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Preterm labor: Its diagnosis and management
CLINICAL SECTION Clinical Opinion Preterm labor: Its diagnosis and management Bernard Gonik, M.D., and Robert K. Creasy, M.D. Houston, Texas Preterm labor and delivery remain a significant problem in contemporary obstetric practice. Although the exact cause remains unclear, it is most likely to be multifactorial in nature. No satisfactory screening tool or marker currently exists to firmly establish the diagnosis of impending labor. However, epidemiologic and historical variables associated with preterm delivery show some promise in this regard and are currently being evaluated in preterm prevention programs. Appropriate management of preterm labor mandates early recognition of subtle signs and symptoms; successful therapy is dependent on this issue. The approach to the clinical management of the patient in preterm labor used at our institution is described. Therapy with [3-adrenergic receptor agonists is currently the recommended pharmacologic treatment of this disorder. A review of other tocolytic agents and their usefulness in the management of preterm labor are presented. (AM J 0BSTET GYNECOL 1986;154:3-8.)
Key words: Preterm labor, obstetrics, 13-adrenergic receptor agonists National, regional, and local perinatal data provide convincing evidence of improved maternal and neonatal health during the past several decades. Conversely, preterm delivery rates in the United States, over the same period of time, have remained relatively unaltered, in the range of 7% to 8%.' The impact of this finding can best be appreciated by the recognition that four of the six leading causes of infant death from 1970 to 1978 are almost exclusively associated with the premature neonate.' The World Health Organization uses, as its definition of a preterm infant, any neonate born prior to 37 completed weeks of gestation. No clear standards are established for the lower limits of this definition although, by tradition, an abortus is considered in any gestation less than 20 weeks. For the purpose of this discussion, we define the preterm infant as one who is born after 20 completed weeks from the first day of the last menstrual period and before 37 completed weeks of gestation. Although a birth weight of <2500 gm has been used in the past synonymously with this definition, a portion of these neonates actually represent growth retardation. Since perinatal morbidity and mortality issues are different for these two types of neonates, this distinction is important in the evaluation of recent lit-
From the Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston. Reprint requests: Robert K. Creasy, M.D., the Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, 6431 Fannin, Suite 3270, Houston, TX 77030.
erature pertaining to preterm labor and delivery management. The mechanisms involving the initiation of labor both before and at term are still poorly understood. An extensive review of this topic has recently been presented by Huszar and Naftolin, 2 who stressed three relatively distinct areas to be considered when addressing this subject. These include: (I) cervical maturational changes, (2) status of the fetal membranes, and (3) myometrial activity. Although the interrelationship of these factors is obvious, regulation of the individual components may not be identical. In addition, one can clinically identify pathologic alterations in each of these factors in isolation. From a practical perspective, the management of preterm labor requires a combined knowledge of all of these factors. However, the above issues support the multietiologic approach to the onset of preterm labor.
Prediction of preterm labor Primary to the reduction in the preterm birth rate is the establishment of criteria for the prediction of preterm labor. Since the causative factors of this event have yet to be clearly defined, systems thus far used to predict preterm labor primarily depend on historical or epidemiologic variables and their association with preterm delivery.' None of these risk-scoring systems have reached the level of discrimination necessary to be used as primary tools in establishing protocols to prevent the initiation of preterm labor. In addition, because these systems rely heavily on past obstetric outcomes, they are better equipped to screen the multiparous patient.
3
4 Gonik and Creasy
January, 1986 Am J Obstet Gynecol
Table I. System for determining risk of spontaneous preterm delivery Points assigned
Socioeconomic factors Two children at home Low socioeconomic status
2 3
4
5
10
Maternal age <20 yr or >40 yr Single parent Very low socioeconomic status Height <150 em Weight <45 kg Maternal age <18 yr
Previous medical history Abortion X I Less than I yr since last birth Abortion x2 Abortion x3
Pyelonephritis
Uterine anomaly Second-trimester abortion Diethylstilbestrol exposure Cone biopsy Preterm delivery Repeated secondtrimester abortion
Daily habits
Aspects of current pregnancy
Works outside home
Unusual fatigue
Smokes more than I 0 cigarettes per day
Gain of <5 kg by 32 wk
Heavy or stressful work that is long and tiring
Breech at 32 wk Weight loss of 2 kg Head engaged at 32 wk Febrile illness Bleeding after 12 wk Effacement Dilation Uterine irritability Placenta previa Hydramnios
Twins Abdominal surgical procedure
Adapted from Creasy RK, Gummer BA, Liggins GC. A system for predicting spontaneous preterm birth. Obstet Gynecol 55:692, 1980. Score is computed by adding the number of points given any item. The score is computed at the first visit and again at 22 to 26 weeks' gestation. A total score of ~I 0 places patient at high risk of spontaneous preterm delivery.
A multi-institutional collaborative study is currently underway to evaluate the utility of a preterm prevention program that incorporates the risk assessment system presented in Table I. These types of programs help to focus attention and provide education to a variety of health care personnel which should ultimately improve any therapeutic intervention program. With the advent of more sophisticated monitoring technology, normal and abnormal patterns of uterine activity are being established throughout the latter half of gestation. Earlier investigations suggested a progressive increase in uterine activity as gestation advances, and, in the patient destined to delivery preterm, a premature increase in this activity may occur. Katz et al.,4 using a portable tocodynamometer, recently reported that there is significantly more uterine activity in the ambulatory patient who later develops preterm labor. The usefulness of this finding relates to its occurrence up to 8 weeks prior to actual development of clinical manifestations of labor. Although this biophysical screening tool shows promise, further studies are needed to help establish its specificity and sensitivity in predicting preterm labor. Perhaps the most useful of all predictive indicators would be a biochemical marker that could be assayed serially in those patients thought to be at increased risk of preterm labor. Earlier work suggested that rising plasma levels of 17(3-estradiol or falling or low levels of serum progesterone may be useful in this regard. However, Block et a!. 5 were prospectively unable to dem-
onstrate any relationship between weekly serum estradiol or progesterone concentrations and the prediction of preterm labor. For the present time, no biochemical marker that can reliably improve one's ability to predict this event has been established.
Early detection of preterm labor Once a patient is categorized as at risk of developing preterm labor, by whatever predictive marker, weekly visits to the clinician for a review of early symptoms and for cervical examination seem warranted. Herron et al. 6 demonstrated that such a prevention program yielded a decreased preterm delivery rate by identifying an increased number of candidates eligible for longterm tocolytic therapy. The value of serial pelvic examinations is further supported by Holbrook et a!.,' who demonstrated the ability to identify 18% of highrisk subjects in premature labor by cervical examination alone, even without other symptoms. Additionally, they reported no increase in the rate of premature labor or infectious complications in this same study population as compared with a control preterm labor group not undergoing serial examinations. Thus no increased iatrogenic risks from preterm serial examinations of the cervix have thus far been identified.
Diagnosis of preterm labor The ability to prevent preterm deliveries is largely a function of early recognition and intervention." Although labor in its later stages is obvious, early symp-
Volume 154 Number 1
Table II. Criteria for diagnosis of preterm labor' Gestation 20 to 37 wk and Documented uterine contractions (4/20 min, 8/60 min) Ruptured membranes or Intact membranes and Documented cervical change or Cervical effacement of 80% or Cervical dilatation of 2 em
toms can be quite subtle and are frequently overlooked. In some series, only l 0% to 20% of patients presenting in preterm labor are candidates for long-term tocolysis. In addition, other studies have demonstrated a 20% to 45% efficacy of placebo treatment alone in "preterm labor" patients, suggesting an inaccurate initial diagnosis. The predicament that confronts the clinician, therefore, is accurate early diagnosis without overzealous treatment of patients not truly in labor. The criteria used in this institution for the diagnosis of preterm labor are presented in Table II. Castle and Turnbull" and later Boylan et al. 9 have used real-time ultrasonography to look at the presence or absence of fetal breathing movements and their relationship to labor. In the presence of fetal breathing, both term and preterm patients who initially presented with contractions were unlikely to progress into labor. The authors suggested that the early diagnosis of labor may be improved with the use of this ultrasonographic finding. Although this diagnostic tool may be of benefit in the future, further prospective studies are needed. Treatment of preterm labor
Once the diagnosis of preterm labor is clearly established, definitive tocolytic therapy should be initiated on an emergent basis. Although some clinicians have used bed rest, hydration, and narcotic sedation as a screening tool to establish the diagnosis of labor, these methods should not be confused with therapeutic modalities. The cornerstone in the pharmacologic management of the preterm patient in labor is currently therapy with a I)-adrenergic receptor agonist. The mechanism of action involves attachment of the drug to the 1)2 -adrenergic receptor with subsequent activation of adenyl cyclase. The resultant increase in cyclic adenosine monophosphate decreases myosin light chain kinase activity, thereby interfering with the actin/ myosin interaction. A variety of associated side effects have been reported with these agents, which are related to both !),-and 1) 2-adrenergic responses throughout the body. We are currently using ritodrine hydrochloride as our I)-adrenergic receptor agonist of choice. However, we are unaware of any study that clearly supports
Preterm labor 5
Table III. Initial measures recommended when tocolytic therapy is initiated Bed rest Admission weight Intravenous access line Electrocardiogram Baseline vital signs Fetal monitor for contractions and fetal heart tones Laboratory studies 1. Complete blood count 2. Electrolytes 3. Serum glucose 4. Colloid osmotic pressure 5. Urinalysis
the superiority of this agent versus any other in this class of drugs for efficacy or side effects. When beginning tocolytic treatment we initially obtain baseline data as shown in Table Ill. Maternal weight is obtained daily, and hematocrit, serum potassium, glucose, and colloid osmotic pressure determinations are repeated every 6 to 12 hours during intravenous therapy. Intravenous administration of the I)adrenergic receptor agonist is currently the route of choice for initial tocolysis. An intravenous infusion pump should be used with the initial dose of 50 to 100 meg/min. We use a 5% dextrose in water solution as our maintenance fluid because of recent evidence demonstrating an increased risk of pulmonary edema with isotonic saline solution. 10 In addition, we concentrate our tocolytic solution (300 mcg/500 ml) to reduce the amount of infused fluids. The starting dose can be gradually increased by 50 meg/min every 10 to 15 minutes and titrated to the desired clinical response of uterine quiescence. The usual effective dose is between 150 and 350 meg/min. If tocolysis is successful (less than one contraction every 10 to 15 minutes), we continue the infusion at that rate for 12 to 24 hours before switching to oral therapy. A limited amount of pharmacokinetic data is currently available for this drug. In patients receiving continuous infusions, ritodrine appears to be eliminated from the maternal plasma at a biphasic rate; a rapid phase of elimination of the drug (half-life 40 to 60 minutes) is followed by a more prolonged disappearance phase (half-life 16 to 28 hours)." Oral ritodrine should be started prior to the discontinuation of intravenous therapy to maintain therapeutic levels. The exact timing of the first oral dose has yet to be determined; empirically we allow 30 minutes before discontinuing intravenous ritodrine. Once oral therapy is begun, dosage determinations are made according to uterine activity, pelvic examination, and the maternal pulse rate. This latter clinical parameter has been shown to correlate with serum ritodrine concentrations and uterine inhibitory effects. 12
6 Gonik and Creasy
We start with an oral dose of 20 mg every 2 hours. If the maternal pulse is <90 bpm and contractions continue, on rare occasions we administer 30 mg every 2 hours to maintain tocolysis. Usually, we are able to decrease our frequency of administration to every 3 to 4 hours without a concomitant rise in uterine activity. We then attempt to sustain a resting pulse between 90 and 100 bpm. The usual dose will be 20 mg every 2 to 4 hours. Ambulation of the patient may be attempted after 24 hours of oral therapy. This activity should be minimal and should equate with those needs the patient anticipates at home after discharge. No further blood work is needed once oral therapy has been started. The patient can be discharged home if uterine activity and cervical findings remain unchanged during the next 24-hour period. Here, again, the potential benefit of portable home monitoring of uterine activity shows promise. The manufacturer's recommendations for surveillance of the patient on a regimen of intravenous ritodrine therapy include a baseline electrocardiogram and serial monitoring of glucose and electrolyte levels. Although both transient hypokalemia and transient hyperglycemia occur with the intravenous use of this medication, no specific therapy is warranted unless other medical complications exist, such as diabetes mellitus. We carefully restrict total administered fluids to 2500 ml/24 hr or less during intravenous treatment and for the first 24 hours of oral therapy, because of alterations in the renin-aldosterone control mechanisms that are known to occur with ritodrine and the recognized potential side effect of pulmonary edema. Although other investigators have suggested an upper limit of 1500 ml, we have not been as restrictive and have anecdotally seen only one documented case of pulmonary edema with our management. Of note, even at a 2500 ml restriction level, patients may still request excess oral fluids, which may relate to increased water imbibition seen in animal studies. Concerns about the more serious maternal complications identified with 13-adrenergic receptor agonists have led to the use of magnesium sulfate as a first- or second-line agent for tocolysis. The efficacy of this agent, however, has never been firmly established in an extensive controlled trial. However, observational data do suggest that uterine contractions can be eliminated when maternal serum levels of magnesium sulfate are in the range of 6 to 8 mEq/L (5.0 to 6.6 mg/100 ml) and the patient is in the early stages of labor. 13 These levels can generally be obtained by the initial administration of 4 to 6 gm of magnesium sulfate intravenously during 20 minutes followed by a maintenance dose of 1.5 to 3 gm/hr. Because of substantial patientto-patient variations in serum levels, we determine
January, 1986 Am J Obstet Gynecol
magnesium levels serially every 6 hours. The exact mechanism of action at the cellular level by which magnesium reduces uterine activity is speculative; in all probability magnesium competes with calcium ion, thereby inhibiting the actin/myosin interaction. As magnesium sulfate has gained acceptance, an increasing number of undesirable side effects have also been identified, including serious problems such as pulmonary edema. In addition, in a preliminary report by Ferguson et al. 14 of an attempt to use magnesium sulfate in combination with ritodrine therapy to reduce untoward cardiovascular side effects, a surprisingly unacceptable increase in serious side effects was reported. This issue remains controversial and requires further evaluation. In the patient who becomes unresponsive to 13-adrenergic receptor agonist therapy (perhaps because of uterine tachyphylaxis) or when a drug-related complication is identified, we use magnesium sulfate in combination with ritodrine or alone. Temporarily discontinuing ritodrine theoretically may help to increase the efficacy of 13-adrenergic receptor agonists so that we can later reinstitute either intravenous or oral ritodrine and achieve maximal effects. In patients who are insulin-dependent diabetics, magnesium sulfate is preferentially used on our service to avoid the risk of uncontrolled hyperglycemia that can occur with 13-adrenergic receptor agonist therapy. Since the terminal process thought to be responsible for uterine contractions is production and release of prostaglandins, it is not surprising that prostaglandin synthetase inhibitors have been studied for tocolytic potential." Their limited use, however, has stemmed from concerns regarding the potential for in utero narrowing or closure of the ductus arteriosus and perhaps persistent fetal circulation in the neonate. These effects have been anecdotally reported and appear to be most often associated with chronic administration beyond 34 weeks' gestation or in association with other risk factors such as sepsis or perinatal asphyxia. The ease of administration of indomethacin via the oral or rectal route makes this agent an attractive alternative to 13-adrenergic receptor agonist therapy. In our institution short-term administration of this agent for up to 72 hours has been occasionally used with the previable fetus when the gravid subject has developed resistance to traditional tocolytic therapy. Under these circumstances, the intermittent use of this agent in a dose of 25 mg every 4 to 6 hours may have merit. Further careful prospective work with this agent is warranted. Other new clinical approaches to the treatment of preterm labor include the use of calcium channelblocking agents. Since calcium appears to have a central role in the initiation of labor, agents such as nifedipine would seem reasonable candidates for tocolytic therapy.
Preterm labor 7
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Preliminary work indicates this drug may be useful as a tocolytic agent. 16 However, substantial concern is currently surfacing regarding the potential adverse effect this group of agents may have on the fetus. Although reports in the human have not demonstrated any overt toxicity, some animal work has demonstrated profound metabolic alterations in the fetus. 17 The use of these agents should be restricted to controlled clinical investigations. In our limited experience, oral administration of nifedipine in the previable and borderline viable fetus has been used with some suggested efficacy. Controversial management issues
The frequent concomitant use of corticosteroid therapy with I)-adrenergic receptor tocolytics has raised some concerns regarding an increased risk of pulmonary edema. From a physiologic standpoint, both groups of agents have been associated with an increase in fluid retention, although betamethasone and dexamethasone are essentially devoid of mineralocorticoid activity. In addition, alterations in fluid fluxes have been implicated as the most influential factor in the development of this complication. However, Robertson et a!.,'" in a series of 343 women treated with intravenous I)-adrenergic receptor agonist therapy, were unable to demonstrate any association between glucocorticoid administration and the development of pulmonary edema. It would seem prudent to institute efforts to reduce the risk of pulmonary edema in patients receiving both agents by maintaining close surveillance of intravenous and oral fluid therapy. Strict recording of intake and output and daily weighing of the patient are routine measures. This is particularly important during the first 24 to 72 hours of therapy since most cases of pulmonary edema have been reported to occur around 48 hours after initiation of tocolysis. Patients with twin gestations (who have an accentuated expansion of plasma volume) and those with low oncotic pressures (< 15 mm Hg) are at particular risk for this complication to develop. In most institutions, rupture of the membranes is a relative contraindication to long-term tocolytic usage. This appears to represent concerns over masking incipient infection as well as the perceived lack of efficacy ofthese agents after membrane rupture. Although controlled studies are not available, our current policy is to limit the use of tocolytic agents under these circumstances to no more than 24 to 36 hours. During this time period we occasionally administer glucocorticoids in an effort to induce fetal lung maturation, recognizing that adequate data are lacking in this regard. On an individual basis, we have used continuous intravenous tocolytic therapy in patients perceived to have a "high" leak that has subsequently resealed or in those with a very preterm fetus. Under these circumstances,
an amniocentesis to rule out the possibility of a subclinical infection is usually attempted. Of particular concern is a recent collaborative study that suggested that the combination of premature rupture of the membranes and tocolytic therapy resulted in a higher incidence of respiratory distress syndrome than that found with these factors evaluated individually.' 9 Before any clinical management protocol is established, this negative effect requires further evaluation and substantiation. The issue of "prophylactic" tocolysis in patients thought to be at high risk for preterm delivery has received surprisingly little attention. Although it has been demonstrated that oral I)-adrenergic receptor agonist therapy can decrease the recurrence rate of preterm labor, controlled prospective studies are lacking regarding the efficacy of these agents in preventing the initial occurrence in the patient at risk. Preliminary prophylactic studies with low-dose I)-adrenergic receptor agonists have failed to demonstrate any significant delays in the onset of preterm labor in twin gestations. However, it is unclear from these study designs whether an adequate dose of the agent was administered. This preventative pharmacologic approach to the management of the high-risk patient requires further study with appropriate doses. Once a patient has been started on a regimen of tocolytic therapy and labor has been successfully inhibited, the question arises as to the length of time the patient should receive these agents. Although some have advocated the use of amniocentesis to identify the neonate with pulmonary maturity, other nonpulmonary complications of prematurity are still important morbidity factors. Goldenberg et a!. 20 reviewed morbidity and mortality data for gestational ages between 22 and 36 weeks. Their conclusions, based on birth weight rather than gestational age, suggest that delaying delivery after 34 weeks of gestation was of little benefit. However, we have found that in the preterm gestation, uncomplicated by other maternal or fetal problems, a delay in delivery from 34 weeks to 36 completed weeks of gestation will decrease the incidence of several neonatal morbidity factors including respiratory distress, patent ductus arteriosus, need for prolonged intensive care, and overall number of hospitalization days. In this institution, we are willing to initiate tocolytic treatment in pregnancies up to 36 completed weeks and continue oral treatment until37 to 38 weeks of gestation. REFERENCES l. Quilligan EJ, Little AB, Oh Wm, et al. An evaluation and
assessment of the state of the science. In: Pregnancy, birth and infant. Bethesda, Maryland: National Institutes of Health, 1983; NIH publication no. 82-02304. 2. Huszar G, Naftolin F. The myometrium and uterine cer-
Gonik and Creasy
3. 4. 5.
6. 7.
8. 9. 10. 11.
vix in normal and preterm labor. N Eng! J Med 1984; 311:571. Creasy RK, Herron MA. Prevention of preterm birth. Semin Perinatal 1981 ;5:295. Katz M, Newman RB, Gill PJ. Assessment of uterine activity in ambulatory patients at high risk of preterm labor and delivery. AM J 0BSTET GYNECOL (in press). Block BSB, Liggins GC, Creasy RK. Preterm delivery is not predicted by serial plasma estradiol or progesterone concentration measurements. AM J 0BSTET GYNECOL 1984;150:716. Herron MA, Katz M, Creasy RK. Evaluation of a preterm birth prevention program: preliminary report. Obstet Gynecol 1982;59:452. Holbrook RH, Lirette M, Creasy RK. Weekly cervical examination in the patient at high risk for preterm delivery [Abstract]. Las Vegas, Nevada: Society of Perinatal Obstetricians, 1985. Castle BM, Turnbull AC. The presence or absence of fetal breathing movements predicts the outcome of preterm labour. Lancet 1983;2:471. Boylan P, O'Donovan P, Owens OJ. Fetal breathing movements and the diagnosis of labor: A prospective analysis of 100 cases. Obstet Gynecol 1985;66:517. Philipsen T, Eriksen PS, Lynggard F. Pulmonary edema following ritodrine-saline infusion in premature labor. Obstet Gynecol 1981;58:304. Post LC. Pharmacokinetics of beta-adrenergic agonists. In: Anderson PA, Beard R, Brudenell JM, Dunan PM, eds. Pre-term labour. Proceedings of the fifth study group
January, I 986 Am J Obstet Gynecol
12. 13. 14. 15. 16. 17.
18. 19.
20.
of the Royal College of Obstetricians and Gynaecologists. London: Royal College of Obstetricians and Gynaecologists, 1977. Lipshitz J. The uterine and cardiovascular effects of oral fenoterol bromide. Br J Obstet Gynaecol 1977;84:737. Elliot JP. Magnesium sulfate as a tocolytic agent. AM J 0BSTET GYNECOL 1983;147:277. FergusonJE, Hensleigh PA, Kredenster D. Adjunctive use of magnesium sulfate with ritodrine for preterm labor tocolysis. AM J OBSTET GvNECOL 1984; 148:166. Niebyl JR, Blake DA, White RD, eta!. The inhibition of premature labor with indomethacin. AM J 0BSTET GvNECOL 1980;136:1014. Forman A, Andersson KE, Ulmsten U. Inhibition of myometrial activity by calcium antagonists. Semin Perinatal 1981;5:288. Ducsay CA, Cook MJ, Veille JC, eta!. Nifedipine tocolysis in pregnant rhesus monkeys: maternal and fetal cardiorespiratory effects [Abstract]. Las Vegas, Nevada: Society of Perinatal Obstetricians, 1985. Robertson PA, Herron M, Katz M, eta!. Maternal morbidity associated with isoxsuprine and terbutaline tacolysis. Eur J Obstet Gynecol Reprod Biol1981;11:317. Curet LB, Rao AV, Zachman RD, et a!. Association between ruptured membranes, tocolytic therapy, and respiratory distress syndrome. AM J OBSTET GvNECOL 1984; 148:263. Goldenberg RL, Nelson KG, Davis RO, KoskiJ. Delay in delivery: Influence of gestational age and the duration of delay on perinatal outcome. Obstet Gynecol 1984;64:480.
Management of postdate pregnancy David C. Lagrew, M.D., and Roger K. Freeman, M.D. Long Beach, California Management of the problems associated with pregnancies that extend beyond 294 days of amenorrhea has become increasingly important in obstetrics. This article outlines some of the methods that minimize the risks to the mother, fetus, and neonate in postdate pregnancy. A brief description of the definitions, incidence, and impact of postdate pregnancy is given for a baseline on which to base management decisions. The current management techniques are then given for the following aspects: (1) diagnosis, (2) antepartum surveillance, (3) timing of delivery, and (4) intrapartum management. Finally a synopsis of research areas that may change management is given. (AM J OssTET GvNECOL 1986;154:8-13.)
Key words: Postdate pregnancy, prolonged pregnancy, postmaturity There has not always been widespread acceptance of the fetal risk when pregnancy lasts more than 14 days past the estimated date of confinement. Ballantyne,' as early as 1902, described postmaturity as a hazard to the safety of both the infant and the mother. His description included the risks of stillbirth, intrapartum asphyxia, and birth trauma associated with prolonged
From Women's Hospital, Memorial Medical Center. Reprint requests: David C. Lagrew, Jr., M.D., Clinical Instructor, University of Louisville, Department of Obstetrics and Gynecology, 550 South Jackson St., Louisville, KY 40292.
8
pregnancy. In 1952, the detailed description of postmaturity by Clifford 2 defined the risks of utero placental insufficiency in postdate pregnancy. The Clifford staging system described increasing degrees of uteroplacental compromise that led to progressive fetal wastage and perinatal mortality. Despite these identifications most American obstetricians debated whether postdate pregnancy was truly a problem while the British and pediatric literature continued to publish on the risks of postterm pregnancy. McClure-Browne 3 presented data from 16,986 pregnancies, which clearly showed that perinatal morbidity increased after 42 weeks, and sug-
Key words: Preterm labor, obstetrics, 13-adrenergic receptor agonists National, regional, and local perinatal data provide convincing evidence of improved maternal and neonatal health during the past several decades. Conversely, preterm delivery rates in the United States, over the same period of time, have remained relatively unaltered, in the range of 7% to 8%.' The impact of this finding can best be appreciated by the recognition that four of the six leading causes of infant death from 1970 to 1978 are almost exclusively associated with the premature neonate.' The World Health Organization uses, as its definition of a preterm infant, any neonate born prior to 37 completed weeks of gestation. No clear standards are established for the lower limits of this definition although, by tradition, an abortus is considered in any gestation less than 20 weeks. For the purpose of this discussion, we define the preterm infant as one who is born after 20 completed weeks from the first day of the last menstrual period and before 37 completed weeks of gestation. Although a birth weight of <2500 gm has been used in the past synonymously with this definition, a portion of these neonates actually represent growth retardation. Since perinatal morbidity and mortality issues are different for these two types of neonates, this distinction is important in the evaluation of recent lit-
From the Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston. Reprint requests: Robert K. Creasy, M.D., the Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, 6431 Fannin, Suite 3270, Houston, TX 77030.
erature pertaining to preterm labor and delivery management. The mechanisms involving the initiation of labor both before and at term are still poorly understood. An extensive review of this topic has recently been presented by Huszar and Naftolin, 2 who stressed three relatively distinct areas to be considered when addressing this subject. These include: (I) cervical maturational changes, (2) status of the fetal membranes, and (3) myometrial activity. Although the interrelationship of these factors is obvious, regulation of the individual components may not be identical. In addition, one can clinically identify pathologic alterations in each of these factors in isolation. From a practical perspective, the management of preterm labor requires a combined knowledge of all of these factors. However, the above issues support the multietiologic approach to the onset of preterm labor.
Prediction of preterm labor Primary to the reduction in the preterm birth rate is the establishment of criteria for the prediction of preterm labor. Since the causative factors of this event have yet to be clearly defined, systems thus far used to predict preterm labor primarily depend on historical or epidemiologic variables and their association with preterm delivery.' None of these risk-scoring systems have reached the level of discrimination necessary to be used as primary tools in establishing protocols to prevent the initiation of preterm labor. In addition, because these systems rely heavily on past obstetric outcomes, they are better equipped to screen the multiparous patient.
3
4 Gonik and Creasy
January, 1986 Am J Obstet Gynecol
Table I. System for determining risk of spontaneous preterm delivery Points assigned
Socioeconomic factors Two children at home Low socioeconomic status
2 3
4
5
10
Maternal age <20 yr or >40 yr Single parent Very low socioeconomic status Height <150 em Weight <45 kg Maternal age <18 yr
Previous medical history Abortion X I Less than I yr since last birth Abortion x2 Abortion x3
Pyelonephritis
Uterine anomaly Second-trimester abortion Diethylstilbestrol exposure Cone biopsy Preterm delivery Repeated secondtrimester abortion
Daily habits
Aspects of current pregnancy
Works outside home
Unusual fatigue
Smokes more than I 0 cigarettes per day
Gain of <5 kg by 32 wk
Heavy or stressful work that is long and tiring
Breech at 32 wk Weight loss of 2 kg Head engaged at 32 wk Febrile illness Bleeding after 12 wk Effacement Dilation Uterine irritability Placenta previa Hydramnios
Twins Abdominal surgical procedure
Adapted from Creasy RK, Gummer BA, Liggins GC. A system for predicting spontaneous preterm birth. Obstet Gynecol 55:692, 1980. Score is computed by adding the number of points given any item. The score is computed at the first visit and again at 22 to 26 weeks' gestation. A total score of ~I 0 places patient at high risk of spontaneous preterm delivery.
A multi-institutional collaborative study is currently underway to evaluate the utility of a preterm prevention program that incorporates the risk assessment system presented in Table I. These types of programs help to focus attention and provide education to a variety of health care personnel which should ultimately improve any therapeutic intervention program. With the advent of more sophisticated monitoring technology, normal and abnormal patterns of uterine activity are being established throughout the latter half of gestation. Earlier investigations suggested a progressive increase in uterine activity as gestation advances, and, in the patient destined to delivery preterm, a premature increase in this activity may occur. Katz et al.,4 using a portable tocodynamometer, recently reported that there is significantly more uterine activity in the ambulatory patient who later develops preterm labor. The usefulness of this finding relates to its occurrence up to 8 weeks prior to actual development of clinical manifestations of labor. Although this biophysical screening tool shows promise, further studies are needed to help establish its specificity and sensitivity in predicting preterm labor. Perhaps the most useful of all predictive indicators would be a biochemical marker that could be assayed serially in those patients thought to be at increased risk of preterm labor. Earlier work suggested that rising plasma levels of 17(3-estradiol or falling or low levels of serum progesterone may be useful in this regard. However, Block et a!. 5 were prospectively unable to dem-
onstrate any relationship between weekly serum estradiol or progesterone concentrations and the prediction of preterm labor. For the present time, no biochemical marker that can reliably improve one's ability to predict this event has been established.
Early detection of preterm labor Once a patient is categorized as at risk of developing preterm labor, by whatever predictive marker, weekly visits to the clinician for a review of early symptoms and for cervical examination seem warranted. Herron et al. 6 demonstrated that such a prevention program yielded a decreased preterm delivery rate by identifying an increased number of candidates eligible for longterm tocolytic therapy. The value of serial pelvic examinations is further supported by Holbrook et a!.,' who demonstrated the ability to identify 18% of highrisk subjects in premature labor by cervical examination alone, even without other symptoms. Additionally, they reported no increase in the rate of premature labor or infectious complications in this same study population as compared with a control preterm labor group not undergoing serial examinations. Thus no increased iatrogenic risks from preterm serial examinations of the cervix have thus far been identified.
Diagnosis of preterm labor The ability to prevent preterm deliveries is largely a function of early recognition and intervention." Although labor in its later stages is obvious, early symp-
Volume 154 Number 1
Table II. Criteria for diagnosis of preterm labor' Gestation 20 to 37 wk and Documented uterine contractions (4/20 min, 8/60 min) Ruptured membranes or Intact membranes and Documented cervical change or Cervical effacement of 80% or Cervical dilatation of 2 em
toms can be quite subtle and are frequently overlooked. In some series, only l 0% to 20% of patients presenting in preterm labor are candidates for long-term tocolysis. In addition, other studies have demonstrated a 20% to 45% efficacy of placebo treatment alone in "preterm labor" patients, suggesting an inaccurate initial diagnosis. The predicament that confronts the clinician, therefore, is accurate early diagnosis without overzealous treatment of patients not truly in labor. The criteria used in this institution for the diagnosis of preterm labor are presented in Table II. Castle and Turnbull" and later Boylan et al. 9 have used real-time ultrasonography to look at the presence or absence of fetal breathing movements and their relationship to labor. In the presence of fetal breathing, both term and preterm patients who initially presented with contractions were unlikely to progress into labor. The authors suggested that the early diagnosis of labor may be improved with the use of this ultrasonographic finding. Although this diagnostic tool may be of benefit in the future, further prospective studies are needed. Treatment of preterm labor
Once the diagnosis of preterm labor is clearly established, definitive tocolytic therapy should be initiated on an emergent basis. Although some clinicians have used bed rest, hydration, and narcotic sedation as a screening tool to establish the diagnosis of labor, these methods should not be confused with therapeutic modalities. The cornerstone in the pharmacologic management of the preterm patient in labor is currently therapy with a I)-adrenergic receptor agonist. The mechanism of action involves attachment of the drug to the 1)2 -adrenergic receptor with subsequent activation of adenyl cyclase. The resultant increase in cyclic adenosine monophosphate decreases myosin light chain kinase activity, thereby interfering with the actin/ myosin interaction. A variety of associated side effects have been reported with these agents, which are related to both !),-and 1) 2-adrenergic responses throughout the body. We are currently using ritodrine hydrochloride as our I)-adrenergic receptor agonist of choice. However, we are unaware of any study that clearly supports
Preterm labor 5
Table III. Initial measures recommended when tocolytic therapy is initiated Bed rest Admission weight Intravenous access line Electrocardiogram Baseline vital signs Fetal monitor for contractions and fetal heart tones Laboratory studies 1. Complete blood count 2. Electrolytes 3. Serum glucose 4. Colloid osmotic pressure 5. Urinalysis
the superiority of this agent versus any other in this class of drugs for efficacy or side effects. When beginning tocolytic treatment we initially obtain baseline data as shown in Table Ill. Maternal weight is obtained daily, and hematocrit, serum potassium, glucose, and colloid osmotic pressure determinations are repeated every 6 to 12 hours during intravenous therapy. Intravenous administration of the I)adrenergic receptor agonist is currently the route of choice for initial tocolysis. An intravenous infusion pump should be used with the initial dose of 50 to 100 meg/min. We use a 5% dextrose in water solution as our maintenance fluid because of recent evidence demonstrating an increased risk of pulmonary edema with isotonic saline solution. 10 In addition, we concentrate our tocolytic solution (300 mcg/500 ml) to reduce the amount of infused fluids. The starting dose can be gradually increased by 50 meg/min every 10 to 15 minutes and titrated to the desired clinical response of uterine quiescence. The usual effective dose is between 150 and 350 meg/min. If tocolysis is successful (less than one contraction every 10 to 15 minutes), we continue the infusion at that rate for 12 to 24 hours before switching to oral therapy. A limited amount of pharmacokinetic data is currently available for this drug. In patients receiving continuous infusions, ritodrine appears to be eliminated from the maternal plasma at a biphasic rate; a rapid phase of elimination of the drug (half-life 40 to 60 minutes) is followed by a more prolonged disappearance phase (half-life 16 to 28 hours)." Oral ritodrine should be started prior to the discontinuation of intravenous therapy to maintain therapeutic levels. The exact timing of the first oral dose has yet to be determined; empirically we allow 30 minutes before discontinuing intravenous ritodrine. Once oral therapy is begun, dosage determinations are made according to uterine activity, pelvic examination, and the maternal pulse rate. This latter clinical parameter has been shown to correlate with serum ritodrine concentrations and uterine inhibitory effects. 12
6 Gonik and Creasy
We start with an oral dose of 20 mg every 2 hours. If the maternal pulse is <90 bpm and contractions continue, on rare occasions we administer 30 mg every 2 hours to maintain tocolysis. Usually, we are able to decrease our frequency of administration to every 3 to 4 hours without a concomitant rise in uterine activity. We then attempt to sustain a resting pulse between 90 and 100 bpm. The usual dose will be 20 mg every 2 to 4 hours. Ambulation of the patient may be attempted after 24 hours of oral therapy. This activity should be minimal and should equate with those needs the patient anticipates at home after discharge. No further blood work is needed once oral therapy has been started. The patient can be discharged home if uterine activity and cervical findings remain unchanged during the next 24-hour period. Here, again, the potential benefit of portable home monitoring of uterine activity shows promise. The manufacturer's recommendations for surveillance of the patient on a regimen of intravenous ritodrine therapy include a baseline electrocardiogram and serial monitoring of glucose and electrolyte levels. Although both transient hypokalemia and transient hyperglycemia occur with the intravenous use of this medication, no specific therapy is warranted unless other medical complications exist, such as diabetes mellitus. We carefully restrict total administered fluids to 2500 ml/24 hr or less during intravenous treatment and for the first 24 hours of oral therapy, because of alterations in the renin-aldosterone control mechanisms that are known to occur with ritodrine and the recognized potential side effect of pulmonary edema. Although other investigators have suggested an upper limit of 1500 ml, we have not been as restrictive and have anecdotally seen only one documented case of pulmonary edema with our management. Of note, even at a 2500 ml restriction level, patients may still request excess oral fluids, which may relate to increased water imbibition seen in animal studies. Concerns about the more serious maternal complications identified with 13-adrenergic receptor agonists have led to the use of magnesium sulfate as a first- or second-line agent for tocolysis. The efficacy of this agent, however, has never been firmly established in an extensive controlled trial. However, observational data do suggest that uterine contractions can be eliminated when maternal serum levels of magnesium sulfate are in the range of 6 to 8 mEq/L (5.0 to 6.6 mg/100 ml) and the patient is in the early stages of labor. 13 These levels can generally be obtained by the initial administration of 4 to 6 gm of magnesium sulfate intravenously during 20 minutes followed by a maintenance dose of 1.5 to 3 gm/hr. Because of substantial patientto-patient variations in serum levels, we determine
January, 1986 Am J Obstet Gynecol
magnesium levels serially every 6 hours. The exact mechanism of action at the cellular level by which magnesium reduces uterine activity is speculative; in all probability magnesium competes with calcium ion, thereby inhibiting the actin/myosin interaction. As magnesium sulfate has gained acceptance, an increasing number of undesirable side effects have also been identified, including serious problems such as pulmonary edema. In addition, in a preliminary report by Ferguson et al. 14 of an attempt to use magnesium sulfate in combination with ritodrine therapy to reduce untoward cardiovascular side effects, a surprisingly unacceptable increase in serious side effects was reported. This issue remains controversial and requires further evaluation. In the patient who becomes unresponsive to 13-adrenergic receptor agonist therapy (perhaps because of uterine tachyphylaxis) or when a drug-related complication is identified, we use magnesium sulfate in combination with ritodrine or alone. Temporarily discontinuing ritodrine theoretically may help to increase the efficacy of 13-adrenergic receptor agonists so that we can later reinstitute either intravenous or oral ritodrine and achieve maximal effects. In patients who are insulin-dependent diabetics, magnesium sulfate is preferentially used on our service to avoid the risk of uncontrolled hyperglycemia that can occur with 13-adrenergic receptor agonist therapy. Since the terminal process thought to be responsible for uterine contractions is production and release of prostaglandins, it is not surprising that prostaglandin synthetase inhibitors have been studied for tocolytic potential." Their limited use, however, has stemmed from concerns regarding the potential for in utero narrowing or closure of the ductus arteriosus and perhaps persistent fetal circulation in the neonate. These effects have been anecdotally reported and appear to be most often associated with chronic administration beyond 34 weeks' gestation or in association with other risk factors such as sepsis or perinatal asphyxia. The ease of administration of indomethacin via the oral or rectal route makes this agent an attractive alternative to 13-adrenergic receptor agonist therapy. In our institution short-term administration of this agent for up to 72 hours has been occasionally used with the previable fetus when the gravid subject has developed resistance to traditional tocolytic therapy. Under these circumstances, the intermittent use of this agent in a dose of 25 mg every 4 to 6 hours may have merit. Further careful prospective work with this agent is warranted. Other new clinical approaches to the treatment of preterm labor include the use of calcium channelblocking agents. Since calcium appears to have a central role in the initiation of labor, agents such as nifedipine would seem reasonable candidates for tocolytic therapy.
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Volume 154 Number 1
Preliminary work indicates this drug may be useful as a tocolytic agent. 16 However, substantial concern is currently surfacing regarding the potential adverse effect this group of agents may have on the fetus. Although reports in the human have not demonstrated any overt toxicity, some animal work has demonstrated profound metabolic alterations in the fetus. 17 The use of these agents should be restricted to controlled clinical investigations. In our limited experience, oral administration of nifedipine in the previable and borderline viable fetus has been used with some suggested efficacy. Controversial management issues
The frequent concomitant use of corticosteroid therapy with I)-adrenergic receptor tocolytics has raised some concerns regarding an increased risk of pulmonary edema. From a physiologic standpoint, both groups of agents have been associated with an increase in fluid retention, although betamethasone and dexamethasone are essentially devoid of mineralocorticoid activity. In addition, alterations in fluid fluxes have been implicated as the most influential factor in the development of this complication. However, Robertson et a!.,'" in a series of 343 women treated with intravenous I)-adrenergic receptor agonist therapy, were unable to demonstrate any association between glucocorticoid administration and the development of pulmonary edema. It would seem prudent to institute efforts to reduce the risk of pulmonary edema in patients receiving both agents by maintaining close surveillance of intravenous and oral fluid therapy. Strict recording of intake and output and daily weighing of the patient are routine measures. This is particularly important during the first 24 to 72 hours of therapy since most cases of pulmonary edema have been reported to occur around 48 hours after initiation of tocolysis. Patients with twin gestations (who have an accentuated expansion of plasma volume) and those with low oncotic pressures (< 15 mm Hg) are at particular risk for this complication to develop. In most institutions, rupture of the membranes is a relative contraindication to long-term tocolytic usage. This appears to represent concerns over masking incipient infection as well as the perceived lack of efficacy ofthese agents after membrane rupture. Although controlled studies are not available, our current policy is to limit the use of tocolytic agents under these circumstances to no more than 24 to 36 hours. During this time period we occasionally administer glucocorticoids in an effort to induce fetal lung maturation, recognizing that adequate data are lacking in this regard. On an individual basis, we have used continuous intravenous tocolytic therapy in patients perceived to have a "high" leak that has subsequently resealed or in those with a very preterm fetus. Under these circumstances,
an amniocentesis to rule out the possibility of a subclinical infection is usually attempted. Of particular concern is a recent collaborative study that suggested that the combination of premature rupture of the membranes and tocolytic therapy resulted in a higher incidence of respiratory distress syndrome than that found with these factors evaluated individually.' 9 Before any clinical management protocol is established, this negative effect requires further evaluation and substantiation. The issue of "prophylactic" tocolysis in patients thought to be at high risk for preterm delivery has received surprisingly little attention. Although it has been demonstrated that oral I)-adrenergic receptor agonist therapy can decrease the recurrence rate of preterm labor, controlled prospective studies are lacking regarding the efficacy of these agents in preventing the initial occurrence in the patient at risk. Preliminary prophylactic studies with low-dose I)-adrenergic receptor agonists have failed to demonstrate any significant delays in the onset of preterm labor in twin gestations. However, it is unclear from these study designs whether an adequate dose of the agent was administered. This preventative pharmacologic approach to the management of the high-risk patient requires further study with appropriate doses. Once a patient has been started on a regimen of tocolytic therapy and labor has been successfully inhibited, the question arises as to the length of time the patient should receive these agents. Although some have advocated the use of amniocentesis to identify the neonate with pulmonary maturity, other nonpulmonary complications of prematurity are still important morbidity factors. Goldenberg et a!. 20 reviewed morbidity and mortality data for gestational ages between 22 and 36 weeks. Their conclusions, based on birth weight rather than gestational age, suggest that delaying delivery after 34 weeks of gestation was of little benefit. However, we have found that in the preterm gestation, uncomplicated by other maternal or fetal problems, a delay in delivery from 34 weeks to 36 completed weeks of gestation will decrease the incidence of several neonatal morbidity factors including respiratory distress, patent ductus arteriosus, need for prolonged intensive care, and overall number of hospitalization days. In this institution, we are willing to initiate tocolytic treatment in pregnancies up to 36 completed weeks and continue oral treatment until37 to 38 weeks of gestation. REFERENCES l. Quilligan EJ, Little AB, Oh Wm, et al. An evaluation and
assessment of the state of the science. In: Pregnancy, birth and infant. Bethesda, Maryland: National Institutes of Health, 1983; NIH publication no. 82-02304. 2. Huszar G, Naftolin F. The myometrium and uterine cer-
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vix in normal and preterm labor. N Eng! J Med 1984; 311:571. Creasy RK, Herron MA. Prevention of preterm birth. Semin Perinatal 1981 ;5:295. Katz M, Newman RB, Gill PJ. Assessment of uterine activity in ambulatory patients at high risk of preterm labor and delivery. AM J 0BSTET GYNECOL (in press). Block BSB, Liggins GC, Creasy RK. Preterm delivery is not predicted by serial plasma estradiol or progesterone concentration measurements. AM J 0BSTET GYNECOL 1984;150:716. Herron MA, Katz M, Creasy RK. Evaluation of a preterm birth prevention program: preliminary report. Obstet Gynecol 1982;59:452. Holbrook RH, Lirette M, Creasy RK. Weekly cervical examination in the patient at high risk for preterm delivery [Abstract]. Las Vegas, Nevada: Society of Perinatal Obstetricians, 1985. Castle BM, Turnbull AC. The presence or absence of fetal breathing movements predicts the outcome of preterm labour. Lancet 1983;2:471. Boylan P, O'Donovan P, Owens OJ. Fetal breathing movements and the diagnosis of labor: A prospective analysis of 100 cases. Obstet Gynecol 1985;66:517. Philipsen T, Eriksen PS, Lynggard F. Pulmonary edema following ritodrine-saline infusion in premature labor. Obstet Gynecol 1981;58:304. Post LC. Pharmacokinetics of beta-adrenergic agonists. In: Anderson PA, Beard R, Brudenell JM, Dunan PM, eds. Pre-term labour. Proceedings of the fifth study group
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12. 13. 14. 15. 16. 17.
18. 19.
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of the Royal College of Obstetricians and Gynaecologists. London: Royal College of Obstetricians and Gynaecologists, 1977. Lipshitz J. The uterine and cardiovascular effects of oral fenoterol bromide. Br J Obstet Gynaecol 1977;84:737. Elliot JP. Magnesium sulfate as a tocolytic agent. AM J 0BSTET GYNECOL 1983;147:277. FergusonJE, Hensleigh PA, Kredenster D. Adjunctive use of magnesium sulfate with ritodrine for preterm labor tocolysis. AM J OBSTET GvNECOL 1984; 148:166. Niebyl JR, Blake DA, White RD, eta!. The inhibition of premature labor with indomethacin. AM J 0BSTET GvNECOL 1980;136:1014. Forman A, Andersson KE, Ulmsten U. Inhibition of myometrial activity by calcium antagonists. Semin Perinatal 1981;5:288. Ducsay CA, Cook MJ, Veille JC, eta!. Nifedipine tocolysis in pregnant rhesus monkeys: maternal and fetal cardiorespiratory effects [Abstract]. Las Vegas, Nevada: Society of Perinatal Obstetricians, 1985. Robertson PA, Herron M, Katz M, eta!. Maternal morbidity associated with isoxsuprine and terbutaline tacolysis. Eur J Obstet Gynecol Reprod Biol1981;11:317. Curet LB, Rao AV, Zachman RD, et a!. Association between ruptured membranes, tocolytic therapy, and respiratory distress syndrome. AM J OBSTET GvNECOL 1984; 148:263. Goldenberg RL, Nelson KG, Davis RO, KoskiJ. Delay in delivery: Influence of gestational age and the duration of delay on perinatal outcome. Obstet Gynecol 1984;64:480.
Management of postdate pregnancy David C. Lagrew, M.D., and Roger K. Freeman, M.D. Long Beach, California Management of the problems associated with pregnancies that extend beyond 294 days of amenorrhea has become increasingly important in obstetrics. This article outlines some of the methods that minimize the risks to the mother, fetus, and neonate in postdate pregnancy. A brief description of the definitions, incidence, and impact of postdate pregnancy is given for a baseline on which to base management decisions. The current management techniques are then given for the following aspects: (1) diagnosis, (2) antepartum surveillance, (3) timing of delivery, and (4) intrapartum management. Finally a synopsis of research areas that may change management is given. (AM J OssTET GvNECOL 1986;154:8-13.)
Key words: Postdate pregnancy, prolonged pregnancy, postmaturity There has not always been widespread acceptance of the fetal risk when pregnancy lasts more than 14 days past the estimated date of confinement. Ballantyne,' as early as 1902, described postmaturity as a hazard to the safety of both the infant and the mother. His description included the risks of stillbirth, intrapartum asphyxia, and birth trauma associated with prolonged
From Women's Hospital, Memorial Medical Center. Reprint requests: David C. Lagrew, Jr., M.D., Clinical Instructor, University of Louisville, Department of Obstetrics and Gynecology, 550 South Jackson St., Louisville, KY 40292.
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pregnancy. In 1952, the detailed description of postmaturity by Clifford 2 defined the risks of utero placental insufficiency in postdate pregnancy. The Clifford staging system described increasing degrees of uteroplacental compromise that led to progressive fetal wastage and perinatal mortality. Despite these identifications most American obstetricians debated whether postdate pregnancy was truly a problem while the British and pediatric literature continued to publish on the risks of postterm pregnancy. McClure-Browne 3 presented data from 16,986 pregnancies, which clearly showed that perinatal morbidity increased after 42 weeks, and sug-