Complications Associated with the Administration of Tocolytic Agents

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OBSTETRICS

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COMPLICATIONS ASSOCIATED WITH THE ADMINISTRATION OF TOCOLYTIC AGENTS Andree Gruslin, MD,FRCSC,l Brigitte Bonin, MD, FRCSC,2 l,2Department of Obstetrics and Gynaecology, Division of Perinatology, Ottawa General Hospital, University of Ottawa ABSTRACT

BecatLSe maternal antenatal steroid administration has been shown to improve neonatal outcome at gestational age less then 34 weeks, many obstetrical practitioners choose to tLSe tocolytic agents in an attempt to delay premature delivery and, thereby, allow enough time for steroid treatment. Unfortunately, tocolytics are not without potentially seriotLS side effects for both mother and fettLS. Our objective was to review the complications associated with variotLS tocolytic agents and describe their management. RESUME

Parce qu'il a ere demontre que l'administration de srero'ides it la mere avant la naissance ameliore Ie resultat neonatallorsque la grossesse a 34 semaines, beaucoup d'obsretriciens choisissent d'utiliser des agents tocolytiques afin de tenter de retarder l'accouchement premature et de gagner ainsi suffisamment de temps pour pouvoir administrer un traitement aux srero'ides. Les agents tocolytiques ne sont malheuretLSement pas sans effets secondaires, qui peuvent etre graves tant pour la mere que pour Ie fc£ttLS. L' etude visait it examiner les complications associees it divers agents tocolytiques et it en decrire la prise en charge. moins de

J SOC OBSTET GYNAECOL CAN 1998;20(10):953-69

KEY WORDS Tocolysis, preterm labor, risks and complications. Received on February 2nd, 1998. Revised and accepted on April 22nd, 1998.

has led to intensive efforts to find effective therapies to stop uterine activity. As early as the 1960s, some of the first ~-sympathomimetic agents were introduced and many other classes of drugs have since been added. Unfortunately, while the efficacy of tocolytics in many

INTRODUCTION

Prematurity remains the leading cause of perinatal morbidity and mortality and still affects six to eight percent of the population.! The prevalence of this problem

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SEPTEMBER 1998

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, , , cases has been questionable, their side effects have been clearly demonstrated. Because of the widespread use of these drugs and their relatively frequent side effects, it is imperative that the obstetrical practitioner be familiar with the treatment of associated complications. We will review potential maternal and fetal complications associated with tocolytic therapy and describe their management.

this type of treatment and may not warrant maternal exposure to these agents. When assessing whether or not to use tocolysis, consideration must be given to the severity of any associated disease and to the availability of tocolytic agents. Individualization of patient care becomes very important.

GENERAL CONSIDERATIONS

1. M ECHAN ISM

Before embarking on tocolytic therapy, the benefits and risks to both mother and fetus must be considered. A careful and thorough evaluation of maternal-fetal status is required prior to the initiation of therapy in order to select which patients may be appropriate candidates for tocolysis. To this end, absolute and relative contraindications to this type of therapy should be recognized (Table O. These include, as a general principle, severe maternal disease and fetal compromise. For example, patients presenting with severe pregnancy-induced hypertension or antepartum haemorrhage with haemodynamic instability, producing maternal or fetal compromise should not receive tocolysis. Using tocolysis for mothers with chorioamnionitis is not only unsafe but also ineffective. Severe intra-uterine growth restriction (IUGR) and non-reassuring fetal status are two concrete examples of absolute contra-indications as, under those circumstances, the intra-uterine environment is so hostile that outcome could be improved by delivery even though premature. Other contra-indications are known lethal anomalies or intra-uterine demise. Relative contraindications include a gestational age of 33 weeks or more when tocolysis would lead to very little gain, if any, in neonatal outcome. Finally, advanced preterm labour (cervix over 5 cms dilated) is likely to be refractory to

~-sympathomimetics are the most commonly used tocolytics.! This class of drugs includes such agents as isoxsuprine, salbutamol, hexoprenaline, terbutaline and ritodrine. Of these, only ritodrine has been the subject of a randomized control trial in Canada. 2 ~-agonists directly stimulate ~ receptors on the outer cell membrane activating adenylate-cyclase. This leads ultimately to reduced intracellular calcium concentrations which decrease the sensitivity of the myosin-actin unit. Two types of ~ receptors exist. ~-1 receptors are found in the heart, small intestine and adipose tissue and ~- 2 in the smooth muscle of the uterus, blood vessels, diaphragm and bronchioles. The non-selectivity of ~-sympathomimetic agents leads to side effects and complications not only for the mother but also the fetus, as these drugs are known to cross the placenta.3 Adverse effects can be divided into physiological, metabolic, cardiac and others (Table 2). They most frequently include apprehension, jitteriness, hypokalaemia, hyperglycaemia, shortness of breath with chest pain and, occasionally, electrocardiographic (ECG) changes.

I. p-SYMPATHOMIMETICS

TABLE 2 PHYSIOLOGICAL EFFECTS ()F P-SYMPATHOMIMETIC STIMULANTS , Cardiac

TABLE 1

P1

CONTRA-INDICATIONS TO TOCOL¥TICS Maternal

Fetal

Absolute Relative Absolute

Relative

.. SeverePIH .. SevereAPH .. Chorioamnionitis .. Uncontrolled diabetes .. Severe IUGR .. Non-reassuring fetal heart tracing .. Lethal congenital and/or lethal chromosomal abnormalities .. Fetal demise .. Gestational age > 33 weeks .. Advanced preterm labour

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Metabolic' Renal

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P2

Metabolic

Renal .

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SEPTEMBER 1998

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gluconeogenesis glycogenolysis ,increased insulin and glucagon intracellular K+ shift t renin i aldosterone

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MATERNAL SIDE EFFECTS

TABLE 3

TREATMENT OFP-SVMPA1HOM1MeTU:::-1Nouceo·

Cardiovascular Effects

.

Pulmonary Oedema One of the most serious complications encountered with the use of p-sympathomimetic agents is pulmonary oedema. This may affect as many as five percent of the treated population. 4 However, by paying close attention to fluid balance, this complication can be markedly diminished as was demonstrated in the large Canadian ritodrine trial where only one case of pulmonary oedema was reported in 352 patients. 2 This particular patient had unrecognized mitral stenosis which may have contributed to the development of pulmonary oedema. The underlying mechanism for the development of pulmonary oedema is likely multifactorial and usually non-cardiogenic. 4 As p-sympathomimetic stimulation induces peripheral vasodilatation, hypotension is commonly seen. In order to stabilize maternal blood pressure, intravenous fluids are used, and this may increase the risk of pulmonary oedema. Glucocorticoids administered to promote fetal lung maturation may contribute, especially when the agent used has mineralocorticoid activity. Finally, p-sympathomimetics also stimulate the renin aldosterone system and increase antidiuretic hormone levels which contribute further to fluid retention. This may be compounded by the normal physiological changes encountered in pregnancy, especially the important 35 to 40 percent increase in blood volume. Certain risk factors for the development of pulmonary oedema have been clearly identified. These include intravenous treatment (especially if given over 24 hours), anaemia, multiple gestation, low colloid oncotic pressure, chronic hypertension, pregnancy-induced hypertension and such infections as chorio-amnionitis and pyelonephritis (increased risk of 21 %). 6 The symptoms of pulmonary oedema are shortness of breath, haemoptysis and rales. These will be accompanied by a decrease in O 2 saturation and an increase in the A-a gradient, and should be confirmed by chest X-ray. Treatment should be initiated promptly as shown in Table 3. Arrhythmias Other cardiovascular complications include tachycardia and other arrhythmias. 1 The most common are supraventricular tachycardia, atrial fibrillation and premature ventricular contractions. Women with W olffParkinson-White and Lown-Ganong-Levine syndromes

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are especially at risk. 8 Other contributing factors include hypokalaemia, hypoxaemia and myocardial ischaemia. Myocardial Effects Pregnant patients treated with B-sympathomimetics have also been found to have a major increase in cardiac output and stroke volume (40-60%) with a widened pulse pressure resulting from an increase in systolic blood pressure and a concurrent decrease in diastolic pressure.9 This may result in a decrease in coronary blood flow as well as an increase in myocardial oxygen requirements. Ultimately, this can lead to myocardial ischaemia which may also be a focus for dangerous arrhythmias. Although myocardial ischaemia and infarction are extremely rare complications, chest pain with changes in the ECG are commonly reported. In fact, in a US multicentre study, 20.6 percent of women treated with ritodrine experienced chest pain.lD Even in asymptomatic patients, ECG changes have been reported. These changes usually occur in leads V 3, V 4' 1 and 2. 8 The findings are usually those of ST segment elevation or depression, peaked P waves, inverted T waves and left axis deviation. It is interesting that these changes have usually been reported early on in the initiation of therapy and have been shown to decrease after 24 hours. One possible explanation for this is that they may only reflect a relative

956

SEPTEMBER 1998

, , , tachycardia or electrolyte imbalance as opposed to true ischaemia. Metabolic Effects ~-sympathomimetic stimulation of the pancreas, liver and adipose tissue account for the diabetogenic properties of these agents. They stimulate gluconeogenesis and glycogenolysis. Through lipolysis, free fatty acids are also increased. Glucose and insulin levels usually peak three hours after initiation of therapy in association with a shift of potassium intracellularly. Although potassium concentrations need to be monitored closely, treatment is not usually warranted unless electrocardiographic changes are present or levels fall to below two mEqJlitre. ll Given these effects, it is easy to understand why ~-sympathomimetics should not be used in the poorly controlled diabetic as they could easily precipitate a state of diabetic ketoacidosis.

3.

fetal lung from a fluid-secreting to a fluid-absorbing organ as shown in animal studies. 16,17 In animal models, they have been shown to cause an increase in alveolar surfactant content through an increase in synthesis and/or release from alveolar cells. At present, this effect remains very controversial and more research is needed to explore the possible association. Recently, Groome et al. in a retrospective study, reported an increased incidence of intraventricular haemorrhage in newborns exposed to ritodrine in utero. 1S Although other investigators have not been able to reproduce those results,19 this remains a major concern and warrants further investigation. Finally, concerns also exist over the administration of ~-sympathomimetic agents to potentially compromised fetuses. This is so because erythropoietin levels (EPO) have been found to be elevated in fetuses exposed to ~-sympathomimetics. 20 As tissue hypoxia is a major stimulus of EPO production, it is felt that these agents might actually lead to decreased fetal oxygenation. It is, therefore, essential to ensure fetal well-being prior to their administration.

FETAL/NEONATAL EFFECTS

Since it has been demonstrated that ~-sympath­ omimetics cross the placenta, there has been much concern over potential cardiovascular and metabolic complications in the fetus and neonate. In a thorough review of the literature, Kast and Hermer concluded that, at present, there is no demonstrable risk for the fetal myocardium despite widespread use of these agents. 12 Although increases in the fetal heart rate by as much as ten percent have been documented within two hours of initiation of therapy, this effect has not been confirmed universally and no myocardial alterations have been shown in the baboon.13 This may be explained by the fact that the density of ~ adrenoreceptors in the myocardium of both premature and mature infants is lower than in the adult, and that their response to stimulation by sympathomimetic agents used clinically is much less, due to this immature sympathetic innervation. 12 Neonatal metabolic effects, however, have been seen and have included hypoglycaemia, hyperinsulinaemia, hypocalcaemia and hyperbilirubinaemia. At this time, controversy still exists as to whether or not ritodrine may be associated with a decrease in respiratory distress syndrome (RDS). Although this could not be shown in the Canadian ritodrine triaF or in meta-analysis by King et al. ,14 several other investigators have reported this association. In a review of 247 neonates, Karem et al. 15 recently showed a significant decrease of RDS in the ritodrine-exposed infants. This result might be explained by the fact that ~-2 agonists can actually convert the

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4.

PREVENTION AND TREATMENT

Adequate prevention should ensure that major complications associated with ~-sympathomimetics are avoided. Patients should be selected carefully for this type of therapy. Contra-indications specific to ~-sympa­ thomimetics deserve mention (Table 4), starting with maternal cardiovascular disease especially, as at least 14 cases of maternal deaths have been reported under these circumstances. 8 The use of these agents in diabetics should also be supervised very closely because of the potential development of diabetic ketoacidosis. This makes the use of ~-sympathomimetics contra-indicated in the poorly controlled diabetic. They should also be avoided in the compromised fetus. Close attention should be paid to fluid volume. To prevent the development of pulmonary oedema, no more

TABLE 4 CONTRA-INDICATIONS TO Il-SYMPATHOMIMETIC AGENTS Underlying cardiac disease Arrhythmia (especially Wolff-Parkinson-White and Lown-Ganong-Levine Syndromes) Poorly controlled diabetes

957

SEPTEMBER 1998

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, , , than 2,500cc/day of either Ringer's lactate or normal saline should be given. In cases of multiple pregnancies, fluid replacement should be limited further, and a total of 1,500 cc/dl is usually recommended. At the same time, fluid input and output should be monitored carefully. Close attention should be paid to electrolyte balance, and it is generally recommended that if potassium levels drop to less than two mEqJlitre or ECG changes occur, especially arrhythmias, prompt replacement of potassium is necessary. 1 If serious complications occur, treatment should be discontinued (Table 3). For example, the development of chest pain, arrhythmias, pulmonary oedema and shortness of breath should prompt immediate discontinuation of therapy. The patient should be given oxygen in order to maintain a pOz of over 60 mm Hg. Electrocardiographic monitoring should also be initiated. Oxygen saturation should be followed closely and when pulmonary oedema is suspected, arterial blood gases, ECG, chest X-ray and electrolytes need to be obtained. In cases of confirmed pulmonary oedema, the patient should undergo diuresis with lasix intravenously. Morphine may be given as necessary. If chest pain develops, serial measurements of creatinine kinase iso-enzymes is advised. In the eventuality that the patient does not respond promptly to these measures, invasive haemodynamic monitoring may become necessary along with transfer to an intensive care unit.

inhibition of calcium influx across the myometrial cell membrane could explain the tocolytic action of MgS04. It is interesting that elevated magnesium levels do not seem to affect calcium release from intracellular stores.

2. MATERNAL SIDE EFFECTS Most side effects of MgS0 4 are minor and this constitutes its major advantage over the ~-sympath­ omimetic drugs. Nevertheless, some major side effects can occur, although rarely, and therefore, every physician using MgS04 should be familiar with their treatment. Elliott has shown that seven percent of patients receiving MgS0 4 will experience side effects, but only two percent of them will be serious enough to warrant interruption of treatment. 22 Minor side effects are listed in Table 5. They are maximum during administration of the bolus, will mostly subside on continuous infusion and require no specific treatment. Major side effects (Table 5) include pulmonary oedema although it occurs much less frequently than with ~-sympathomimetic drugs (1.1 %22 versus up to 5%). Some authors advocate dual therapy using both MgS0 4 and ritodrine. This

TABLE 5 MATERNAL SIDE EFFECTS AND CONTRA.INDICATIONS TO MAGNESIUM SULPHATE Minor

• • • • • • • • • • •

Major

• • • • •

MAGNESIUM SULPHATE

Magnesium sulphate (MgS0 4) was first found to have tocolytic properties in 1959. 21 Although there is still controversy about its efficacy, it has become very popular because of its ease of administration, and its rare serious side effects for either the mother or the fetus. It is used as a first-line agent in numerous centres across Canada although it has not received approval as a tocolytic. 1. MECHANISM OF ACTION

It is only recently that the mechanism of action of MgS0 4 has been elucidated. 7 We now know that high extracellular concentrations of magnesium lead to an increase in intracellular concentrations of magnesium, which inhibits calcium influx through the calcium channels. As myometrial contractions :lre dependent on an increase in intracellular calcium levels leading to an activation of the myosin light chain kinase activity, this

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Flushing Warmth Nausea/vomiting Dizziness Blurred vision/nystagmus Weakness Lethargy Drymouth Headaches Paralytic ileus/constipation Mild vasodilatation/decreased blood pressure/palpitations • Chest heaviness • Urinary retention • Alterations in calcium metabolism Pulmonary oedema (1.1 %) Loss of reflexes (10 mEq/L or 12 mg/dl) Respiratory depression (15 mEq/L or 18 mg/dl) Cardiac arrest (> 30 mEq/L or > 36 mg/dl) Neuromusc.ular blockade

SpeCific • Myasthaenia Gravis Contra-indications • Heart block • Renal impairment • Do not use with: - calcium channel blockers - aminoglycosides Other

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SEPTEMBER 1998

• .I. maternal bone mineralization

, , , increases the risk of pulmonary oedema to 46 percent without changing the outcome and, therefore, cannot be recommended. 23,24 Magnesium sulphate is mostly excreted by the kidneys, and intoxication is a well-known risk of this type of therapy. It is important to ensure that renal function is normal in patients receiving MgS04. As serum magnesium levels increase, the patient will experience different signs and symptoms, and she should be followed closely. Reflexes should be assessed, as these will disappear first. Respiratory depression requiring ventilatory support can happen, and at very high magnesium levels, cardiac arrest will occur. Serum levels at which the patient will experience these different symptoms are listed in Table S.2S If signs of intoxication occur, MgS04 should be stopped immediately and the patient should be given calcium gluconate to reverse the effects of the MgS0 4. The response will not be instantaneous and ventilatory support may be required. Maternal contra-indications to MgS04 are listed in Table 5. There is an increased risk of neuromuscular blockade and severe hypotension in patients receiving both MgS04 and calcium channel blockers. This should be avoided. 26 A potentiation of neuromuscular weakness has also been reported when gentamicin or other aminoglycosides are used.27 Because, unlike j3-sympathomimetics, there is no tachyphylaxis, MgS0 4 can be used for longer periods. s In fact, when necessary, it can be given to patients with resistant pretenn labour for a prolonged period with minimal maternal side effects. 2s-3o Secondary to alterations in calcium metabolism and prolonged bed rest, a decrease in maternal bone mineralization was noted with longterm treatment (average 26 days).3! The clinical significance of these changes remains unclear.

3.

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nervous system depression. This should be taken into account when fetal well-being is assessed. The neonate may be hypotonic or lethargic for a few hours after birth, but this is not severe enough to require treatment. 34 Hypermagnesaemia, if present, will resolve within 48 hours. 3s The effect of MgS04 on neonatal calcium concentration is unclear. Levels have been reported as being high, normal and 10wY-31 Some authors have also reported demineralization of the bones and even congenital rickets in neonates whose mothers had received MgS04 for long periods (more than 7 days).38,39 The clinical significance of these bony changes is unknown as they disappear rapidly and, in fact, a recent study has failed to confirm this association. 40 Antenatal treatment with magnesium sulphate has also been linked to a decrease in the risk of cerebral palsy in very low birth weight infants in several observational studiesY-44 A recent study by Grether et al, 4S has reassured us that the possible neuroprotective effect in infants surviving the neonatal period is not explained by selective early mortality of MgS04-exposed infants. In this same work, the study group was restricted to exclude women whose labour was too advanced for tocolytic treatment, who had maternal or fetal indications for immediate delivery or other contra-indications to tocolysis, or who had pre-eclampsia. In this selective subgroup they found no excess of deaths among those infants exposed to magnesium in utero. In fact, after controlling for all the possible confounders, they observed a strongly negative association between in utero exposure to magnesium sulphate and neonatal death, suggesting a possible protective effect from magnesium sulphate. Further randomized trials are currently underway to evaluate magnesium sulphate as a neuroprotective agent. These studies will also

6)

No severe fetal or neonatal side effects have been reported. The fetal heart rate pattern may be modified, with a slight decrease in baseline and a loss of reactivity, especially at high doses. There may also be a decrease in breathing movements. No significant effect on fetal tone or gross body movements and amniotic fluid volume has been encountered. 32 A blunted response to vibroacoustic stimulation has also been reported. 33 These changes do not reflect compromise but central

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FETAL AND NEONATAL SIDE EFFECTS

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SEPTEMBER 1998

, , , Antiprostaglandin agents include aspirin, ibuprofen and the more widely used indomethacin. Another compound, sulindac, is also under investigation for potential use as a tocolytic agent. Indomethacin is a competitive inhibitor that acts by blocking the conversion of arachidonic acid into the intermediate endoperoxide prostaglandin O 2, which is subsequently converted to POE 2 and POF 2a . The effects of indomethacin are reversible once drug levels decline. 48

provide us with additional data on neonatal mortality in pre term infants. 4.

PREVENTION AND TREATMENT OF

COMPLICATIONS (TABLE

7)

Fetal and neonatal side effects are minor and do not warrant treatment. Minor maternal side effects will also be transient and require no intervention. To avoid major complications, patients should be carefully selected, excessive hydration should be avoided, the patient should be regularly assessed for signs of intoxication and magnesium serum levels should be measured if the patient is at risk. In the event of intoxication, the magnesium sulphate infusion should be stopped immediately, the antidote given and oxygen therapy and ventilatory support should be readily available. As MgS04 is eliminated by the kidneys, active diuresis is recommended.

2.

Most of the maternal side effects are minimal and are related to the route of administration of the drug (Table 8). Because antiprostaglandins have antipyretic properties, they can mask signs of infection and should be avoided in patients with ruptured membranes. Maternal contra-indications to their use are listed in Table 9. This class of agents is mostly metabolized by the liver and so, hepatic dysfunction is a contra-indication to their use. Three cases of acute maternal renal insufficiency have also been reported with documented elevation of serum creatinine levels and oliguria. 49 This effect is thought to be secondary to a change in regulation of renal blood

ANTI PROSTAG LANDI NS

1.

MATERNAL SIDE EFFECTS

MECHANISM OF ACTION

Prostaglandins are important in the process of myometrial contractions and labour. They act by raising intracellular calcium levels in human myometrial cells through an influx of calcium from the extracellular to the intracellular milieu. They also stimulate intracellular calcium release from the sarcoplasmic reticulum. This increase in intracellular calcium concentrations activates the myosin light chain kinase and phosphorylation of the myosin light chain leading to myometrial contraction. 46 Prostaglandins also favour more effective and coordinated muscle contractions by stimulating gap junction formationY

TABLES ANTIPROSTAGLANDINS. MATERNAL SIDE EFFECTS Nausea/vomiting Pyrosis Diarrhoea Proctitis/rectal bleeding Headaches Tinnitus/vertigo Allergic skin rash Increased bleeding time Rarely: - Acute renal insufficiency - Hypertensive crisis - Depression/psychosis

TABLE 7 MAGNESIUM SULPHATE. PREVENTION AND TREATMENT OF MAJOR MATERNAL COMPUCATIONS Major Maternal

- Select patients carefully (see contra-indications)

Complications

- Avoid fluid overload - Monitor reflexes closely - Magnesium serum levels should be measured if patient at risk of intoxication

TABLE 9 ANTIPROSTAGLANDINS. MATERNAL CONTRA-INDICATIONS Coagulation disorders

Treatment of

- Discontinue magnesium infusion

Active peptic ulcer disease

Intoxication

Pulse oximetry , O 2 by mask PRN Ventilatory support PRN Calcium gluconate 19IV in ten percent solution given over three minutes - Diuresis (furosemide 20-40 mg IV PRN)

Renal dysfunction

-

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Hepatic dysfunction Allergy to salicylate Asthma Poorly controlled hypertension

SEPTEMBER 1998

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, , , more than 48 hours. However, this has been shown to be transient, as all Doppler indices reverted to normal rapidly after discontinuation of treatment. 51 ,58 The ductus is also more sensitive as gestational age increases. Indomethacin should not be used in pregnancies of 32 weeks or more. Moise 59 found that 28 percent of exposed fetuses will suffer from premature closure of the ductus and that it will happen in 70 percent of fetuses by 31 weeks. Vermillion60 described an even higher incidence of closure with 50 percent of fetuses exposed being affected in total and 70 percent of fetuses by 31 weeks gestation. Both authors demonstrated closure as early as 25 weeks gestation. Neonates who received indomethacin while in utero seem to have become sensitized as they do not respond as well to medical treatment of patent ductus ateriosus (PDA) and more infants require surgicalligation (37% versus 13%).61 Oligohydramnios is also associated with in utero exposure to indomethacin. Fetal urinary output decreases as early as five hours after initiation of therapy.62 This tocolytic is, thus, the ideal treatment for preterm labour secondary to polyhydramniosY.64 Renal dysfunction is partially reversible but some authors have described prolonged neonatal renal insufficiency secondary to in utero exposure. 65 If indomethacin is to be used, discontinuation of treatment after 48 to hours is recommended. Alternatively, the fetus can be followed closely with ultrasound assessments of amniotic fluid volume and ductal flow. The drug should be stopped immediately if oligohydramnios or velocity changes in the ductus are detected. Recently, a compound by the name of sulindac has been under investigation as a potential tocolytic. This drug is closely related structurally to indomethacin but is a prodrug with little or no placental transfer shown in animal studies. 66 In the treatment of refractory preterm labour, Carlan et al. 67 have shown it to be as effective as indomethacin with fewer fetal side effects. It does affect

flow and glomerular filtration rate in susceptible patients predisposed to overactive local vasoconstriction. It is reversible and the mean recovery time is five days. Indomethacin should not be used simultaneously with aminoglycosides or any nephrotoxic drugs 50 or in patients with already impaired renal function. Its use concurrently with beta blockers has also resulted in hypertensive crises in mothers. 51 Antiprostaglandins sometimes will prolong the bleeding time as much as twice the normal. No change in prothrombin time and activated partial thromboplastin time (anT) have been observed. 52 There is at least a theoretical risk of increased bleeding at the time of delivery and an epidural may not be an option for some patients. This is especially true shortly after receiving the medication, as maternal peak levels are reached in one to two hours. 1 Depression and psychosis have been described with longterm treatment with indomethacin (more than 7 days).53

3.

FETAL AND NEONATAL SIDE EFFECTS

A. Immediate/Short Term Effects Both fetal and neonatal side effects have been described (Table 10). In utero, there are two well described complications. Closure of the ductus arteriosus has been seen with long-term use of indomethacin (> 48h) but not with short-term therapy.54,55 This can lead to tricuspid regurgitation, congestive heart failure, hydrops and eventually, death. 56 Doppler studies have confirmed closure of the ductus with treatment given for

n

TABLE 10 ANTIPROSTAGLANDINS. FETAL AND NEONATAL SIDE EFFECTS Fetal

In utero closure of the ductus leading to: - tricuspid regurgitation - congestive heart failure - hydrops - death Oligohydramnios

Neonatal

- necrotizing enterocolitis - Grade II to IV intraventricular haemorrhage - patent ductus arteriosus with failure to respond to medical treatment and an increase in requirement of surgical ligations - renal dysfunction - bronchopulmonary dysplasia or respiratory distress syndrome

TABLE 11 ANTI PROSTAGLANDINS. FETAL CONTRA-INDICATIONS - Ductus-dependent fetal cardiac defects - Gestational age:> 32 weeks - Intra-uterine growth restriction - Oligohydramnios

Rarely: - isolated small bowel perforations

- TITS

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, , , the ductus but decreases in pulsatility indices appear only 24 hours after initiation of treatment, are of less importance and are transient, reverting to normal even with continuation of treatment. This new agent appears promising but more research is needed before clinical use can be recommended. Neonatal side effects are also of concern. Changes in neutrophil and platelet function but not in number have been described in neonates receiving indomethacin for patent ductus arteriosus (PDA). Indomethacin inhibits platelets from producing cyclo-oxygenase products and prolongs the bleeding time. 68 Similar changes could occur in newborns exposed to this same therapy in utero. Mesenteric, cerebral and renal haemodynamic changes are also seen in these circumstances. This may explain the association seen with in utero exposure to indomethacin and the increased risk of necrotizing enterocolitis (19% versus 2%), grade II to IV intraventricular haemorrhages, patent ductus arteriosus (62% versus 44%)61,69 and renal insufficiency.65 Major 69 also reported an even higher incidence of necrotizing enterocolitis if neonates were exposed to indomethacin for more than 48 hours with an interval to delivery ofless than 24 hours. This reported increase in complications remains controversial however, as other authors have not confirmed these findings. 70 ,71 Isolated small bowel perforations have also been reported. 72 ,73 Additionally, neonates are at increased risk of persistent fetal circulation, pulmonary artery hypertrophy, bronchopulmonary dysplasia and respiratory distress.

TABLE. 12 PREVENTION OF ANTIPROSTAGlANDIN SIDE EFFECTS AND'COMPLlCAT10NS -Do not use for more than 48 to 72 hours _ Monitor ductal Doppler indices ,... Monitor amniotic fluid volume ,... Discontinue treatment if changes occur ,... Do not use in patients with premature rupture of membranes, oligohydramnios . ,... Limit to pregnancies < 32 weeks - Do not use if delivery anticipated in less than 24 hours - Inform neonatologist of in utero exposure

pregnancies ofless than 32 weeks. As neonatal complications, especially necrotizing entercolitis/9are more frequent if the fetus is exposed to indomethacin close to the time of birth, it is best to avoid using it in patients in whom it is unlikely to achieve a delay in delivery of more than 24 hours. The neonatologist should also be aware of in utero exposure to be given every opportunity to try and minimize neonatal complications. CALCIUM CHANNEL BLOCKERS (TABLE 13)

1.

The use of calcium channel blockers as tocolytic agents is becoming more widespread. 75 Their mechanism of action involves the blockage of voltage-dependent calcium channels on the cell membrane, reducing intracellular calcium concentration, thereby preventing

B. Long-term Effects

TABLE 13

Al-Alaiyan et al. 74 studied neurodevelopmental outcomes in infants exposed to indomethacin antenatally and found no significant difference in fine and gross motor, adaptive and language skills at six and 12 months of age. This study was retrospective, however, with a small sample size and a short follow-up period. More work needs to be done in this area before any conclusion can be drawn.

4.

PREVENTION (TABLE

MECHANISM OF ACTION

CALCIUM CHANNEL BLOCKADE 1.' Ensure patient is not treated with MgS04 and nounder.lying liver disease 2. Use nifedipine per os and avoid sublingual route (could precipitate hypotension)

3. Follow liver function tests if long-term treatment Minor side effects:

,... mild hypotension - nausea - flushing - headache Major side effects and complications: ,... hepatotoxicity ,... hypotension - neuromuscular blockade

12)

Avoiding prolonged use, monitoring ductal flows and amniotic fluid volume closely and stopping the medication as soon as changes occur are important for the prevention of complications from indomethacin. It should not be used in patients at risk of infection or with oligohydramnios. Its use should also be limited to

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Treatment of severe complications:

1. Oiscontinue nifedipine . 2. Ventilatory and haemodynamic support 3. Calcium gluconate 19m IV

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T

T

myometrial cell contraction. Their first use as tocolytics was reported in 1971 with the introduction of verapamil, which was soon replaced by nifedipine as verapamil was found to slow the atrial ventricular conduction in the heart. Since then, nifedipine has been investigated further and found in many trials to compare favourably to ~-agonists. 76

2.

fetal PaOz and 0z saturations, the same has not been confirmed in the human, and so far, there is no evidence of detrimental effects of these drugs on the fetus and neonate. 4.

Selection of patients for tocolysis is of major importance. Patients with liver disease or who require MgS04 are not suitable candidates for nifedipine. Complications and side effects are usually mild and do not generally warrant intervention. However, in the rare case of significant hypotension or neuromuscular blockade, immediate action is necessary, including the discontinuation of treatment, oxygen supplementation and ventilatory as well as haemodynamic support. Calcium gluconate can be administered at a dosage of one gram intravenously over two to three minutes. Obviously, if MgS04 has been administered concomitantly, it should be discontinued immediately. Overall, the use of nifedipine as a tocolytic agent is gaining more widespread acceptance and nifedipine appears to be well tolerated. Its side effects and compfications are often reported as less common and less severe than those of ~-agonists, and its efficacy appears similar. Its use as a tocolytic agent deserves further investigation.

MATERNAL SIDE EFFECTS

FUTURE DIRECTIONS

Recently, research efforts have focused on the development of more organ-specific tocolytics in order to increase efficacy and decrease side effects. Oxytocin antagonists may fulfill these criteria. These agents work by competitive inhibition of oxytocin binding to receptors in both the myometrium and decidua. 8) It has been demonstrated that decidua and membranes can bind radio-labelled oxytocin and that in the rat model, both in vivo and in vitro, synthetic oxytocin antagonist inhibited oxytocin induced contraction. S) The same effects were found in human myometrium in vitro. More recently, in a randomized placebo controlled trial, oxytocin antagonists were found to decrease pre term uterine activity significantly.84 Two small uncontrolled studies have also suggested that these agents could in fact delay premature delivery in over 50 percent of patients. 85 ,86 As oxytocin antagonists are very specific and only affect the breast and the uterus, it is expected that adverse effects and complications would be very rare. To

FETAL AND NEONATAL SIDE EFFECTS

Initial animal studies involving monkeys, sheep and goats have demonstrated a decrease in uteroplacental blood flow following exposure to calcium channel blockers. Doppler studies of human fetuses have failed to show any alteration in the maternal or fetal circulation. 79 ,82 While animal studies have shown a decrease in

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PREVENTION AND TREATMENT OF

COMPLICATIONS

Most studies have found similar effectiveness and emphasized that side effects were much less common with calcium channel blockers than with ~-sympath­ omimetics. 76.78 As an example, while maternal diastolic blood pressure was found to be slightly decreased with nifedipine (from 68.5 mmHg to 64.5 mmHg) it was still less so than with ritodrine (from 68.3 mmHg to 51.8 mmHg).78,79 However, most side effects and complications are still related to the peripheral vasodilation induced by this class of agents. This results in nausea, flushing, headaches and dizziness. The practitioner should also be aware of reported cases of hepatotoxicity following the use of nifedipine and should monitor liver function if this drug is to be administered for a prolonged period.8o In addition, the concomitant use of MgS0 4 is contra-indicated as this can result in serious neuromuscular blockade. Finally, concerns have been raised recently over the safety of calcium channel blockers administration to the general population. 8l Reports on the use of short-acting agents have shown a slight increase in cardiovascular mortality, gastro-intestinal bleeding and certain cancers. So far, none of these complications has been reported in the obstetrical population. The major differences between populations (older patients often with underlying cardiac disease, prior myocardial infarction) and the duration of use probably explains why this has not been a concern for the pregnant patient. However, most recommend the use of these agents in their long-acting forms if possible and for the shortest possible duration. 3.

T

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, , , 15. Karem E, Dollberg 5, Paz I, Armon Y, Seidman DS, Stevenson DK, Gale R. Prenatal ritodrine administration and the incidence of respiratory distress syndrome in premature infants. J PerinatoI1997;17(2):1 01-6. 16. Chapman DL, Carlton DP, Cummings JJ, Poulain FR, Bland RD. Intrapulmonary terbutaline and aminophylline decrease lung fluid in fetal Iambs. Pediatrics 1991 ;29:357-61. 17. Hooper SB, Harding R. Effect of beta-adrenergic blockade in lung liquid secretion during fetal asphyxia. Am J Physiol 1989;257:R: 705-10. 18. Groome U, Goldenbert RL, Cliver SP et a/. Neonatal periventricular-intraventricular hemorrhage after maternal beta-sympathomimetic tocolysis. The March of Dimes Study Group. Am J Obstet Gynecol1991 ;167:873-9. 19. Ozcan T, Turan C, Ekici E et al. Ritodrine tocolysis and neonatal intraventricular-periventricular hemorrhage. Gynecol Obstet Invest 1995;39:60-2. 20. Rouse DJ, Widness JA, Weiner CPo Effect of intravenous beta-sympathomimetic tocolysis on human fetal serum erythropoietin levels. Am J Obstet GynecoI1993;168:1278-82. 21. Hall DG, McGaughery HS, Corey EL et a/. The effects of magnesium therapy on the duration of labor. Am J Obstet GynecoI1959;78:27-32. 22. Elliott JP. Magnesium sulfate as a tocolytic agent. Am J Obstet GynecoI1983;147:277-84. 23. Ferguson JE, Hensleigh PA, Kredenster D. Adjunctive use of magnesium sulfate with ritodrine for preterm labor tocolysis. Am J Obstet GynecoI1984;148:166-71. 24. Wilkins lA, Lynch L, Mehalik KE et al. Efficacy and side effects of magnesium sulfate and ritodrine as tocolytic agents. Am J Obstet GynecoI1988;159:685-9. 25. Hoff HE, Smith PK, Winkler AW. Effects of magnesium on the nervous system in relation to its concentration in serum. Am J PhysioI1940;130:292-7. 26. Snyder SW, Cardwell MS. Neuromuscular bockade with magnesium and nifedipine. Am J Obstet Gynecol 1989;61 :35-6. 27. L'Hommedieu CS, Nicholas D, Armes DA et al. Potentiation of magnesium sulfate-induced neuromuscular weakness by gentamicin, tobramycin and amikacin. J Pediatr 1983;102:629-31. 28. Wilkins LA, Goldbert JD, Phillips RN et a/. Long-term use of magnesium sulfate as a tocolytic agent. Obstet Gynecol 1986;67:385-405. 29. Hill WC, Jurgensen WW. Continuous long-term intravenous magnesium sulfate tocolysis. Abstract #324 from the Seventh Annual Meeting of the Society of Perinatal Obstetricians, Lake Buena Vista, Florida, USA 1987. 30. Dudley D, Gagnon D, Varner M. Long term tocolysis with intravenous magnesium sulfate. Obstet Gynecol 1989;73:373-8. 31. Smith LG, Burns PA, Schanker RJ. Calcium homeostasis in pregnant women receiving long-term magnesium sulfate therapy for preterm labor. Am J Obstet Gynecol 1992;167:45.

date, only symptoms of nausea and vomiting have been reported. There have been no fetal or neonatal complications nor any maternal cardiovascular or metabolic disturbances. The available data on oxytocin antagonists as tocolytics are promising, and it appears that this class of agent would be associated with far fewer maternal and fetal complications and toxicities. REFERENCES 1.

2.

3.

4.

5. 6.

7. 8. 9. 10.

11.

12.

13.

14.

Creasy RK. Preterm Labor and Delivery. In: Creasy RK, Resnik R (Eds). Maternal-Fetal Medicine-Principles and Practice. Philadelphia: W.B. Saunders. 1994; 3rd ed:494-520. Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 1992;327:308-12. Higby K, Xenakis EM-J, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993;168(4):1247-59. Katz M, Robertson PA, Creasy RK. Cardiovascular complications associated with terbutaline treatment for preterm labor. Am J Obstet Gynecol1981 ;39:605-8. Washington Clark Hill. Risks and complications of tocolysis. Clin Obstet Gynecol 1995;December 38(4): 725-45. Hatjis CG, Swain M. Systemic tocolysis for premature labor is associated with an increased incidence of pulmonary edema in the presence of maternal infection. Am J Obstet GynecoI1988;159:723-8. Monga M, Creasy RK. Pharmacologic management of preterm labor. Semin Perinatol1995;February 19(1):84-96. Clark SL, Cotton DB, Hankins GDV, Phelan JP. Critical Care Obstet 1991 ;2nd ed. Blackwell Scientific Publications. Wagner JM, Morton MJ, Johnson HA et al. Terbutaline and matemal cardiac function. JAMA 1981 ;246:2697 -701. Lipshitz J, Depp R, Harth J, Hayashi R, Morrison J, Schneider J. Comparisons of the cardiovascular effects of hexaprenaline and ritodrine in the treatment of preterm labor. Third Annual Meeting of the Society of Perinatal Obstetricians. San Antonio, Texas, January 1983. Elliott P. Management of complications associated with administration of tocolytic agents. In: Foley M, Strong T (Eds). Obstetrics Intensive Care: A Practical Manual. W.B. Saunders. 1997. Kast A, Hermer M. Beta-adrenoreceptor tocolysis and effects on the heart of fetus and neonate. A review. J Perinat Med 1993;21 :97 -106. Caritis 5, Morishama H, Stark R, DanielS, James L. Effects of terbutaline on the pregnant baboon and fetus. Obstet GynecoI1997;50:56. King JF, Grant A, Keirse MJN, Chalmers I. Beta mimetics in preterm labor: an overview of the randomized controlled trials. Br J Obstet GynaecoI1988;95:211-22.

JOURNAL SOGC

967

SEPTEMBER 1998

, , , 32. Peaceman AM, Meyer BA, Thorp JA et al. The effect of magnesium sulfate tocolysis on the fetal biophysical profile. Am J Obstet Gyneco11989;161 :771-4. 33. Sherer DN. Blunted fetal response to vibroacoustic stimulation associated with maternal intravenous magnesium sulfate therapy. Am J Perinatol1994;11 :401-3. 34. Petrie RH. Tocolysis using magnesium sulfate. Semin Perinatol1981 ;5:266-73. 35. McGuinness GA, Weinstein MM, Cruikshank DP et al. Effects of magnesium sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol 1980;56:595-600. 36. Donovan EF,Tsang RC, Steichen JJ et al. Neonatal hypermagnesemia: effect on parathyroid hormone and calcium homeostasis J Pediatr 1980;96:305-10. 37. Cruikshank DP, Pitkin RM, Reynolds WA et al. Effects of magnesium sulfate treatment on perinatal calcium metabolism. I. Maternal and fetal responses. Am J Obstet GynecoI1979;134:343-9. 38. Lamm CI, Norton KI, Murphy RJ et al. Congenital rickets association with magnesium sulfate infusion for tocolysis. J Pediatr 1988;113:1078-82. 39. Holcomb WL, Shackelford GD, Petrie RH. Magnesium tocolysis and neonatal bone abnormalities: a controlled study. Obstet Gynecol1991 ;78:611-4. 40. Schanler RJ, Smith LG Jr, Burns PA. Effects of long-term maternal intravenous magnesium sulphate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest 1997;43:236-41. 41. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263-9. 42. Schendel DE, Berg CJ, Yeargin-Allsopp M et al. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth weight children aged 3 to 5 years. JAMA 1996;276: 1805-1 O. 43. Hauth JC, Goldenberg RL, Nelson KG et al. Reduction of cerebral palsy with maternal MgS04 treatment in newborns weighing 500-1000g (abstract). Am J Obstet GynecoI1995;172(suppl.):419. 44. Wiswell TE, Graziani IJ, Caddell JL, Vecchione N et al. Maternally-administered magnesium sulfate (MgS0 4) protects against early brain injury and long-term adverse neurodevelopmental outcomes in preterm infants: a prospective study (abstract). Pediatr Res 1996;39:253A. 45. Grether JK, Hoogstrate J, Selvin S, Nelson KB. Magnesium sulfate tocolysis and risk of neonatal death. Am J Obstet GynecoI1998;178(1) Part 1:1-6. 46. Phaneuf S, Europe-Finner GN, Varney M et al. Oxytocinstimulated phosphoinositide hydrolysis in human myometrial cells: involvement of pertussis toxin-sensitive and insensitive G-proteins. J EndocrinoI1993;136:497-509. 47. MacKenzie LW, Garfield RE. Hormonal control of gap junctions in the myometrium. Am J Physiol 1985;248:C296-308.

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48. Ramwell PW, Foegh M, Loeb R et al. Synthesis and metabolism of prostaglandins, prostacyclin and thromboxane: the arachidonic acid cascade. Semin Perinatol 1980;4:3-13. 49. Steiger RM, Boyd EL, Powers DR et al. Acute maternal renal insufficiency in premature labor treated with indomethacin. Am J PerinatoI1993;10:381-3. 50. Walker MP, Cantrell CJ. Maternal renal impairment after indomethacin tocolysis. J PerinatoI1993;13:461-3. 51. Schoenfeld A, Freedman S, Hod M et al. Antagonism of antihypertensive drug therapy in pregnancy by indomethacin? Am J Obstet Gyneco11989;161 :1204-5. 52. Lunt CC, Satin AJ, Barth WJ Jr, Hankins GD. The effect of indomethacin tocolysis on maternal coagulation status. Obstet Gynecol1994;Nov 84(5):820-2. 53. Tepperman HM, Beydoun SN, Abdul-Karim RW. Drugs affecting myometrial contractility in pregnancy. Clin Obstet GynecoI1977;20:423-45. 54. Gerson A, Abbasi S, Johnson A et al. Safety and efficacy of long-term tocolysis with indomethacin. Am J Perinatol 1990;7:71-4. 55. Besinger RE, Niebyl JR, Keyes WG et al. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol1991 ;164:981-8. 56. Van den Veyver IB, Moise KJ. Prostaglandin synthetase inhibitor in pregnancy. Obstet Gynecol Surv 1993;48: 493-502. 57. Moise KJ, Huhta JC, Sharif DS et al. Indomethacin in the treatment of premature labor. Effects on the fetal ductus arteriosus. N Engl J Med 1988;319:327-31. 58. Eronen M, Pesonen E, Kurki T et al. Effect of indomethacin and a f3-sympathomimetic on the fetal ductus arteriosus during treatment of premature labor: a randomized double blind study. Am J Obstet Gynecol 1991;164:141-6. 59. Moise KJ. Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use. Am J Obstet Gynecol 1993;168:1350-3. 60. Vermillion ST, Scardo JA, Lashus AG, Wiles HB. The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age. Am J Obstet Gynecol1997;August 177(2):256-61. 61. Norton ME, Merrill J, Cooper BAB et al. Neonatal complications after administration of indomethacin for preterm labor. New Engl J Med 1993;329:1602-7. 62. Kirshon B, Moise KJ, Wasserstrum N et al. Influence of short-term indomethacin therapy on fetal urinary output. Obstet GynecoI1988;72:51-3. 63. Kirshon B, Mari G, Moise KJ. Indomethacin therapy in the treatment of symptomatic polyhydramnios. Obstet GynecoI1990;75:202-5. 64. Moise KJ Jr. Indomethacin as treatment for symptomatic polyhydramnios. Contemp Obstet Gynecol 1995;May:53-60.

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SEPTEMBER 1998

, , , 65. Van der Heijden BJ, Carlus C, Narcy F et a/. Persistent anuria, neonatal death and renal microcystic lesions after prenatal exposure to indomethacin. Am J Obstet GynecoI1994;171:617-23. 66. Flower RJ, Moncada S, Vain JR. Analgesics-antipyretics and antiinflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Gilman A (Eds). The Pharmacologic Basis of Therapeutics. New York: MacMillan 1985:697-8. 67. Carlan SJ, O'Brien WF, O'LearyTD, Mastrogiannis D. Randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor. Obstet Gynecol 1992;79:223-8. 68. Friedman Z, Whitman V, Maisels MJ, Berman W Jr, Marks KH, Vessels ES. Indomethacin disposition and indomethacin induced platelet dysfunction in premature infants. J Clin Pharmacol 1978;18:272-9. 69. Major CA, Lewis DF, Harding JA et al. Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low birth weight neonate. Am J Obstet GynecoI1994;170:102-6. 70. Niebyl JR, Blake DA, White RD et al. The inhibition of premature labor with indomethacin. Am J Obstet GynecoI1980;44:787-90. 71. Zuckerman H, Shalev E, Gilad G et al. Further study of the inhibition of premature labor by indomethacin. Part II. Double-blind study. J Perinat Med 1984;12(1}:2s-30. 72. Fejgin MD, Delpino ML, Bidiwala KS. Isolated small bowel perforation following intrauterine treatment with indomethacin. Am J PerinatoI1994;11(4}:29s-6. 73. Van Haesebrouck P, Thiery M, Leroy JG et al. Olighydramnios, renal insufficiency and ilial perforation in preterm infants and after intrauterine exposure to indomethacin. J Pediatr 1988;113:738-43. 74. AI-Alaiyan S, Seshia MMK, Casiro OG. Neurodevelopmental outcome of infants exposed to indomethacin ante natally. J Perinat Med 1996;24:405-11. 75. McCombs J. Update on tocolytic therapy. Ann Pharmacother 199s;May 29:515-22. 76. Van Dijk KGJ, Dekker GA, van Geijn HP. Ritodrine and nifedipine as tocolytic agents: a preliminary comparison. J Perinat Med 1995;23:409-15. 77. Meyer WR, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 1990;35:649-53. 78. Ferguson JE, Dyson DC, Schutz R et al. A comparison of tocolysis with nifedipine and ritodrine: analysis of efficacy and maternal, fetal and neonatal outcome. Am J Obstet GynecoI1990;163:10s-11. 79. Ferguson JE, Dyson DC, Holbrook RH et al. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol 1989;161 :788-95. 80. Sawaya GF, Robertson PA. Hepatotoxicity with the administation of nifedipine for treatment of preterm labor. Am J Obstet GynecoI1992;167:s12-3.

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81. Davis WB, Wells SR, Kuller JA, Thorp JM Jr. Analysis of the risks associated with calcium channel blockade: implications for the obstetrician-gynecologist. Obstet Gynecol Surv 1997;s2(3}:198-201. 82. Mari G, Kirshon B, Moise KJ Jr et al. Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labor. Am J Obstet Gynecol 1989;161 :1514-8. 83. Fuchs AR, Vangsted A, Ivanisevic M et al. Oxytocin antagonist (dTVT) and oxytocin receptors in myometrium and decidua. Am J Perinatol 1989;6;205-10. 84. Goodwin TM, Paul R, Silver H et al. The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human. Am J Obstet GynecoI1994;170:474-8. 85. Akerlund M, Stromberg P, Hauksson A et al. Inhibition of uterine contractions of premature labor with an oxytocin analogue. Br J Obstet Gynaecol 1987;94:1040-4. 86. Anderson LF, Lyndrys J, Akerlund M et al. Oxytocin receptor blockade: a new principle in the treatment of premature labor? Am J PerinatoI1989;6:196-9.

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