CURRENT DEVELOPMENTS

Pharmacologic

inhibition

STEVE

M.D.

DANIEL

N.

CARITIS, I.

EBERHARD Pilt.hqli,

EDELSTONE,

of preterm labor

M.D.

MUELLER-HEUBACH,

M.D.

Pfvznsylz~nnin

Preterm labor is responsible for a majority of cases of perinatal morbidity and deaths. Prevention of preterm labor is not usually possible; thus pharmacologic treatment is the only recourse available. Numerous agents have been used to treat preterm labor, but none has proved to be superior. This report reviews the current information available about the pharmacology of labor-inhibiting drugs and discusses the clinical approach to the management of preterm labor. (AM. J. OBSTET. GYNECOL. 133557, 1979.)

RECENT IMPROVEMENTS in neonatal intensive care have resulted in reductions in neonatal morbidity and death. An increase in neonatal survival has been most apparent in infants with birth weights greater than 1,500 grams but survival rates have also improved in smaller infants.‘-> Despite these considerable gains in neonatal outcome, the impact of preterm delivery on the perinatal mortality rate is staggering. Although accounting for a relatively small percentage of total births, infants born prior to term account for a majority of neonatal deaths.‘j In addition, a disproportionately large percentage of preterm infants suffers significant neonatal morbidity and long-term sequelae such as motor and intellectual handicaps-” The incidence of preterm birth can be reduced only by adequate prenatal care with active treatment of factors that predispose pregnant women to preterrn labor.” When preventative measure” fail, pharmacologic suppression of preterm labor is commonly undertaken since significant decreases in neonatal morbidit) Fmm

the Department of Obstetrics and Gynecology, of Pittsburgh School of Medicine. Magee-Wornens Hospital. ITnirrerrity

Reprint requests: Dr. Steve N. Caritti, Department qf Ob.jtetricJ and Gynecology, The University of Pittsburgh School of Medicine, Magee-Wornens Hospital, Forbes Aw. and Hnlkrt St., Pittsburgh, Pennsyluania 15213. 0002.9378/79/050557+22$02.2016

0 1979 The C. V. Mosby

Co.

and death may be realized with the addition of one or two weeks of intrauterine existence.‘O An enormous amount of basic and clinical research on labor-inhibiting agents has recently appeared, making the subject of labor inhibition a very confusing one. This review will discuss the clinical approach to the treatment of preterm labor and will summarize the pertinent information currently available about labor-inhibiting drugs.

Preterm labor-Definition,

incidence, and etiology

In this review, “preterm” will refer to events occurring prior to the onset of the thirty-seventh week of amenorrhea (259 days).“’ In the United States in 1969, 9.8% of pregnancies ended prior to 37 weeks of amenorrhea. The incidence of preterm birth was higher in black women (18.6%) than in white women (8.3%). ‘I Similar statistics were reported from 40 states and the District of Columbia in 1975. In Britain in 1970, 6.4% of all births were preterm whereas only 3.3% of all births in East Germany in 1974 were preterm.6 Table I lists some conditions which occur with increased frequency in cases of preterm labor; such associations, however, do not necessarily indicate causality. In some cases, a direct cause-and-effect relationship is obvious, such as iatrogenic causes of preterm labor, but in other cases the relationship is less clear. The 557

558

Table

Caritis,

Edeistone,

and Mueller-Heubach

I. Factors implicated

in preterm

labor

Maternal:

Severe systemic diseases Endocrine disorders Trauma Orgasm Socioeconomic status History of preterm birth Genital infection F&placental:

Genetic abnormalities Fetal death Abruptio placentae Placenta previa Utrrinr:

Overdistention Malformation Infection Foreign body Rupture of membranes Cervical trauma Othrr:

Iatrogenic

majority of cases of preterm labor are without apparent cause.“. I3 Iatrogenic reasons for preterm delivery are most often due to fetal compromise or deteriorating maternal condition, or both. Man) infanrs. however, arc delivered elecrively prior to term because of an error in estimated gestational age. The use of’ fetal ultrasonic cephalometry and tests of fetal pulmonary maturity have reduced the incidence of such errors in most institutions, buL considerable room for improvement still exists.” Acute qstemic illnesses such as pyelonephritis and febrile viral infections may be associated with increased uterine contractility and preterm labor.‘* Severe chronic systemic illnesses. such as chronic renal or cardiac disease or chronic hypertension, have been associated with delivery of lowbirth-weight infants, but frequently it is unclear whether such infants are also preterm. Preterm label commonly occurs in patients with untreated hyperthyroidism,1,5 hyperparaLhyroidism,l” or hyperadrenocorticism.” Blunt injuries or penetrating wounds of the abdomen or uterus are obviously hazardous to the maintenance of pregnancy. Increased uterine contractions and an increased incidence of prematurity have been reported in women experiencing orgasm in late of maternal sociopregnancy. I83 Iy Several indicators economic status have been repeatedly linked to preterm labor. According to some studies, maternal nutrition, hygiene, sexual habits, race, age, medical care. working habits, drug usage, and smoking habits influence the incidence of low-birth-weight infants, but in many of these studies a distinction between preterm, appropriately grown infants and term growth-retarded infants has not been made.l”, *’ Retrospective analysis

of’ the data of the First British Collaborative Study has indicated that low maternal age, disadvantaged social status, low maternal weight, single marital status, and smoking are associated with an increased incidence of preterm birth. Maternal parity and height do not influence the duration of pregnancy. The incidence of preterm labor and delivery of lobv-birth-weight infants is increased in \I omen who have previously experienced these events.“” Although a clear relationship between vaginal infectiotls and preterm labor has not been established, tertain organisms such as the genital tnycoplasmas are isolated more frequently from the cervices of patients with a histor)- of pre’erm labor.“’ (;enetic ~lbtlormalitics of the fetus may be associated with prcLerm labor-. Fctai death usually results in deli\,rry of’thr fetur \vithin I\\(] lverks. I’here ih an increased incidence of‘ prctcrm labor in patients bvitli alitepartum hcrno~rhag~ f roni placenra prcvia or abruptio placelltile.“. ” Ovcrdistention of the uterus f’rom multiple pregtiaric\ OI f,olyli~dt-arnnios f.recluelllly results in preterm labor-. ‘I‘he rate of prelerm deli\-cry in twin geslalioti raliges from SO!? to 47% ,2i and in comparwn to un~onif,lic,ated pregmnc\ 1~ol!;hvdI.~lrnnios is asjociatetl lvith ~)reterrn iabot LF\,ic,eas often.‘” Llterine Inalforrrialioti i5 comnionl~ associated \\itli preterm deliver\ .“’ ‘1 II indomethacin > naproxen > phenylbutazone > aspirin. ‘* Inhibition of prostaglandin synthesis can be demonstrated very soon after ingestion of inhibitor. Prostaglandin synthesis in platelets is reduced within one hour following the ingestion of 600 mg of aspirin or 50 mg of indomethacin.“” Bnsic cl& cliCccr/ rrs~~& In vitro studies with the pregnant rat uterus indicate that prostaglandin antagonists inhibit spontaneous uterine contractions and reduce the amount of prostaglandin produced and released by the uterine muscle strips.Qfia g’ In the pregnant rat, inhibitors of prostaglandin synthesis such as aspirin, indomethacin, or naproxen prolong both the time of onset of labor and the process of expulsion.“‘~ !” Prostaglandin-inhibiting agents also delay the onset of parturition in the subhuman primate.9” Lewis and Sctlulman’OO reported that chronic aspirin ingestion by pregnant women influenced the onset and duration of labor. In a retrospective study of 103 patients who ingested high doses (>3,250 mg daily) of acetylsalicylic acid for at least the last 6 months of pregnancy, these authors reported that the length of gestation, frequency of postmaturity, and mean duration of spontaneous labor were greater when compared to these parameters in a group of women with similar medical conditions (rheumatoid arthritis, nonspecific collagen disease, and degenerative musculoskeletal disease) who did not consume aspirin. According to two studies with a control group of patients, 600 mg of aspirin or 25 mg of indomethacin or both administered every 6 hours significant]), prolong the instillation-abortion interval in women undergoing abortion by intra-amniotic hypertonic saline or hyperosmolar urea, 101, IO? A few reports have suggested that prostaglandin inhibitors reduce uterine contractility in term or preterm labor.‘“5-1”” Zuckerman and associates’“’ treated 50 women of 25 to 36 weeks’ gestation who lvere in preterm labor with indomethacin suppositories and oral tablets. In 80% of women receiving indomethacin. uterine contractions were abolished by the drug whether the membranes were intact or ruprured. Unfortunately, a control population was not used in this study or in any of the studies cited here so that the effectiveness of prostaglandin inhibitors in preterm labor cannot be determined. Of considerable interest, however, is the fact that in the study of Zuckerman and associateslO” indomethacin successfully inhibited uterine contractions for more than 7 days in 11 of I3 patients (85%) with ruptured membranes in preterm labor. In nine of these 11 patients, pregnancy MXS continued until term. Dosnge, Zuckerman and associates”‘.’ administered

564

Caritis,

Edelstone,

and Mueller-Heubach

100 mg of indomethacin rectally and followed rhis with 25 mg orally every 6 hours until contractions ceased. Repetitive courses of indomethacin were given and the total dosage used in their study ranged from 200 to 1,100 mg. In the United States, none of the prostaglandin-inhibiting agents is approved for use in preterm labor. :Wat~~crl .sj& c@rt.\. ‘l‘here are numerous potential side effects from prostaglandin inhibitors because of the ubiquitous nature of the prostaglandins. These include effects on the gastrointestinal tract, central nervous system, hematologic and cardibvascular systems, eye, liver, kidneys, and spine.‘“’ The most serious potential side effects are peptic ulceration, gastrointestinal perforation, bleeding, thrombocytopenia, and allergic reactions. Nausea. dizziness, vertigo, headache, and allergic manifestations are commonly seen, but these side effects arc usually mild. Most side effects are related to the dose of the drug and to the duration of therapy. Chronic ingestion of aspirin by pregnant lcornen increases the incidence of anemia and antepartum and intrapartum hemorrhage.‘Ox Postpartum hemorrhage occurred in three of 16 women who received a single 100 mg suppository of indomethacin during early term labor. Ini Women undergoing midtrimester abortion and concomitantly receiving prostaglandin inhibitors are at increased risk of postpartum hemorrhage. ““L I”’ Nausea, vomiting, dyspepsia, and allergic rashes have been observed in pregnant women in preterm labor treated briefly with prostaglandin inhibitors, 101.IIIH Fctcrl/rlc,o,cccttr(.\i& c~fect.~ The risks to the fetus and neonate from exposure to prostaglandin inhibitors are the same as those of adults but in addition some side effects and potential risks not observed in adults have been reported in the fetus and newborn inf’ant. No studies ha\e shown indomethacin to be teratogenic. but in rats the drug produces neuronal necroses in the br-Iin.“’ ‘ This may be due to a reduction in cerebral blood floes.“’ Cnlike indomethacin. however, aspirin is tcratogenic in several animal species.“” Although retrospective studies in humans suggest that aspirin ma) produce human nialf’ormations,““‘” a prospective study of women consuming aspirin throughout pregnancy showed that aspirin ingestion during pregnancy did not increase the incidence of congenital malformation.“’ Insufficient data are available to evaluate the teratogenic potential of short-term prostaglandin inhibition during the perinatal period. The effect of chronic aspirin ingestion during pregnancy on perinatal mortalit\- is controversial. Turner and Collins”’ reported an increase in the perinatal

mortality rate but Shapiro and associates.“” in an analysis of data from the Collaborati\-e PeI-inatal Project, could not demonstrate an\ adverse effect of chronic aspirin ingestion on the pet-inatal mortality rate. Ingestion of salicylates during the latter stages ot pregnancy may produce abnormalities in fetal platelet function and may rarei? result in neoilatal hemorrhage, II!)--,?I Inhibition ot’ pi-ostaglandin synlhcsis IILI! interfere with the normal mechanisms of transition froln f’etal to neonatal life. This is not unexpected since prohtaglandins affect umbilical blood floes”” and \ascnlar resiatance in the placenta, ductus arteriosus, ;incl pulmonary vessels.“” In animal fetuses. prostaglandin inhibition is associated with premature closure of the ductIts arteriosus. Sharpe and associates”’ obscr\ed ititrauterine contraction of- the ductus artei-io\ua in rat fetuses whose mothers received ;I single tlos~ cut indomethacin 12 to 1X hours prior to tleli\cI-!. Similatresults have been reported in rabbit and sheep fetuses exposed to prostaglandin inhibitors.‘“, I’“’ I’r-ostaglandin inhibitors ma\ also afftct the fetal and neonatal response to h) poxia. Neonatal goats a11tl talvea and adults dogs compared with control animals exposed to indomethacin demonstrate ;I greater rise iI1 pulmoi~ar~ vascular resistance t’ollo\viIig a h\-posit ctiniuhls.“‘. “’ Manchester ;~nd associates”‘! t-eportetl tl\o GLSC’S 01’ transient primart pulnionat~~ hypertcnaion in tl\o human neonates \vhose mothers received indomethatin prior to delivery. These authors suggested that the inhibition of prostaglandin synthesis b! intlomcthaciI1 led to an exaggerated pulmonar! vascular- response to hypoxia with resultant pulmonar! h) pertell5ion. There are IW data on inf’:ints exposed to l)rost;lglandin inhibitors during the treatment 01’ pt-eterm labor. Congenital anomalies, prematul c closure of the ductus arteriosus, pulmonary h) pel-tension, or an esaggerdted r-csponse IO hvposia were not repot-tecl in those infants exposed to ]“ostaglantliIl-irlhibiting drugs during pregnalic) .““- I”(’ The number. of cases studied, howevet-. was ver! small and detailed descriptions of patholoCqic and clinical findings 1cet.c’ not reported. The potentially serious side effects of the prostaglandin inhibitor5 mitigate against the rorltine WC of these agents in obstett-its until additional animal and human studies have been performed. (;o,,t~cii,lclic.rtiolc \. Prostaglandin-inhibiting agents should not be used in patients with active gastrointestinal lesions or in paCents with a history of recurrent gastrointestinal lesions. Aggravation of epilepsy and psychiatric disturbances havr been reported with rhe use of prostaglandin inhibitors; therefore. such agents

Volume Number

133 5

should be used cautiously in these conditions. Gastritis commonly occurs following ingestion of prostaglandin inhibitors. therefore, concomitint use with ethanol should be avoided. Patients in whom aspirin induces asthma, rhinitis, or urticaria should not receive nonsteroid anti-inHammatory drugs for labor inhibition because of potential cross-sensitivity.Y4 Magnesium sulfate. The inhibitory effect of magnesium sulfate on uterine muscle contractility has been recognized for over 50 years. This knowledge combined with the enormous clinical experience with magnesium sulfate in patients with pre-eclampsia has undoubtedly provided an impetus to use the drug in cases of preterm labor. Phnrmcology (I nd phyciology. In vitro studies have demonstrated conclusively that magnesium abolishes uterine contractions.‘““-‘“” The mechanism by which magnesium exerts its relaxant effect on smooth muscle differs from that by which the ion paralyzes skeletal muscle. In skeletal muscle, magnesium inhibits release of acetylcholine at the motor-nerve terminal, thus preventing translation of the nervous impulse to mechanical action. In smooth muscle, however, acetylcholine is not necessary for spontaneous activity and contractions are not dependent on nervous innervation; therefore, magnesium must affect smooth muscle contractions by a direct effect on the muscle cell. Marshall’“’ has demonstrated in vitro that magnesium decreases the frequency of action potentials and decreases the force of contraction in uterine smooth muscle. Magnesium also uncouples excitation and contraction in smooth muscle, i.e.. action potentials produced by electrical stimulation do not result in muscle contraction, A direct effect of magnesium on the contractile elements may also contribute to the relaxant effect of the drug on smooth muscle.‘“’ Bnsir and cli,lictrl mearch. Hall and associates’“’ have reported that magnesium sulfate in a concentration of 9.6 to 12.0 mg/dl (1.0 mEq/L equals 1.2 mg/dl) cornpletely inhibits spontaneous contractility of uterine muscle strips from pregnant humans. This inhibition is dose related.‘:j3, IX In pregnant women, magnesium at a serum concentration of 4 to 8 mg/dl effectively reduces uterine contractility.‘“‘-‘“’ Both oxytocin-induced and spontaneous uterine contractions are suppressed by the drug.‘“” Clinical studies of the effects of magnesium sulfate in preterm labor are extremely scarce. Steer and Petriefi” in a partially randomized study compared the laborinhibiting effects of alcohol, magnesium sulfate, and 5% dextrose in water. Patients received either magnesium sulfate or ethanol randomly. but the control

Pharmacologic

inhibition

of preterm

labor

565

group of nine patients who received only glucose was selected from the general population. Treatment was considered to be successful if contractions stopped for 24 hours or more. Their study included only patients with intact membranes and with a cervical dilatation of 4 cm or less. Success was seen in 45% of patients treated with alcohol, 77’1 of patients treated with magnesium sulfate, and 45% of patients receiving only dextrose in water. If more stringent criteria for success were used (prolongation of pregnancy for 1 week or more), SLICcess rates were 42% for alcohol, 74% for magnesium sulfate, and 339 f’or 5%’ dextrose in water. Although the small number of control patients and the absence of a fully randomized protocol limit the conclusions that can be drawn from this study, the data do suggest that magnesium sulfate is superior to ethanol for the treatment of preterm labor. Clinical studies have demonstrated that magnesium sulfate inhibits spontaneous and oxytocin-augmented term labor’““, I33 but additional controlled studies in patients with preterm labor are required to establish the usefulness of magnesium sulfate as a laborinhibiting agent. The relative safety of magnesium sulfate and the large obstetric experience with its use make it a rather convenient agent for labor inhibition although it is not approved by the Food and Drug Administration (FDA) for that purpose. Dosage. Steer and PetrieGY gave 4 gm of a 10%) solution of magnesium sulfate intravenously as an initial loading dose. The initial injection was given slowly enough to avoid Hushing and vomiting. A maintenance infusion of 2 gm per hour was maintained until uterine contractiohs stopped or until labor progressed to an irreversible stage. If contractions reappeared, the maintenance infusion was restarted. The serum concentrations achieved with this protocol have not been reported. There are insufficient data available to determine if intramuscular or combined intramuscular and intravenous administration of magnesium sulfate inhibits uterine contractility. Matermd side efjerts. Because of its peripheral vasodilatory effects the intravenous infusion of magnesium sulfate results in a sensation of warmth and flushing. Rapid injection of the drug commonly produces transient nausea, headache, and palpitations. Perspiration, nystagmus, dizziness, and dryness of the mouth have also been reported with magnesium sulfate infusion. The knee-jerk reflex disappears at a serum concentration of 10 to 12 mg/dl: therefore, testing the reflex frequently should prevent excessive toxicity. Respiration is depressed when the plasma concentration of magnesium reaches 12 to I5 mgidl. At serum

566

Caritis,

Edelstone,

5 s OH -

40

nlenl

B

-A*-“H-C”3

of the concentration

illso

minimize

the

I on

I CH3

I C”3

eliminatioll,

tion

in patients

renal

CH I 6H

NH -

CH3 -

-OH

CH,-

tvith

lvith

1925 the

P3

I

-CH-CH3-NH-C

OH -

CH , -Cl*-NH-I-CH3

/

side

OH

preterm

C”3

\

aline

0

-CH-CH3-NH-CH-CH,-

0

I C”3

OH

-OH

butamol. with

Fig. 1. Chemical

and

related

beta-

and two

T

of 6 to 12 mg/dl

QRS

wave

in

cardiac

duration the

arrest

and

an increased

an increase

electrocardiogram does

not

occur

are until

P-R

in height

inter-

stimulation

of the

betd-receptor

observed,

a serum

but

ergic

neonate

sulfate but

usually

isolated

does

reports

not

of

of

compromise

neonatal

the

depression

tor

response

‘3H-‘42 The concentration of magnesium have appeared. in umbilical cord blood is similar to that of maternal

and

blood at delivery the concentration

glycogenolysia.

but Apgar scores are not related to of magnesium in cord blood. There

is a correlation mother the

and

between the

newborn

mother reflexes

infant.

during

of

duration

‘39. 14” Serious hourly,

the respiratory depressants magnesium

of therapy

neuromuscular

are not

checked

exceeds 30 ml, and respiratory given

the

risk

or neonate are

salted

likely

side if prior

the

to the

depression effects

in in

to delivery

hourly

urine

the output

rate exceeds 14/minute, such as morphine are not therapy.

Periodic

measure-

uterus.

the

b)

beta-2

wcrc’ blood

‘I‘he

dominant vessels,

adrcnet-gic

and

norepinephrine

ally

similar

to these

agotlists

acceleration and

dominated tissue.

in Lhe smooth bronchioles.

receptor

interacts

so that naturally

any

that

beta-2 of the

diaphragm. w-ith

agent

that

occurring

have

rcmuscle in the

The tttuscle

and

ac-

recep-

stimulation

adipose

can also react with the beta-adrenergic shows the str-uctural formulas of adrenergic

cardiac-

receptot-

1 receptors

and

were

Beta-l

vasodilatation.

intestine,

effector

which site.

associ-

beta-adren-

comparing

receptor

‘1‘1~ beta-

small

receptors

by

in vasoand

the

of catecholamines

in hronchodilatatiorl,

heart.

Lands

wah characterized

and

resulted

separated types

and

vasoc.onstriction often

stimulation.

whereas

classic alpha

Alpha-receptor

in most

uterine effects.

Atitquist’s”4 receptorx.

resulted

beta-adrenergic

lipolysis

side

phart~~acologicalt~.

two

receptot for

sever? In

sal-

compared

specific

fewer

further

is being

ritodrine, agents

more

adrenergic

into

useful orcipren-

beta-adrenergic.

~/~~.\iolo~~:\‘.

cardiac

treating

f’w

isoprenaline

latter

of

with

to ;I varier\-

at the

and

The

sLirn&tion

ti\-e

its cardiovascular

as fenoterol.

associated

receplors

response

but

of

effective

as isoxsuprine,

lasting,

I967

of

synthesis

of clinically

generation

and

the

to be an

generation

longa.

“Ii in

in

ideal

agents

usually

treatment

epinephrine-like

it less than such

of

the

an

has proved

CZ!?,

kinds

in

the cardiovascular-stimulating

first

defined

dilatation ates”‘“,

concentl-a-

tion of magnesium of 30 mgidl is reached.‘““. “’ Fetulirwonatal sidr effects. Maternal administration magnesium

were

use

contractility

Phtrt-tttclcolo~~~ O)K/ beta,

val and

its

terbutaline.

are

muscle, paper.

concentrations

of

made

the earlier

stimulants

structure of epinephrine stimulants.

receptor

and

inhibited ef-

agent

such

in

side

(metaproteratlol). b!

Rucker””

of epinephrine

culminated

The

depres-

cardiovascular

stimulants

supplanted

FENOTEROL

adrenergic

labor.

respirator!

to produce

uterine

hypnotic

marked

lacked

ha\-c

adrrnergic

TERWTALINE 0”.

of

rff’ects

COII-

or

nature

limited

This

function.

the transient

epinepht-ine

isoxsuprine.

renal

of cau-

administered

stimulants.

doses

Efforts

which of

inhibitor

0 0

OH

effect

of

with

however. the

drug

labor.

compound

%

\

small

and

of’ the

I-isk

bc

route

be used

narcotic,

receptor

that

primaq

be

barbiturate.

not

or myocardial

impaired not

01‘ thy

response

preterm

is the

se]-iously

hyperacti\it!:

tects

-CH3

I C”3 SALDUTAYOL

CH3OH

noted

uterine

should

block

should

should

Beta-adrenergic

I EIH3 RITOORINE

OH-

excretion

sulfate

drugs becatthe sion, I:tli. I:(; -CM-

heart

will

effects.

sulfate

with

magnesium

Magnesium

in sel’uni

side

Magnesium

Since

drug

comitantl!

OH-

of adverse

to patient5

damage. -CH-CN-NH-CH-CH3-O-

of magnesium

risk

(:otttl.ctittdtcoltori\. administered

EPINEPHIINE

OH-

1, 1979 Gynecol.

.4m. J. Obstet.

2 ‘I:

3

/

OH

March

and Mueller-Heubach

epinephrine is structur-

catecholamines some

demonstrated

receptor. Fig. I of the betainhibitor!

Volume Number

133 5

effects on uterine contractility. All are structurally sitnilar to epinephrine; differences in the effects of these agents result from substitutions on the aromatic ring, the (Y- and P-carbon, and the terminal amino group. In general, increasing the size of the alkyl substitution at the amino group increases beta-receptor activity. The most selective beta-2-adrenergic receptor stimulants have large amino group substitutions. Alpha-adrenergic receptor activity is increased by limiting the size of the substitution on the amino group. Hydroxy groups at the 3 and 5 position of the aromatic ring confer beta-2 receptor selectivity on those compounds with large amino substitutions. Substitution on the a-carbon blocks oxidation by monoamine oxidase (MAO); thus the duration of action is prolonged in such compounds. ‘-li The adrenergic receptors are located on the outer surface of the target cell. The interaction of an agonist and its receptor is specific, rapid, and reversible. In smooth muscle the coupling of an agonist with the adrenergic receptor results in activation of adenyl cyclase, an enzyme located within the cell membrane. Adenyl cyclase accelerates the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP). Cyclic AMP increases the activity of membrane-bound enzymes known as kinases. The protein kinases are active in phosphorylation of a number of proteins in the cell membrane and, by some as yet unesplained process, this increases the uptake and sequestration of intracellular calcium. The reduction of intracellular calcium prevents activation of the contractile proteins of the muscle cell and results in muscle relaxation.“X~ “’ the ideal beta-adrenergic For labor inhibition, agonist would primarily influence the beta receptors of the uterus but minimally influence the beta receptors of the heart and blood vessels. The uterine and cardiac beta receptors vary considerably in their response to beta-adrenergic agents; hence the uterine receptors are considered to be primarily beta-2 and the cardiac receptors primarily beta- 1. The newer beta-adrenergic agonists represent attempts to pharmacologically separate uterine inhibition (beta-2 effect) from cardioacceleration (beta-l effect). Unfortunately, the beta-adrenergic receptors in vascular smooth muscle are also primarily of the beta-2 variety and uterine suppression is accompanied by vascular smooth muscle relaxation and some degree of hypotension, primarily diastolic. This hypotension results in reflex cardioacceleration and an increase in cardiac output and blood pressure. The cardioacceleration noted with these agents may also be caused by a direct effect of the beta-adrenergic agent on the adrenergic receptors in the heart. The

Pharmacologic

inhibition

of preterm

labor

567

relative effects of a beta-adrenergic agent on the vascular, myometrial, and myocardial beta-adrenergic receptors determine the value of the drug in treating preterm labor. Basic ad clinical research. In this section, only a few of the beta-adrenergic receptor stimulants will be considered. Isoxsuprine will be discussed because of its historical interest and because of its use in this country. Ritodrine, salbutamol, and fenoterol are commonly used to treat preterm labor in Europe and terbutaline has recently received attention in this regard. Only ritodrine and terbutaline will be discussed here, but this is not meant to imply a superiority of these agents over salbutamol or fenoterol. Many of the maternal and fetal side effects of the newer beta-adrenergic agonists are similar qualitatively but vary quantitatively. In general, the contraindications listed at the end of this section apply to all of these agents. Isoxsz@ine.* Isoxsuprine suppresses spontaneous and induced uterine contractility in myometrial strips from pregnant and nonpregnant women.‘“0-‘“2 In vivo the drug inhibits both spontaneous and oxytocin-augmented term labor.‘“‘, Is3 Two controlled studies have demonstrated that isoxsuprine is effective in treating preterm labor. Dasis4 reported that among 50 women with threatened preterm labor delivery was delayed for more than 7 days in 72% of patients receiving isoxsuprine but in none treated with bed rest alone. Csapo and Herczeg’JJ reported similar results in 36 patients in preterm labor with progesterone deficiency. Women treated with isoxsuprine experienced postponement of delivery for an average of 5 1 days compared to 13 days for the control group of patients. Mean birth weight of infants whose mothers received isoxsuprine was 2,954 grams compared to 2,117 grams for the control group of infants. Bishop and Woutersz’“’ and Hendricks and associates42 have also reported that isoxsuprine effectively inhibits preterm labor, but a control group of patients was not used in either of these studies. Although Castren and associates4’ reported that isoxsuprine was no better than placebo in prolonging pregnancy to 37 weeks or until the fetus attained a birth weight of 2,500 grams, these investigators infused isoxsuprine for only 1 hour compared to 4 hours in the study of DastZ* and 24 hours in the report of Csapo and Herczeg.‘“” Stander and associates’“T studied the maternal and fetal cardiovascular response to isoxsuprine in patients in term labor. Increases of 30 to 50 beats per minute in maternal heart rate and 10 to 20 beats per minute in fetal heart rate were observed during a 40 minute in*Vasodilan, Indiana.

Mead

Johnson

Laboratories,

Evansville,

568

Caritis,

Edelstone,

March 1, 1979 Am. J. Ohstet. Gynecol.

and Mueller-Heubach

Table V. Studies in which preterm

labor was treated

with ritodrine

Ritodrinp study

COMTOL

No. of patient.5

success* (%)

43 (8) 33 40 (11) 64 47

77 (70) 70 48 (40) 66 90

Wesselius-de Casparis43 Sivasamboo’64 Decelle and Vokae? Renaud and associates’@ Thiery and associates’6’

No. of patients

Success* (%}

38 32 0 0 0

45 (51) 41 -

Numbers in parentheses are the numbers of patients with ruptured membranes or the success rate when patients with ruptured membranes are included. *Success defined as maintenance of pregnancy for more than 7 days. fusion of isoxsuprine at a rate of0.5 mg per minute. In 20%, of patients severe maternal hypotension led to discontinuation of the infusion. Although a reduction in blood pressure commonly occurs during isoxsuprine therapy severe hypotension is unlikely if infusion rates are less than 0.5 mg per minute.‘“‘~‘“” UOSAGE. According to Hendricks’“’ the usual dosage for the treatment of preterm labor with isoxsuprine is 0.25 to 0.50 mg per minute intravenously. The rate and duration of infusion are adjusted according to the maternal cardiovascular and uterine response. The lateral supine position and intravenous infusion of physiologic saline are utilized to minimize the side effects. The duration of the intravenous infusion ma? varv from 1 to 24 hours.‘““, ‘XI With the longer infusions lower doses of the drug are used after contractions have been suppressed. After discontinuation of’ the intravenous infusion, intramuscular therapy with isoxsuprine is begun with a dose that varies from 5 to 20 mg every 3 to 6 hours. The same dose that was given intramuscularly is then administered orally after 24 hours. Infusion of isoxsuprine may produce nausea. sweaing. drowsiness. headaches, maternal tachycardia, and ti) potension. Isoxsuprine is not approved for use in pretcrm labor. Ril~ltj~ (DC’-2122(/).* Ritodrine is a potent inhibitor 01’ myometrial contractility in the riongravid”! and gravid term”O-‘fi3 and pretermd”. “i’+‘Ri uterus. In term labor, the infusion of ritodrine suppresses uterine contractility without adversely affecting fetal pH, PO,, md l’c:oy.

IR3

Several studies have reported favorably on the use of ritodrine in preterm labor (Table V). Wesselius-de (:asparis and associates”” in a multicenter double-blind study found that ritodrine was more ef’fective than placebo in prolonging pregnancy in women in preterrn labor. A high failure rate was noted if’ the membr;tncs *Yutopar (Pre-Par), Netherlands.

Philips-Duphar.

Amsterdam,

The

were ruptured or the cervix was dilated more than 2 to 3 cm prior to treatment. In patients with intact memhrdnes pregnancy was prolonged an average of 28 days if ritodrine was used for labor inhibition and 17 days if placebo was used. With rupture of the membranes. ritodrine treatment prolonged pregnancy m average of X.4 days compared to 1.2 days for placebo. The percentage of women in pr-eterm labor who eventually had their- pregnancies prolonged beyond 37 weeks was similar in the ritodrine (23%) and placebo (32%) groups. During the period of intravenous therapy with ritodrine the maximal average increase in maternal heart rate was 32 beats per minute while the rnaximal average decrease in blood pressure was 16 torr. SivasambooIS’ reported that ritodrine was more eff’ective than chlordiazepoxide in treating preterm labor.. The studies of Decelle and Vokaer,“” Renaud and associates,‘“” Thiery and associates, Iti7 and Bieniarz and associates”’ also suggest that ritodrine is an effective inhibitor of preterm labor, but none of the studies included a control group of patients. Umbilical blood flow in fetal lambs is not altered b) ritodrine infusion to the mother but a reduction in uterine blood flow has been reported in sheep receiving ritodrine intravenously at a rate of 100 pg/rninute. ;I dose similar to that used in pregnant women.” There is no evidence that rirodrine reduces uterine blood How in the human: in fact, uterine perf’usion may be increased during ritodrine treatment.“” DOSAGE. Wesselius-de Casparis and associates”” irrfused 200 pg per minute of ritodrine for 24 to 48 hours and followed this with an oral dose of 10 mg f‘our times daily for 5 to 7 days. The infusion rate was r-educed if excessive side effects occurred. Thiery and associates’“’ initiated therapy with 50 IO 200 yg of r-irodrine per minute and increased or decreased the inf’usion I-ate according to the response ohtained. The infusion was maintained for at least 12 hours beyontl cessation of uterine contractions: then oral treatment was srarted at a

dose

of 10 to 20 rng,

tour

to 38 weeks of pregnancy.

to eight

times

daily

until

36

Volume 133 Number 5

Pharmacologic

Ritodrine is currently Undergoing the final phases of clinical testing and should soon gain approval for use in preterm labor. Trrhutnliw. * Terbutaline effectively inhibits myometrial contractility in vitro”” and in nonpregnant women.“’ Spontaneous and oxytocin-augmented labor in pregnant women at term is inhibited by terbutaline. even when cervical dilation is far advanced.“‘* “’ In a small double-blind study by Ingemarsson,“” terbutaline proved to be effective in treating preterm labor in patients with intact membranes. Pregnancy was maintained to the thirty-seventh week in 80% of 15 patients receiving terbutaline compared to 20% of 15 patients receiving placebo. The mean birth weight of infants in the group treated with terbutaline was 3,060 grams compared to 2,190 grams for the infants in the group receiving placebo. Maternal heart rate and pulse pressure each increased an average of 30% during intravenous therapy with terbutaline. Garcia and associates”” and Wallace and associates”’ also reported that terbutaline effectively abolished preterm labor, but control populations were not used in either of these studies. In the pregnant baboon, maternal and fetal acid-base state and mean blood pressure are unaltered by infusion rates of terbutaline necessary to inhibit labor in this species, but maternal and fetal blood glucose are increased. Direct administration of terbutaline to the preterm baboon fetus in doses far in excess of those required to inhibit labor does not alter fetal acid-base state, blood gases, blood pressure, or heart rate.176 In pregnant sheep terbutaline does not reduce uterine blood flow when doses required for labor inhibition in sheep are infllsed intravenously for 1 to 3 hours.“’ DOSAGE. I ngemarsson -(: infused terbutaline at an initial rate of 10 /.~g per minute and increased the rate by 5 pg per minute every 10 minutes up to a maximum of 25 pg per minute or until uterine contractions ceased. Once contractions stopped, he maintained the infusion for 60 minutes at the same rate. The infusion rate was then decreased by 5 pg per minute every 30 minutes until the lowest effective maintenance dosage was reached. The maintenance infusion was stopped after 8 hours if uterine contractions had completel! subsided. Following intravenous therapy, terbutaline was given intrarntIsc~llarly at a dose of 250 pg four times daily f’or 3 days. Concomitantly, the drug was given orally at a dose of 15 mg per day until the end of the thirty-sixth week. Terbutaline may be administered orally or in*Brethine (Bl-icanyl), Astra Pharmaceutical M’orceste~. Rl;lssachusetts.

Products, Inc.,

inhibition

of preterm

labor

569

tramuscularly to women with asthma, but the drug is not approved for the treatment of preterm labor. The intravenous use of terbutaline is not approved even for asthmatic patients. There is no evidence that either oral or intramuscular terbutaline is effective in treating preterm labor. Side ~ffccts of. bdo-odr~wrgir rewptor .din~ulnut.c. Betaadrenergic agonists commonly produce cardiovascular and metabolic side effects. As indicated earlier, the specificity of a given agonist for the beta-2-adrenergic receptor determines the likelihood of side effects due to beta-1-adrenergic stimulation. It must be emphasized that separation of the two types of’ beta-adrenergic receptors is somewhat arbitrary and in many instances a response cannot be attributed wholly to the stimulation of a single type of adrenergic receptor. Side effects occur even if the adrenergic agonist is ver) specific for the beta-2 receptor since these receptors are not limited to the uterus. Stimulation of the beta-“adrenergic receptors in blood vessels relaxes vascular smooth muscle and produces some degree of’ bypotension. In clinical studies in which beta-adrenergic agonists have been used to inhibit labor, an increase in maternal heart rate and a reduction in blood pressure is universally present. More severe tachycardia and hypotension are produced by isoxsuprine than b) ritodrine, fenoterol, salbutamol. or terburaline. Hppotension is occasionally so severe with isoxsuprine therapy that the infusion must be discontinued. Placental transfer of the beta-adrenergic agonists may result in an increase in fetal heart rate. but the heart rate is usually less than I70 beats per minute. Hypotension has not been reported in neonates of mother-s treated with beta-adrenergic stimulants. Stimulation of‘ the beta-2%adrenergic reccptol-s in liver and muscle causes glycogenol)sis. Therefore, mild maternal hyperglycemia and elevations in the concentrations of lactate and free fatty acids are often observed with the use of beta-adrenergic agonists. These agents also enhance both insulin and glucagon secretion. but they do not affect the secretion of growth hormone.“X~‘X’ Similar metabolic effects ma! be seen in the fetus. Miller and associates”’ ha\.e reported that lactacidosis may be observed in the fetus f’ollowing the intravenous infusion of ritodrine to the mother with toxemia. Beta-adrenergic stimulation markedly increases the insulin needs of pregnant diabetic patients’“” so that diabetes may be considered a relative contraindication to the use of these agents. In nondiabetic patients, long-term oral therapy with ritodrine is not associated with an elevation of blood glucose or an abnormal glucose tolerance.lR4 Co,,t,trir,tliccrtio,r.c. Patients with any cardiac or mcta-

570

Caritis,

Edelstone.

and Mueller-Heubach

bolic disease that may be adversely atftcted b) stimulation of’ adrenergic receptors should not receive hetaadrenergic agonists. These agents should be used with caution in patients with hypertension since srimulation of‘vascular adrenoreceptors may result in severe hypetension. Caution should also be used if’beta-adrenergit agonists are used in patients with hyperthyroidism. Diabetes mellitus is a relative contl-aindication to the use of these agents. Frequent monitoring of blood glucose and acetone is essential if the diabetic patient is treated with bera-adrenergic receptor stimulants. Diazoxide.* Diazoxide is a powerful antih) perter]si\:e agent. When the drug \cas administered to II!pertensive women in labor to reduce the blood preasure, a dramatic inhibition of uterine contracrions \vas noted.‘“’ This earl) observation provided the rationale l’or f’urther studies of the uterine inhibiting effect of the drug. f-‘lrrc,.,nrrcolo~!’ UN! ph~.~io/o,q~ Diazoxide is a benzothiadiazinc structurally similar to the thiazide diuretics but uirhout their diuretic properties.“” Diazoxide rrduces blood pressure by a direct effect on vascular smooth miiscle.“‘~ IX’ Systemic and pulmonary arterial pressures and resistances are decreased b\ diazoside while heart rate, cardiac output, stroke volume, and blood flow to the coronary, ftmoral, and renal vascular beds are increased.‘x’ The cardiovascular rftects of diazoxide are greater when the drug is administered intravenously as a bolua than wlieii it is administered as a slow inf’usion.‘x” The cardiovascular effects are also grearei. in the hypertensive tlian in the normotensive paticm Although the half’ life of‘ diazoxidc ih 28 hours.““’ the antihypertensive ef’fect is much shorter and dots not relate to the serum concentra(ion of the drug. Diazoxide reduces the urinary excretion of’ sodium. water, potassium, chloride, bicarbonate, and llric acid, but the secretion of’ renin is increased b)- the drug.‘“’ Blood sugar increases follo\+ing diazoxide administr-aCon, probably because of a11 inhibition of’ insulin release since the production of’insulin is not impaired.‘!‘” Diazoxide is similar to the beta-adrenergic-stimulating agents in hoth its ca,.diovascular cf’fects (increased heart rate and cardiac olrtput and decreased peripheral vascular resistance) and its metabolic effects (increase in blood sugar and f’ree fatty acids); howevrr. diazoxide is not considered to be a beta-adrenergic stimulant since its beta-adrenergic-like effects are nc)l blocked by beta-adrenergic blockade. *Hyperstat, Jersey.

Schering

Corporation,

Kennilworth,

New

L3n.G CIU~ cli~icctl r~.w(~rrh. Diazoxide itlhibits ~~OIItaneous contractions of uterine muscle strips f‘rom hoth nonpregnanr and pregnant wonien.‘!“3 In \ivo the drug reduces spontaneous and ox~tocili-augxliell(e(t uterine contractions in nonpregnant women and pregnant !+7(jme*l ‘*t is given a\ an L tc,.*n, ‘!U. I%; When diazoxide intravenous holus to patients with screw roxemia Io reduce blood pressure, marked inhibitioll of utcrillc contractions is ohserved.““. ‘!” The effect 01 ctiarositle on preterm labor ha> not been t horoughh waluatt’d and controlled studies have not been reporrcd. &II-den and Keenan’!” and Rert’!‘X have presented preliminal-\ data that suggest that diazoxide effective]\ inhibils pieterm labor. The label.-inhibiting, metabolic, and cardiovasctll;~1ef’fects of’ diazoxide have been evaluated during pregII;IIKJ~ in rats, xheep, and subhuman primate>. D&oxide prolongs pregnancy in rats fed high closes of the drug. Structuml or behavioral abnormalities are not observed in sue-11animals nor is litter sire rtduced.‘x’i In pregnant baboons, holus injection of dia/oxide redllcts osytocinand I~rostaglandin-iridrlcetl IITc‘rinc ;I( ii\ it! .“‘!’ Prolonged infusion of the drug it1 lo\\ dews also inhibits spontaneous and oxytocin-induced uterine contrdctions \4irhoul producing significant Iirpolen~ion in the mother.“““. S’ Fetal acid-base status in rhe h;thoon is not compromised b\ slow infusion ot diazoxide but significant acidosis is noted when the same dose ot‘drug is administered as a bolus. In sheep. bolus injection of d&oxide at a dose of’ .?Imgikg (recon~n~ended dose ~‘OI treatment of hypertension in the human) significalltl! reduces maternal blood pressure and urrrine blood flow. Slow infusion of‘ the same dose fol, 90 minulrs. 1lowever, does not reduce uterine blood flo~.~“” Dow,q. Se\,eral regimen\ have been suggrsted f’or rhe treatmen of preterm lalm~ with diazoxide. Srudies ill humans ;tnti animals indicate chat the cardiovascular ef’fects of’ diaLoxide are reduced when the drug is infusecl slow11 in 101~ doses.‘q5. “‘w2”’ In animals adequate inhibition of uterine activity is achieved with lolv-dose infusion of diaroxide.“““~ 3” If this method is effective in pregnant lvomen, as reported h\ Landesman anti associates.“” then slo~v infusion ~vo~~lrl 1~ tile safest method of’drug atlmi~listl~ation. Bert’“” infrlscd 300 nlg of diazoxide inrravenouslv over 13 minutes and ob served onI>, mild tachycardia and a mild retlilcrion in blood pi-essurc. Dialoxide is not approved f’or the treatment of pre1errn laboi-. ~Vf~ltcwtrrl .sidr cjf~p(./.\. In nonhypertensive pregnant women, 60 to 300 mg of diazoxide administered rapid]) as a holus results in an average increase in heart

Volume

133

Pharmacologic

Number i

rate of 30 heats per minute and average decreases in systolic and diastolic pressures of 16 and 21 mm Hg, respectiveI?-. I”’ Diazoxide causes hyperglycemia in both hypertensive and nonhypertensive individuals. In pregnant women receiving the drug for a short period, only mild hyperglycemia occurs. “‘, “‘3 Iy7, 2”3 Diazoxide causes sodium and water retention’g’; however, these effects are more likely to occur with long-term use of the drug. Although sodium retention has not been a problem in pre-eclamptic patients receiving intravenous diazoxide,‘H”. 1Hli. ‘O:i most of’ these patients were delivered shortly after the initiation of drug therapy. This precludes adequate assessment of the effect of diazoxide on sodium and water metabolism in pre-eclampsia. F&l cord ~1wtutul sidr cfjiicts. In nonhypertensive patients at term treated with diazoxide, fetal heart rate and Apgar scores are not affected, but hypoglycemia may occur in the neonate.lY7. lRR Prolonged oral diazoxide therapy in toxemic mothers does not alter neonatal blood pressure, heart rate, blood count, immunoglobulins, or ocular development. Alopecia and hypertrichosis lanuginosa have been reported in some infants exposed to diazoxide in utero for several weeks, but the significance of these findings is uncertain. In sheep and goats, extremely high doses of diazoxide produce cataracts, muscle fibroses, and destruction of the pancreas’““; however, none of these effects has been observed in human neonates whose mothers received diazoxide during pregnancy. Cant,-rri,lnicritio?/,\. Because of diazoxide’s positive chronotropic effects, the drug should not be given to patients with compensated hypertension, such as that associated with coarctation of the aorta, or to women with coronary insufficiency, myocardial infarction, congestive heart failure, or cardiac arrhythmias. Diazoxide should be used with extreme caution in women receiving other medication that may affect heart rate or blood pressure. Diazoxide enhances insulin secretion and may be used in diabetic women but blood glucose should be monitored frequently in these and nondiabetic patients receiving the drug.207 Drugs of questionable preterm labor

value

in treating

Progesterone. Progesterone and related compounds prolong pregnancy in the rat and rabbit.“08 In these animals. progesterone suppresses myometrial contractions by elevating the excitation threshold and inhibiting propagation of impulses.?O” In humans, progesterone reduces uterine contractions in nonpregnant women but the effect of the hormone on the pregnant

inhibition

of preterm

labor

571

uterus is uncertain. Csapo” O8has suggested that progesterone exerts an inhibitory effect on the pregnant uterus and has termed this effect “progesterone block.” Relative progesterone deficiency results in uterine activation and, according to Csapo,20R restoration of progesterone dominance will result in uterine quiescence. Several studies have failed to demonstrate any laborinhibiting effect of progesterone in women with preterm labor. Fuchs and Stakemann”‘o in a double-blind study of 126 patients in preterm labor were unable to demonstrate any difference in pregnancy maintenance between progesteroneand placebo-treated groups. Similar results were reported by Brenner and Hendricks?” in a double-blind study that compared medroxyprogesterone acetate to placebo in 98 women in preterm labor. The concentration of progesterone at the placental site may be much higher than the concentration of the hormone in peripheral plasma. Thus, the usual doses of progesterone used to treat preterm labor may produce concentrations at the placental site that are inadequate to inhibit uterine contractility.“? Johnson and associatesZ1” reported that 17a-hydroxyprogesterone caproate (Delalutin) was significantly more effective than placebo in preventing preterm delivery in women at risk for this complication. Adverse neonatal effects were not seen in the offspring of treated patients, although the drug was administered from approximately the seventeenth week of amenorrhea. The number of patients studied was too small to make a valid judgment about this form of therapy. Others. Several agents have been used to treat preterm labor or have been shown to inhibit uterine contractility including general anesthetic drugs such as halothane, analgesic drugs such as morphine, and tranquilizers such as chlordiazepoxide. These agents are generally ineffective or impractical for clinical use.35, 37, Meperidine should not be used for labor inhibition since it increases uterine contractility.“4 Recently, in European studies, calcium antagonisis have been used to inhibit preterm labor. Most often, these agents are administered concomitantly with beta-adrenergic-receptor stimulating drugs. The calcium antagonist reduces the cardiovascular effects and may enhance the uterine inhibitory effect of the betareceptor stimulant.“” The effectiveness of these agents has not been adequately evaluated. The effect of labor-inhibiting drugs on perinatal outcome The value of labor-inhibiting drugs must be judged not only by their ability to inhibit labor but also by their

572

Mat-ch 1. 1979 Am. J. Obstet. Gvne~ol.

Caritis. Edelstone, and Mueller-Heubach

effect on pet-inatal mot-bidit) and mortality rates. If widespread use of’ these agents does not improve perinatal outcome in a considerable proportion of treated cases, then the extraordinary effort directed at the qnthesis and use of these drugs would be pointless. Reports f’rom se\et-al c-ountries ittdicatc that the use of labor-inhibiting agents results in a significant prolongation of pregnancy in a majorit! of patients treated.” Since an adtlitional one or tlvo weeks of’ intrauterine existence bet\\.een “5 and 35 \teeks’ gestation dramatically reduces perinatal tttot~bidi~~ and mortality rates,“’ the use of. lat)ot--itthihiring drugs should improve tieotiatal outcome in a si/.able pi-oportion of’ treated cases ot’ preternt labor. Ho\\w,er, Llatnic-k”” in 197:! of motttet-s delivered of i-eported that onl? 16’4 I()\~-birth-~~eigitl ititanrs (