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Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women.We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia (37 weeks), as well as 480 randomly selected women--120 women with preeclampsia at term (ator =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age.Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone.Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia.

Objective Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies. Study design Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges. Results In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester. Conclusion These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.

The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role.We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia.During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant.Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

OBJECTIVE: The purpose of this study waS to determine if endothelin levels are elevated in women with preeclampsia and if these levels correlated with other laboratory features of disease severity. STUDY DESIGN: Parameters were compared in four groups of women volunteers by means of analysis of variance: (1) 16 women with preeclamptic pregnancies, (2) 11 pregnant women without preeclampsia, of similar lengths of gestation, (3) six otherwise normal women with pregnancies at term or beyond (>38 weeks), and (4) 22 normotensive young women. RESULTS: Endothelin levels were elevated in women with preeclampsia as compared with those of gestation-matched pregnant and nonpregnant controls (22.6 ± 2.0 vs 12.0 ± 1.0 vs 10.4 ± 1.3 pmol 1 L, P < 0.005, preeclampsia vs controls) and also were increased in late gestation (17.7 ± 2.0 pmoI/L). Endothelin correlated positively with plasma levels of uric acid (r = 0.698, P < 0.005) and inversely with creatinine clearance (r = 0.659, P < 0.05). CONCLUSION: Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations suggest that endothelin may contribute to renal vasoconstriction in preeclampsia. (AM J OSSTET GVNECOL 1992;166: 962-8.)

Present techniques for prenatal diagnosis are invasive and present significant risks of fetal loss. Noninvasive prenatal diagnosis utilizing fetal nucleated red blood cells (fNRBC) circulating in maternal peripheral blood has received attention, since it poses no risk to the fetus. However, because of the failure to find broadly applicable identifiers that can differentiate fetal from adult NRBC, reliable detection of viable fNRBC in amounts sufficient for clinical use remains a challenge. In this Letter we show that fNRBC light-scattering spectroscopic signatures may lead to a clinically useful method of minimally invasive prenatal genetic testing.

Twin pregnancies are a risk factor for preeclampsia with a reported incidence of 2-3 times higher than singleton pregnancies. Soluble fms-like tyrosine kinase 1 (sFlt1), which is a circulating antiangiogenic molecule of placental origin, plays a central role in preeclampsia by antagonizing placental growth factor (PlGF) and vascular endothelial growth factor signaling in the maternal vasculature. Increased sFlt1 and the ratio sFlt1/free PlGF have been shown to antedate clinical signs in preeclampsia. Although the cause of the upregulated sFlt1 in preeclampsia still is not understood clearly, placental ischemia with accompanying hypoxia is thought to play an important role. We therefore hypothesized that the higher risk of preeclampsia in twin pregnancies results from high sFlt1 (or sFlt1/PlGF) and that the sFlt1 upregulation was due to either relative placental hypoxia and/or increased placental mass.Maternal serum samples and placentas from third-trimester twin and singleton pregnancies without preeclampsia were used. Serum samples were analyzed for levels of sFlt1 and free PlGF by enzyme-linked immunosorbent assay and reported as means (in nanograms per milliliter and picograms per milliliter, respectively). Placentas were weighed and examined for content of sFlt1 and PlGF messenger RNA (mRNA) by quantitative polymerase chain reaction and hypoxia inducible factor-1alpha (HIF-1alpha) protein by Western blot.Soluble Flt1 concentrations in twin pregnancy maternal serum were 2.2 times higher than those that were measured in singleton pregnancy maternal serum samples (30.98 +/- 9.78 ng/mL vs 14.14 +/- 9.35 ng/mL, respectively; P = .001). Free PlGF concentrations were not significantly different between twin and singleton maternal serum samples, but the mean sFlt1/PlGF ratio of twin pregnancy maternal serum samples was 2.2 times higher than the equivalent ratio in singleton pregnancy samples (197.58 +/- 126.86 ng/mL vs 89.91 +/- 70.63 ng/mL, respectively; P = .029). Quantitative polymerase chain reaction for sFlt1 and PlGF mRNA revealed no significant differences between the 2 study groups. Western blot analysis of placental samples for HIF-1alpha revealed a mean ratio HIF-1alpha/actin of 0.53 vs 0.87, for the twins vs singletons placental samples respectively (twins showed lower HIF-1alpha, not higher). The mean weights of twin and singleton placentas were 1246 vs 716 g, respectively (P.001). Importantly, the placental weights correlated very well with the circulating sFlt1 levels (R(2) = .75).In twin pregnancies, circulating sFlt1 levels and sFlt1/PlGF ratios were twice as high as those in singleton pregnancies. The increased serum sFlt1 levels in twin pregnancies were not accompanied by any changes in the levels of sFlt1 mRNA and HIF-1alpha protein in the twin placentas but were correlated with increased placental weight. These findings suggest that the increased risk of preeclampsia in twin pregnancies may be due to increased placental mass that leads to increased circulating levels of sFlt1.

To evaluate the effect of teamwork training on the occurrence of adverse outcomes and process of care in labor and delivery.A cluster-randomized controlled trial was conducted at seven intervention and eight control hospitals. The intervention was a standardized teamwork training curriculum based on crew resource management that emphasized communication and team structure. The primary outcome was the proportion of deliveries at 20 weeks or more of gestation in which one or more adverse maternal or neonatal outcomes or both occurred (Adverse Outcome Index). Additional outcomes included 11 clinical process measures.A total of 1,307 personnel were trained and 28,536 deliveries analyzed. At baseline, there were no differences in demographic or delivery characteristics between the groups. The mean Adverse Outcome Index prevalence was similar in the control and intervention groups, both at baseline and after implementation of teamwork training (9.4% versus 9.0% and 7.2% versus 8.3%, respectively). The intracluster correlation coefficient was 0.015, with a resultant wide confidence interval for the difference in mean Adverse Outcome Index between groups (-5.6% to 3.2%). One process measure, the time from the decision to perform an immediate cesarean delivery to the incision, differed significantly after team training (33.3 minutes versus 21.2 minutes, P=.03).Training, as was conducted and implemented, did not transfer to a detectable impact in this study. The Adverse Outcome Index could be an important tool for comparing obstetric outcomes within and between institutions to help guide quality improvement.(www.ClinicalTrials.gov), NCT00381056I.

Objective We sought to determine the present-day risk of maternal death with cesarean delivery. Methods We reviewed the recent literature (years in analysis: 1975-2001) identified in a literature search and included data from the Royal College of Obstetricians and Gynaecologists. Findings There were no publications with an ideal trial design and adequate power to establish the relationship between maternal mortality and method of delivery. Three studies, including the one randomized control trial included in analysis, and the Royal College of Obstetricians and Gynaecologists data suggest no significant difference in maternal mortality with cesarean delivery as compared with vaginal delivery. Conclusions The strongest publications suggest there may not be an increased risk of maternal death with cesarean delivery as compared with vaginal delivery; however, there are inadequate data to accurately demonstrate the present-day risk of maternal death with cesarean delivery.

Objective The objective of this pilot study was to evaluate the clinical utility of soluble fms-like tyrosine kinase 1 (sFlt 1) and soluble endoglin (sEng) in the differential diagnosis of hypertension in late pregnancy. Study Design We analyzed serum levels of sFlt 1 and sEng in women with gestational hypertension (GHTN; n = 17), chronic hypertension (CHTN; n = 19), preeclampsia (n = 19), and normal pregnancy (n = 20) in the third trimester. We calculated the sensitivity, specificity, and positive and negative likelihood ratio (LR) for each factor in diagnosing preeclampsia. Results The sensitivity and specificity of sFlt 1 in differentiating preeclampsia from normal pregnancy were 90% and 90%, respectively, and 90% and 95% for sEng. In women with GHTN, they were 79% and 88% for sFlt 1; 84% and 88% for sEng; 90% and 63% for uric acid. In women with CHTN, they were 84% and 95% for sFlt 1; 84% and 79% for sEng; 68%; and 78% for uric acid. The positive LR for preeclampsia was 9 for sFlt 1 and 7 for sEng in women with normal pregnancy; in women with GHTN; 6.7 for sFlt 1 and 7.2 for sEng; in CHTN, 16 for sFlt 1 and 4 for sEng. Serum uric acid had a positive LR of only 2.4 in women with GHTN and 3.1 in women with CHTN. Conclusion Both sFlt 1 and sEng may prove useful in differentiating preeclampsia from other hypertensive diseases of pregnancy. A prospective cohort study should be performed determine the clinical utility of measuring these proteins.

In 1995, the rate of cesarean delivery in the United States was 21 percent.1 The goal of Healthy People 2000, a project of the Department of Health and Human Services, is to reduce this rate to 15 ...

The circulating antiangiogenic protein soluble fms-like tyrosine kinase 1 (sFltl), also known as soluble vascular endothelial growth factor (VEGF) receptor 1, sequesters the proangiogenic proteins placental growth factor (PlGF) and VEGF. Its circulating level correlates with the severity of preclampsia and with the onset of hypertension or proteinuria. Increased expression of sFltl in pregnant rats creates a state resembling preeclampsia. Soluble endoglin, a coreceptor for transforming growth factors, is another antiangiogenic protein that acts with sFltl to produce a severe preeclampsia-like syndrome in pregnant rats. This nested case-control study, enrolling healthy nulliparous women taking part in the Calcium for Preeclampsia Prevention (CPEP) trial, was designed to show whether endoglin is associated with preeclampsia in humans. Seventy-two women having preeclampsia before 37 weeks' gestation were compared with four groups, each comprising 120 women, who had preeclampsia at term; had gestational hypertension; were normotensive but had an small-for-gestational-age infant; or were normotensive and delivered a normal-sized infant. Severe preeclampsia developed in 61% of women with preterm preeclampsia and 25% of those with preeclampsia at term (after 37 weeks' gestation). Symptomatic women with preterm preeclampsia had significantly higher serum levels of soluble endoglin than control women. Term preeclampsia also was associated with elevated circulating levels of endoglin. At 17-20 weeks' gestation, endoglin levels were significantly higher in women who later developed preterm preeclampsia than in control women. The same was the case at gestational weeks 25 through 28 for women who developed term preeclampsia. Elevated endoglin levels usually were accompanied by an increased sFltl:P1GF ratio. The risk of preeclampsia was greatest for women in the highest quartile of the control distributions for both biomarkers but not for either one alone. On multivariable analysis, large increases in the risk of preeclampsia with a small-for-gestational-age infant were associated with the highest quartile of soluble endoglin or sFltl:P1GF ratio. These findings, combined with those of experimental rodent studies, suggest that circulating soluble endoglin and spil-which cause endothelial dysfunction by different mechanisms-may contribute to the development of preeclampsia. Whether levels of these biomarkers will be useful in predicting the onset of clinical preeclampsia remains to be determined by longitudinal prospective studies.

Vaginal birth after cesarean delivery (VBAC) is an increasingly controversial procedure. Apart from medicolegal issues, there is uncertainty about identifying patients at risk and questions about what is an appropriate emergency response time. The risk of uterine rupture, although small, is very significant. This study surveyed a random sample of 1200 fellows of the American College of Obstetricians and Gynecologists in mid-2003 to define trends over the past 5 years in the management of VBAC. The 639 responses received after 3 mailings represented a response rate of 53%. No gender differences were found between those who did and those who did not respond. Respondents in general felt that they were familiar with the benefits and risks of VBAC as well as with ACOG guidelines for identifying the best candidates and for properly using oxytocin to induce labor in the setting of VBAC. There was a strong consensus that encouraging the procedure will lower overall rates of operative delivery. Respondents were less certain that they can reliably determine which patients would be successes. Nearly all of them reported being more confident if there had been a previous vaginal birth. Multifetal gestation, obesity, and diabetes all were thought to compromise the outcome of VBAC. Nearly three fourths of respondents reported that more than half of women having a previous cesarean again had an operative delivery. Male physicians were likelier than females to do repeat cesarean deliveries. Nearly half the group reported doing more cesareans at present than 5 years earlier, and approximately one third were doing about the same number. The same trends were evident for repeat section deliveries. Respondents cited liability risk and patient preference as major reasons for increasing rates of repeat cesarean section. Only 29% of respondents believe that that the current U.S. rate of cesarean delivery is too high. Uncertainty continues about whether elective repeat section is the safest procedure for the infant. Obstetricians/gynecologists appear to be well aware of the benefits and risks of VBAC, but doubt remains about which women should be offered a trial of labor and about what factors predict successful VBAC.

Cancer-related maternal mortality is a rare event. We report the first population-based study of this issue using data collected by the Committee on Maternal Welfare of the Massachusetts Medical Society between 1954 and 1985. The incidence of cancerrelated maternal mortality during the study period fell from 3.16 to 0 per 100,000 live births. The most common cancer-associated maternal deaths were due to central nervous system tumors and hematological cancers. To determine the effects of pregnancy on cancer mortality, we compared our data with figures from the Connecticut Register of Mortality for Women aged 15–44. In the pregnant group there was a significantly higher incidence of mortality due to central nervous system tumors and a significantly ower incidence of mortality due to breast cancer. The data suggest that pregnancy may not be contraindicated for a woman with a history of breast cancer, but may be contraindicated for a woman with a history of a central nervous system tumor.

ContextPreeclampsia may be caused by an imbalance of angiogenic factors. We previously demonstrated that high serum levels of soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and low levels of placental growth factor (PlGF), a proangiogenic protein, predict subsequent development of preeclampsia. In the absence of glomerular disease leading to proteinuria, sFlt1 is too large a molecule to be filtered into the urine, while PlGF is readily filtered.ObjectiveTo test the hypothesis that urinary PlGF is reduced prior to onset of hypertension and proteinuria and that this reduction predicts preeclampsia.Design, Setting, and PatientsNested case-control study within the Calcium for Preeclampsia Prevention trial of healthy nulliparous women enrolled at 5 US university medical centers during 1992-1995. Each woman with preeclampsia was matched to 1 normotensive control by enrollment site, gestational age at collection of the first serum specimen, and sample storage time at −70°C. One hundred twenty pairs of women were randomly chosen for analysis of serum and urine specimens obtained before labor.Main Outcome MeasureCross-sectional urinary PlGF concentrations, before and after normalization for urinary creatinine.ResultsAmong normotensive controls, urinary PlGF increased during the first 2 trimesters, peaked at 29 to 32 weeks, and decreased thereafter. Among cases, before onset of preeclampsia the pattern of urinary PlGF was similar, but levels were significantly reduced beginning at 25 to 28 weeks. There were particularly large differences between controls and cases of preeclampsia with subsequent early onset of the disease or small-for-gestational-age infants. After onset of clinical disease, mean urinary PlGF in women with preeclampsia was 32 pg/mL, compared with 234 pg/mL in controls with fetuses of similar gestational age (P

Technology plays an important role in the practice of medicine, and it is essential that controlled clinical trials be conducted before new technologies are widely disseminated. In this article, information from the medical literature is summarized and critiqued for several common obstetric technologies which are aimed at reducing the incidence or sequelae of low birth weight and preterm birth. These technologies include home uterine activity monitoring, tocolytic drugs to suppress uterine contractions, corticosteriods to accelerate fetal lung maturity, bed rest to prevent preterm delivery, delivery methods, multifetal pregnancy reduction, and cervical cerclage. A major challenge to the practice of medicine is to find effective ways to modify physician behavior to encourage the use of proven, effective technologies, and discourage the use of unproven, ineffective technologies. Despite widespread use, most obstetrical technologies appear to have had little impact on reducing the incidence of low birth weight or preterm births, as rates of low birth weight and preterm birth have not decreased appreciably in the past 25 years. Uncovering the basic mechanisms responsible for the onset of preterm labor will undoubtedly facilitate the discovery of new technologies to prevent low birth weight and preterm births.

SUMMARY 1. Electronic fetal monitoring (EFM) can predict fetal hypoxia as defined by low Apgar scores at birth. However, the predictive value is poor in low-risk patients. 2. A normal fetal heart rate tracing is a good predictor of fetal well-being. 3. It is unclear whether EFM can prevent cerebral palsy and mental retardation. 4. Severe perinatal asphyxia, particularly in full-term infants, usually leads to neonatal demise. However, in some cases it can lead to long-term neurological handicap. In such infants, the asphyxia is usually severe and prolonged. It is usually associated with seizures, other abnormal neurological signs in the neonatal period and the long-term handicap probably always involves the motor system. 5. Studies of the aetiology of cerebral palsy and mental retardation have shown that only a small percentage of both can be attributed to perinatal asphyxia.

A retrospective review was conducted of all pregnant women discharged undelivered during fiscal year 1985. If the current Medicare prospective payment plan were applied to these admissions, Diagnostic Related Group 383 (other antepartum diagnoses with medical complications) and Diagnostic Related Group 384 (other antepartum diagnoses without medical complications) would together generate a negative cash flow. Supplementation for capital costs and direct and indirect medical education costs would result in a positive cash flow; however, the supplementation is vulnerable to political and social forces that will tend to diminish or eliminate it.

To identify ways in which the safety of childbirth might be increased, we investigated the causes of death among the 886 women who died during pregnancy or within 90 days post partum ("maternal deaths") in Massachusetts from 1954 through 1985. The maternal mortality rate declined from 50 per 100,000 live births in the early 1950s to the current rate of 10 per 100,000 live births. Between one third and one half of the maternal deaths were considered to have been preventable. The leading causes of maternal death from 1954 through 1957 were infection, cardiac disease, pregnancy-induced hypertension, and hemorrhage. In contrast, from 1982 through 1985 the leading causes of death were trauma (suicide, homicide, and motor vehicle accidents) and pulmonary embolus. We observed a rapid increase in the frequency of death among women who received little or no antenatal care. From 1980 through 1984 the maternal mortality rate for white women was 9.6 per 100,000 live births, whereas for nonwhites it was 35 per 100,000 live births (relative risk, 2.9; 95 percent confidence limits, 2.5 and 3.2). Fifty percent of the nonwhite women who died during pregnancy or within 90 days post partum received little or no antenatal care, in contrast to only 15 percent of the white women. These data show that the leading causes of maternal death have changed markedly in Massachusetts during the past 30 years. Although the overall maternal mortality rate has declined sharply, further improvement may occur with better antenatal care and specific efforts to prevent trauma and pulmonary embolus.

The leukocyte count was evaluated in 479 laboring gravida women. Increasing leukocyte counts appeared to be linearly related to the duration of elapsed labor (y = 0.2174x + 10.31; p less than 0.001; 95% confidence interval of the slope = 0.1414 to 0.2934). Isolated mild elevations and mild increases of leukocyte count in labor may be managed expectantly. Elevations greater than 2 SD are unlikely to represent normal variation; a diligent search for unapparent infection is warranted.

A case discussing the medical management of a 30-year-old gravid patient with recurrent pericarditis and pericardial constriction secondary to juvenile rheumatoid arthritis is presented.

1. Kan YW, Dozy AM. Antenatal diagnosis of sickle-cell anemia by DNA analysis of amniotic-fluid cells. Lancet 1978;2:910-912. 2. Rigby PW, Dieckmann M, Rhodes C, Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase Int J Mol Biol 1977;1 !3:237-251. 3. Goossens MG, Kan YW. DNA analysis in the diagnosis of hemoglobin disorders. Methods Enzymol 1981 ;76:805-817. 4. Gray G R, Towell ME, Wright V J, Hardwick DF. Thalasse- mic hydrops fetalis in two Chinese-Canadian families. Can Med Assoc J 1972;107:1186-1190. 5. Weatherall D J, Clegg JB, Boon WH. The hemoglobin consti- tution of infants with haemoglobin Bart's hydrops foetalis syndrome. Br J Haematol 1970;18:357-367. 6. Horton BF, ThomPson RB, Dozy AM, et al. Inhomogeneity of hemoglobin. VI. The minor hemoglobin components of cord blood. Blood 1962;20(3):302-313. 7. Tuchinda S, Nagai K, Lehmann H. Oxygen dissociation curve of haemoglobin Portland. FEBS Lett 1975;49:390- 391. 8. Thumasathit B, Nondasuta A, Silpisornkosol S, et al. Hydrops fetalis associated with Bart's hemoglobin in northern Thailand. Trop Pediatr 1968;73(1):132-138. 9. Bryan EM, ChaimongkoI B, Harris DA. Alpha-thalassaemic bydrops fetalis. Arch Dis Child 1981;56:476-478.

This is a population-based study of the safety of obstetrical anesthesia in the Commonwealth of Massachusetts between 1954 and 1985. We used data collected by the state Committee on Maternal Mortality, which was founded in 1941. There were a total of 37 maternal deaths during the study period due to anesthetic-related complications. During the same time period, there were 886 maternal deaths. Thus, anesthetic-related mortality comprised 4.2% of all deaths, and the mortality rate was 1.5 per 100,000 live births between 1955 and 1964, 1.5 per 100,000 live births between 1965 and 1974, and 0.4 per 100,000 live births between 1975 and 1984. In the first decade of this study, aspiration during administration of a mask anesthetic was the primary cause of death. During the second decade, cardiovascular collapse associated with regional anesthesia was the primary cause of death. During the last decade of this study, all deaths were associated with general endotracheal anesthesia. As a result of this study and having identified the changes in the standard of care in Massachusetts that led to the reduction in maternal mortality, we offer recommendations to further improve the safety of anesthesia for childbirth in this country.

Almost half (47.6%) of all deliveries with shoulder dystocia occurred in association with the delivery of an average-weight infant (under 4000 g). Of 4294 nondiabetic gravidas delivering infants of birth weight 3500 to 3999 g, 94 (2.2%) experienced a shoulder dystocia. Protraction and arrest disorders were associated with a statistically significant increase in the incidence of shoulder dystocia, and this effect was further augmented by low forceps delivery. Among 6252 infants weighing 3000 to 3499 g, there were 40 instances of shoulder dystocia (0.6%). Only arrest disorders were associated with an increased rate.

This article reviews currently available epidemiologic and experimental data on the effects of cigarette smoking on reproductive health. Specifically addressed are the evidence for and possible physiologic causes of disturbance in 3 areas: female fertility, male fertility, and the effect of smoking on reproduction and pregnancy. Approximately 30% of women and 36% of men of reproductive age in the US are smokers. The literature offers clear support for an association between smoking and decreased female fecundity and fertility, especially with a relationship to primary tubal infertility. Cigarette smoke appears to have adverse effects along a continuum of preimplantation and implantation reproductive processes, including gamete production and function, ovulation and cyclicity, fertilization, early embryonic cleavage, embryo transport, and implantation. In men, there is clear evidence that smoking results in fewer and less motile sperm as well as a lower proportion of normally shaped sperm; however, it remains unclear whether this impairment in spermatogenesis results in clinical impairment of fertility. Studies have demonstrated a significant increase among smoker both in the risk of spontaneously aborting a chromosomally normal fetus and in the risk of spontaneously aborting a chromosomally normal fetus and in the risk of prematurity. Moreover, smoling has been shown to cause a 150-300 gram decrease interm infant birthweight. Al these risks to fecundity and pregnancy outcome are minimized or absent in former smokers. It is stressed that efforts to persuade women to stop smoking have been inadequate. It is particularly imperative for women who have had divviculties conceving or have had a history of miscarraiges to give up cigarette smoking.

In Reply.— Dr Nabors' kind words are appreciated. We were unable to assess either the cost of long-term care for infants that do not die or the decreased cost for those infants less traumatized because of a cesarean delivery. We therefore emphasized that our study was not meant to be a cost-benefit analysis but an opening shot in a discussion that needs to take place.

To identify ways in which the safety of childbirth might be increased, we investigated the causes of death among the 886 women who died during pregnancy or within 90 days post partum ("maternal deaths") in Massachusetts from 1954 through 1985. The maternal mortality rate declined from 50 per 100,000 live births in the early 1950s to the current rate of 10 per 100,000 live births. Between one third and one half of the maternal deaths were considered to have been preventable. The leading causes of maternal death from 1954 through 1957 were infection, cardiac disease, pregnancy-induced hypertension, and hemorrhage. In contrast, from 1982 through 1985 the leading causes of death were trauma (suicide, homicide, and motor vehicle accidents) and pulmonary embolus. We observed a rapid increase in the frequency of death among women who received little or no antenatal care. From 1980 through 1984 the maternal mortality rate for white women was 9.6 per 100,000 live births, whereas for nonwhites it was 35 per 100,000 live births (relative risk, 2.9; 95 percent confidence limits, 2.5 and 3.2). Fifty percent of the nonwhite women who died during pregnancy or within 90 days post partum received little or no antenatal care, in contrast to only 15 percent of the white women. These data show that the leading causes of maternal death have changed markedly in Massachusetts during the past 30 years. Although the overall maternal mortality rate has declined sharply, further improvement may occur with better antenatal care and specific efforts to prevent trauma and pulmonary embolus.

Maternal mortality in the United States has declined by 50% during the last decade. This decline took place at the same time as changes in the availability and use of contraceptive measures, including temporary contraceptives and sterilization. To examine the impact of these changes on mortality we estimated the reproductive mortality rate, which includes pregnancy-related deaths as well as deaths from the side effects of contraceptive methods. The estimated reproductive mortality rate fell by 73% from 1955 to 1975. The decrease was greater for women younger than 35 years. The slower decline for women aged 35 years and older was due to oral-contraception-related deaths. By 1975, pregnancy prevention was responsible for nearly as many deaths as pregnancy itself. The reproductive mortality rate is more appropriate than the maternal mortality rate for evaluating the health risks of reproduction and contraception. We urge that national surveillance of maternal mortality should be expanded to include deaths associated with contraceptive methods. ( JAMA 1982;247:2789-2792)