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Changes in maternal physiology occur normally during pregnancy and have the potential to alter the absorption, distribution, and elimination of drugs used therapeutically in pregnant women. These physiologic changes include: plasma volume expansion and increases in extracellular fluid space and total body water; decreased plasma albumin concentration; a compensated respiratory alkalosis; increased cardiac output with regional blood flow changes; increased renal blood flow associated with increased glomerular filtration; changes in hepatic drug metabolizing enzymes; and changes in gastrointestinal function. These changes begin in early gestation but are most pronounced in the third trimester of pregnancy. Further maternal physiologic changes occur intrapartum with some normalizing themselves within 24 hours of delivery, while others are sustained only returning to normal some 12 weeks postpartum. These physiologic changes form the basis for the need for pharmacokinetic studies during pregnancy.

Objective: Our purpose was to compare the efficacy and safety of misoprostol and extra-amniotic sodium chloride infusion with oxytocin for induction of labor. Study Design: This randomized trial compared two methods of labor induction in women requiring cervical ripening. One hundred twenty-three women undergoing labor induction with a Bishop score ≤5 were randomly selected to receive either misoprostol, 50 μg intravaginally every 4 hours, or extra-amniotic sodium chloride infusion. The primary outcome variable was the time interval from induction to vaginal delivery. Results: Sixty-one women received extra-amniotic sodium chloride infusion and 62 women received misoprostol. The mean time interval from the start of induction to vaginal delivery was 15.0 ± 5.0 hours and 16.5 ± 7.2 hours for the extra-amniotic infusion and misoprostol groups, respectively ( P , not significant). The cesarean delivery rate was not significantly different between the 2 groups (32.8% for the extra-amniotic infusion group; 19.4% for the misoprostol group). Maternal and neonatal outcomes were similar between the 2 groups. Conclusions: Both methods of induction are equally efficacious and result in similar maternal and neonatal outcomes. (Am J Obstet Gynecol 2000;182:1039-44.)

Objective: To report the clinical features, management, and outcome of twin pregnancies consisting of a complete hydatidiform mole and a coexisting normal fetus. Methods: Between 1966 and 1997, seven women with complete hydatidiform mole and coexisting normal fetus were treated at the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School. Clinical features, including presenting symptoms, gestational dates, hCG levels, and complications, as well as route of delivery or evacuation, pregnancy outcome, genetic analysis, and need for chemotherapy were assessed. Results: Four women required uterine evacuation before 20 weeks’ gestation because of vaginal bleeding or medical complications, one woman required an emergency hysterotomy because of hemorrhage at 24 weeks, and two women delivered normal, viable infants at 26 and 34 weeks. The pathologic diagnosis of complete hydatidiform mole was confirmed in each case and the chromosome complement was 46,XX in all molar gestations. Four of seven women required chemotherapy for treatment of nonmetastatic gestational trophoblastic tumors, including both women who delivered viable infants and two of the five women whose pregnancies were evacuated before 24 weeks’ gestation. All four patients were treated with five to seven cycles of a 5-day methotrexate regimen and achieved complete remission. Conclusion: Patients with a twin pregnancy consisting of a complete mole and a normal fetus are at increased risk for hemorrhage and medical complications, as well as the development of persistent gestational trophoblastic tumor.

OBJECTIVE: Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN: A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS: The mean pretreatment level of β-human chorionic gonadotropin was 1896.4 ± 2399 mIU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment β-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management ( p = 0.0011). The mean time to resolution of β -human chorionic gonadotropin was 26.5 ± 17 days. Higher pretreatment levels correlated with longer resolution time ( r = 0.83, p CONCLUSIONS: In our series single-dose methotrexate was only 64% successful. Women with a pretreatment β-human chorionic gonadotropin level >5000 mIU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk. (Am J Obstet Gynecol 1996;174:1840-8.)

Publisher Summary This chapter describes drug therapy in pregnant and nursing women. There are two compelling reasons for studying drugs and drug therapy during pregnancy. The first relates to the changing age of reproduction. The second relates to the physiologic changes that occur with gestation. To accommodate fetal growth and development and provide a measure of safety for the woman, pregnancy alters a woman's underlying physiology. Regional blood-flow changes also occur in pregnant women and can affect drug distribution and elimination. Blood flow increases to the uterus, kidneys, skin, and mammary glands, with a compensatory decrease in skeletal muscle blood flow. Pregnancy is also associated with a partially compensated respiratory alkalosis that may affect the protein binding of some drugs. The clearances of drugs metabolized by cytochrome P450 3A4 (CYP3A4) have been shown to be consistently increased in multiple studies of pregnant women. The hepatic clearance (CLH) of phenytoin, a restrictively eliminated drug that is predominantly a CYP2C9 substrate, increases during pregnancy, thereby resulting in correspondingly lower total plasma concentrations.

The new US Food and Drug Administration Proposed Rules for pharmaceutical products for the special population of pregnant women were published in May 2008. With these new rules in place, clinicians caring for women who are pregnant may begin to have clearer and more relevant information in the product label to guide clinical decisions regarding drug use during pregnancy.

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Sera from 10 subjects in the third trimester of pregnancy and from 10 nonpregnant women were studied to elucidate the mechanism underlying decreased theophylline protein binding during pregnancy. Consistent with the physiologic hypoalbuminemia of pregnancy, serum albumin concentrations averaged only 3.2 +/- 0.3 gm/dl (+/- SD) in pregnant subjects, compared with 4.4 +/- 0.3 gm/dl in control subjects (p less than 1 x 10(-6], and this was the main cause of decreased theophylline binding. Saturation binding studies indicated a single class of theophylline binding sites. Theophylline binding capacity (N) was greater in pregnant (N = 4.3 +/- 1.0) than in nonpregnant (N = 3.3 +/- 0.4) subjects, but binding affinity (ka) averaged only 227 +/- 69 (mol/L)-1 in pregnant subjects, compared with 303 +/- 44 (mol/L)-1 in control subjects (F2,17 = 4.26; p = 0.032). At a theophylline plasma concentration of 10 micrograms/ml, the combined effects of hypoalbuminemia and lowered ka would reduce theophylline binding to 31% +/- 3% in pregnant women, compared to 39% +/- 3% in nonpregnant control subjects (p less than 1 x 10(-5]. Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy-associated decrease in theophylline binding.

During pregnancy, physiologic changes occur in the woman's body, which potentially can alter the way in which drugs are handled. A few pharmacokinetic (PK), pharmacodynamic, or clinical trials are conducted during pregnancy because of concerns for fetal safety. The risk most commonly considered is the fetal risk of teratogenesis or drug-induced malformation. Maternal physiologic changes occur during gestation to accommodate fetal growth and development. This altered maternal physiology has the potential to affect the PK of drugs. These changes may increase drug distribution volume, decrease drug binding to plasma proteins, alter peak drug concentration and time to peak drug concentration, and cause changes in hepatic and/or renal drug clearance. Disregard of these changes in maternal physiology may affect drug efficacy impacting maternal disease and potentially overall pregnancy outcome. The expanded age of reproduction coupled with pregnancy occurring later in life effectively increases the number of women who require drug therapy for diseases present before pregnancy and who need to continue therapy during pregnancy. Adequate and well-studied therapies are needed to optimally treat pregnant women with underlying diseases.

Women who have had a cesarean section have a risk of uterine rupture when undergoing a second-trimester pregnancy termination. Beyond the first trimester, uterine rupture has been associated with the use of labor-induction agents and, less often, a placenta accreta. Scar dehiscence, a less disruptive form of scar separation, has not been reported with dilation and evacuation abortion. We present two cases of uterine scar dehiscence causing serious bleeding after otherwise uncomplicated dilatation and evacuation procedures. Neither case was associated with uterine contractions, an iatrogenic perforation or placenta accreta. Uterine scar dehiscence, a surreptitious process, can be the cause of hemorrhage after uncomplicated dilatation and evacuation.

The drug development process in the United States includes extensive pre-clinical testing and a series of clinical trials designed to explore the safety and efficacy of a new drug entity. As part of this process, animal studies are conducted to assess the effects of the new drug on the reproductive process. These studies, called developmental and reproductive toxicology studies, form the basis for the information included in the current pregnancy subsection of the drug label. The new drug's effects on the human fetus are gathered through post-marketing studies, usually observational registries. There is usually no information regarding the dose appropriate for pregnancy. The usual adult dose is assumed to be appropriate. Proposed changes to the current pregnancy subsection would replace the categories with narrative text, allow more detailed clinical management advice, including inadvertent fetal exposure, and provide a summary of risks associated with the drug. The sections on fertility, pregnancy and lactation would be combined, since they are a continuum. A provision is also being made to incorporate information from pharmacokinetic and pharmacodynamic studies relevant to pregnancy.

Our purpose was to identify what anesthetic method is safer for women with a placenta previa.We retrospectively reviewed all women with placenta previa who underwent cesarean delivery during the period January 1, 1976-December 31, 1997 at Northwestern Memorial Hospital.Of 93,384 deliveries, placenta previa was found in 514 women. Identifiable trends with time included an increasing incidence of placenta previa (r = 0.54, P.01); cesarean hysterectomy (r = 0.54, P.01); placenta accreta (r = 0.45, P.03); and regional anesthesia (r = 0.84, P.0001). The mean gestational age at delivery was 35.3 +/- 3.4 weeks and did not change with time. General anesthesia was used for delivery in 380 women and regional anesthesia was used for 134 women. Prior cesarean delivery and general anesthesia were independent predictors of the need for blood transfusion, but only prior cesarean delivery was a predictor of the need for hysterectomy. General anesthesia increased the estimated blood loss, was associated with a lower postoperative hemoglobin concentration, and increased the need for blood transfusion. Elective and emergent deliveries did not differ in estimated blood loss, in postoperative hemoglobin concentrations, or in the incidence of intraoperative and anesthesia complications. Regional and general anesthesia did not differ in the incidence of intraoperative and anesthesia complications.In women with placenta previa, general anesthesia increased intraoperative blood loss and the need for blood transfusion. Regional anesthesia appears to be a safe alternative.

Most sources of information regarding drugs in pregnancy include information on whether a drug causes congenital anomalies and whether a drug causes changes in fetal function or neonatal adaptation. Therapeutic issues related to the treatment of maternal disease are not readily available. Despite known physiologic changes of pregnancy, drug dosages are widely assumed to be the same as the healthy adult. An informational source is needed which addresses the therapeutic issues of pregnant women.

The objective of this article is to define normative fetal heart rate (FHR) tracing characteristics between 25-28 weeks' gestation in a low-risk population with normal pregnancy outcomes and to determine which criteria best determine FHR reactivity. Continuous FHR tracings were reviewed from 188 low-risk women participating in a trial of the Mammary Stimulation Test (MST) at 25-28 weeks' gestation. A reactive tracing required the presence of > or =two accelerations in 20 min. Different acceleration criteria were evaluated based upon the width of the acceleration (short vs. long) and the amplitude of the acceleration (10 vs. 15 bpm). Seventy-one percent of the FHR tracings were reactive using the higher amplitude (15 bpm), short criteria. This number increased significantly to 92% when the lower amplitude (10 bpm), short criteria were used (p

To evaluate whether once-daily gentamicin dosing is as effective as the traditional 8-hour regimen for the treatment of postpartum endometritis.Postpartum women with endometritis were randomized to receive gentamicin 5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also received clindamycin. Each participant had a peak serum gentamicin level of at least 5.0 micrograms/mL within the first 24 hours. The dosing regimens were compared by analyzing the number of hours that patients were febrile, the length of hospital stay, occurrence of complications, pharmacy costs, and nursing time required to administer the regimens.The study group (n = 62) and the control group (n = 65) were similar in demographic characteristics and the presence of endometritis risk factors. No differences were found between the groups in the number of patients who completed therapy without complications, required changes in antibiotics, or required readmission for endometritis. The groups did not differ in the number of hours that patients remained febrile after the start of therapy or in the length of hospital stay. No patient in the study group had an initial peak serum concentration less than 5.0 micrograms/mL, whereas 24 patients in the control group had initial peak serum concentrations less than 5.0 micrograms/mL and required dose adjustment, a statistically significant difference (P.001). Pharmacy costs averaged $16.12 +/- 5.68 for the study group and $41.75 +/- 17.41 for the control group, also a significant difference (P.001). Nurse tasking time averaged 13.62 +/- 2.56 minutes for the study group and 28.06 +/- 8.77 minutes for the control group (P.001).In patients with postpartum endometritis, once-daily gentamicin dosing provides consistently high peak serum levels of gentamicin, requires less nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

Our goal was to determine whether the mammary stimulation test combined with a risk scoring system and cervical examination at 26 to 28 weeks' gestation could effectively identify private nulliparous patients at risk for spontaneous preterm birth.The mammary stimulation test was performed by 267 nulliparous patients with singleton gestations at 26 to 28 weeks. Risk scores were determined by the method of Creasy et al. and cervical examinations were performed at the first prenatal visit and at 26 to 28 weeks. Summary predictive values were calculated for each test, and a stepwise discriminate analysis was performed.Spontaneous preterm birth occurred at37 weeks in 26 of 265 (9.8%) patients. The following variables were independently associated with spontaneous preterm birth: positive result of mammary stimulation test, risk scoreor = 10, soft cervix at 26 to 28 weeks, bacteriuria, and current smoking. The best discriminate model included positive result of mammary stimulation test, soft cervix, bacteriuria, current smoking, and prior spontaneous abortion(s). This model identified 19 patients as being at risk for spontaneous preterm birth with sensitivity of 35%, specificity of 96%, and positive predictive value of 47%.Combining the mammary stimulation test with a cervical examination at 26 to 28 weeks' gestation and routinely obtained prenatal data correctly identified 35% of spontaneous preterm births in nulliparous patients with a positive predictive value of 47%. Prospective validation of this model is warranted.

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2-urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three-compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 ± 0.009 L/kg (± SD) for inulin and of 0.670 ± 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient-surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 ± 0.49 L/min and was similar to dual-beam Doppler measurements of cardiac output (5.47 ± 0.40 L/min). Clinical Pharmacology and Therapeutics (1993) 53, 419–425; doi:10.1038/clpt.1993.45

Although most pharmacokinetic studies are conducted in normal subjects, their clinical utility depends on the reliability with which the results can be extrapolated to patients. This reliability can be improved by increased understanding of how drug absorption and disposition mechanisms are affected by physiological changes or by disease. In recent years, important insight has been gained regarding the effects of altered renal function on drug elimination by the kidneys. There has also been considerable progress in defining the interaction of hemodynamic and metabolic factors that affect the hepatic elimination of drugs. Although comparatively little progress has been made in elucidating the underlying basis of changes in the rate and extent of drug distribution, Arthur Atkinson and colleagues analyse methods of compartmental pharmacokinetic analysis that may provide physiological insight into the factors affecting drug distribution.

Purpose To compare the steady-state pharmacokinetics (PK) of oral metronidazole in pregnant and non-pregnant women requiring treatment for bacterial vaginosis (BV). Methods In an open-label, multi-centered study, 27 non-pregnant and 21 pregnant women between 17 - 27 weeks' gestation with BV received metronidazole extended release, 750 mg, once daily for 7 days. Blood and urine samples were collected on Days 6-8 for metronidazole and 2-hydroxy metronidazole levels. On Days 8 and 35–39, patients were evaluated for BV status and safety. Results Twenty pregnant and 25 non-pregnant women completed the PK analysis. Mean Cmax was significantly lower in pregnant women (8.20 μg/mL + 3.59 vs 11.08 + 3.91; P=0.019). Mean metronidazole AUC was also smaller in pregnant women with a difference that approached significance (136.22 (μg/mL)*hr + 60.57 vs. 179.55 + 75.4; P=0.057). Total oral metronidazole clearance was significantly greater in the pregnant group (P=0.043). There were no differences between renal and non-renal metronidazole clearances; however, renal clearance of 2-hydroxy metronidazole was significantly greater in pregnant women (P=0.0003). Of the women who were Nugent positive for BV, 12 of 17 pregnant women (70.6%) and 10 of 25 non-pregnant women (40.0%) were Nugent negative on Day 35. Study drug was well tolerated by both groups. Conclusions Metronidazole levels are reduced in pregnancy through possible increased CYP3A4 conversion of metronidazole to its hydroxy metabolite; however, dosage adjustments are not required to maintain efficacy. Clinical Pharmacology & Therapeutics (2004) 75, P24–P24; doi: 10.1016/j.clpt.2003.11.091

Summary This article reviewed newer drugs and techniques to control pain during labor, provide anesthesia for cesarean section, and control postpartum pain. PCA and epidural narcotics are now commonly used for pain after cesarean section. Ancillary drugs, used by both obstetricians and anesthesiologists, were discussed. The obstetric anesthesiologist can use this information to understand current trends in this area of anesthetic practice.

We evaluated the cervical dilator device (CDD), an expanding balloon, as a substitute for laminaria tents before abortion at 13 to 16 1/2 weeks by extraction and vacuum curettage. The CDD was found to be an effective dilator, although it did not appear to have any advantage over laminaria tents when placed overnight and was associated with significant pain upon insertion and an apparent increased risk of endometritis. The present CDD or a subsequent modification may offer advantages over laminaria tents for short-term placement.A volunteer study was conducted to evaluate the cervical dilator device (CDD) as a substitute for laminaria tents before induced abortion at 13-16 1/2 weeks by extraction and vacuum curettage. 58 2nd-trimester abortion patients were offered the CDD instead of laminaria. Amounts of dilatation resulting from the CDD were compared to results with laminaria; the results are presented in tabular form. The mean dilatation resulting from the CDD compared favorably with use of 1 medium laminaria tent. Parity had no consistent relation to dilatation. The CDD was found to be an effective dilator, but it had no advantage over laminaria tents placed overnight. The CDD caused significant pain on insertion and increased the risk of endometritis, as measured by fever and uterine tenderness. Further modification and refinement of the CDD are necessary to render insertion easier and less painful.

The kinetics of epsilon-aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10-gm iv dose. Steady-state distribution volume averaged 30.01 or 0.39 l/kg. Mean elimination t 1/2 was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet-rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half-maximal inhibition (IC50) of 63 +/- 19.7 microgram/ml. This agrees with the value of 0.55 mM or 72 microgram/ml that has been reported for the dissociation constant of the EACA-plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.

Theophylline pharmacokinetics were studied serially in five women during and after pregnancy. Theophylline protein binding was reduced to 11.1% +/- 4.7% (P less than 0.01) and 13.0% +/- 5.9% (P less than 0.01) during the second and third trimesters of pregnancy, respectively, compared with 28.1% +/- 2.8% when the patients were more than 6 months postpartum. Similar comparisons indicate that theophylline distribution volume and elimination t1/2 were increased from 30.7 +/- 4.4 L and 262 +/- 57 minutes to 36.8 +/- 4.2 L (P less than 0.05) and 389 +/- 73 minutes (P less than 0.01) in the third trimester of pregnancy. In the second and third trimesters, intrinsic nonrenal clearance was reduced to 0.82 +/- 0.25 ml/min X kg (P less than 0.05) and 0.67 +/- 0.18 ml/min X kg (P less than 0.01) compared with a remote postpartum value of 1.25 +/- 0.37 ml/min X kg. However, these reductions were offset by increases in theophylline intrinsic renal clearance so that apparent reductions in the overall unbound clearance of this drug did not reach statistical significance either during pregnancy or in the early postpartum period.

Analyses of hemoglobin A1c concentrations were performed throughout gestation in 377 nondiabetic women. We observed significant biphasic changes in hemoglobin A1c concentrations, with an initial gradual decline to a nadir level at 24 weeks, followed by a subsequent slow reascension to peak near term. All these changes fell within the usual range of normal values for hemoglobin A1c. Values for plasma glucose estimated 1 hour after a 50 gm oral glucose load in 1,756 normal gravid women showed similar biphasic excursions, with the nadir occurring 4 weeks earlier, i.e., at 20 weeks' gestation. We conclude that the small but significant changes in hemoglobin A1c during the course of normal gestation reflect, with an appropriate displacement in time, the biphasic alterations in mean blood sugar that characterize the sequential changes in glucoregulation during normal pregnancy.

[4 - 14 C]Progesterone was administered to two cycling female monkeys during the luteal phase of the cycle, and blood and urine were sampled over a 24 h period. Progesterone had a volume of distribution of 1.75 ± 0.3 L/kg, and a plasma elimination clearance of 0.06 ± 0.03 L/kg/min. In comparison to the human, plasma progesterone binding was greater and progesterone clearance was slower in the cynomolgus monkey. The major unconjugated metabolite in plasma was 20α-hydroxy-4-pregnen-3-one. In urine 6.2% of 14 C - steroids were unconjugated, 2.3% of which were [ 14 C]progesterone. Thin-layer chromatography (TLC) of conjugated metabolites in urine revealed that 24% had the mobility of sulfates, 19% that of glucuronides, and 52% were more polar. After hydrolysis of conjugates, a major fraction chromatographed with pregnanediol. However, despite evidence for the presence of a 20α-hydroxyl group, none of the pregnanediol isomers could be identified among these 14 C - steroids. Nevertheless, over 80% of urinary metabolites had sufficient analogy to pregnanediol to bind to an antiserum specific for ring D and the C-17 side-chain of pregnanediol.

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.

in dense clumps adherent to the inner coat of the nuclear envelope toward the periphery. The age of the patient and the presence of vaginal bleeding caused by a nodular, ulcerated mass are consistent with a primary malignant melanoma of the vagina. As often seen with vaginal melanomas, the aggressive tumor led to the patient’s rapid death. With electron microscopy, it was possible to distinguish between those diagnoses which had been considered with the use of light microscopy. The diagnosis of a poorly differentiated squamous cell carcinoma was excluded by the lack of desmosomes and keratin; an extra-adrenal pheochromocytoma was eliminated by the lack of eccentrically placed, dense-core norepinephrine granules, and rhabdomyosarcoma was excluded by the absence of rhabdomyoblasts and filaments similar to skeletal muscle fibers.2 The features of this tumor characteristic of an amelanotic malignant melanoma were the presence of junctional activity in the vaginal epithelium and the presence of numerous premelanosomes in the cytoplasm. The diagnoses which had been considered included a benign tumor, carcinoma, or sarcoma. The importance of electron microscopy in distinguishing between the possible diagnoses relates to the different prognostic and therapeutic factors in all these lesions. It is recommended, therefore, that when the diagnosis of a pelvic tumor is unclear by light microscopy, the electron microscope should be used to aid in making the correct diagnosis.

We evaluated the adequacy of a new large-bore vacuum cannula system for midtrimester abortion by randomly allocating patients to be treated with a standard 12-mm vacuum system or the new 15.9-mm system. Cervical dilatation was accomplished by overnight placement of laminaria tents. Blood loss was similar for the two treatment groups and was significantly greater at gestational ages 17 to 18 weeks than for abortions at 16 weeks or less. Operating time was slightly less in the large-cannula group. When the 12-mm cannula was used beyond 13 weeks' gestation, forceps were usually needed to empty the uterus completely. The large-cannula system was able to empty the uterus through 16 weeks, but at 17 and 18 weeks it offered no advantage over the smaller system and forceps were always needed. Complications were minimal. We caution against forcible cervical dilatation to 16mm and urge the use of laminaria instead. Our findings, together with published reports of the safety of late dilatations and evacuation, would appear to justify wider clinical trials by experienced investigators.