in patients with gestational diabetes, as it does not cause an increase in blood glucose levels (Economy & Abuhamad, 2001). Using Tocolytics in Practice As with all tocolytics, nurses must assess the effectiveness of the medication in addition to any side effects. Nurses should be keenly aware of the fact that when caring for a pregnant woman there are actually two patients: one who can be seen and easily assessed and another who can only be heard through indirect assessment of fetal well-being. It s important to realize that side effects often affect the fetus as well as the woman. While no tocolytic therapy is without side effects or risk, the overall goal of tocolytic therapy is to prolong the pregnancy for as long as possible, provided that the fetus continues to grow appropriately and shows no signs of compromise. Even if pregnancy can only be prolonged for 48 hours, this is usually long enough for corticosteroid administration to assist in lung development of the fetus. This small time frame also can allow for transfer of the pre-term labor patient to a hospital with a level III NICU so that if delivery occurs, there will be staff readily available to care for this pre-term infant. Assessing the effectiveness of tocolytic therapy is not complex and is part of routine nursing care for high-risk pregnant women. The side effects of some of the tocolytic medications discussed can be very difficult to tolerate, and therapy may, therefore, be discontinued. Nurses need to carefully assess their pre-term labor patients for these side effects because some of them can be very serious or even fatal. Because of the better profile with both effectiveness and side effects, use of nifedipine for most pre-term labor patients should be advocated. References Bernhardt, J., & Dorman, K. F. (2004). Exploring fetal fibronectin and cervical length for validating risk. AWHONN Lifelines, 8(1), Economy, K. E., & Abuhamad, A. Z. (2001). Calcium channel blockers as tocolytics. Seminars in Perinatology, 25(5), Freda, M. C., & Patterson, W. T. (2001). Pre-term labor: Prevention and nursing management (2nd ed., March of Dimes Nursing Module Series). White Plains, NY: March of Dimes. Goldenberg, R. L. (2002). The management of pre-term labor. Obstetrics & Gynecology, 100(5), Haram, K., Mortensen, J. H. S., & Wollen, A. (2003). Pre-term delivery: An overview. Acta Obstetricia et Gynecologica Scandenavia, 82, Jeyabalan, A., & Caritis, S. N. (2002). Pharmacologic inhibition of pre-term labor. Clinical Obstetrics and Gynecology, 45(1), Lowe, E. P., Gallen, E. C., Cammon, S. A., Damico, C. M., Farnese, T. A., Laplante, N., et al. (Eds.). (2002). Nurse practitioner s drug handbook (4th ed.). Philadelphia: Lippincott Williams & Wilkins. March of Dimes Perinatal Data Center. (2002). Final natality data for Washington, DC: National Center for Health Statistics. Moore, M. L. (2003). Pre-term labor and birth: What have we learned in the past two decades? Journal of Obstetrics Gynecology and Neonatal Nursing, 32(5), Moos, M. K. (2004). Understanding prematurity: Sorting fact from fiction. AWHONN Lifelines, 8(1), Papatsonis, D., Van Geijn, H. P., & Dekker, G. A. (2000). Nifedipine as a safe and effective tocolytic agent in the treatment of pre-term labor. American Journal of Obstetrics and Gynecology, 183, Pryde, P. G., Besinger, R. E., Gianopoulos, J. G., & Mittendorf, R. (2001). Adverse and beneficial effects of tocolytic therapy. Seminars in Perinatology, 25(5), Tsatsaris, V., Papatsonis, D., Goffinet, F., Dekker, G., & Carbonne, B. (2001). Tocolysis with nifedipine or betaandrenergic agonists: A meta analysis. Obstetrics & Gynecology, 97(5), U.S. Department of Health and Human Services, Centers for Disease Control, National Center for Health Statistics. (2002). Births: Final data for National Vital Statistics Report, 51(2). Retrieved April 19, 2004, from Witcher, P. S. (2002). Treatment of pre-term labor. Journal of Perinatal and Neonatal Nursing, 16(1), February March 2005 AWHONN Lifelines 61