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Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies
Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies Baha M. Sibai, MD,a Steve N. Caritis, MD,b John C. Hauth, MD,c Cora MacPherson, MS,d J. Peter VanDorsten, MD,e Mark Klebanoff, MD,f Mark Landon, MD,g, h Richard H. Paul, MD,j Paul J. Meis, MD,k Menachem Miodovnik, MD,i Mitchell P. Dombrowski, MD,l Gary R. Thurnau, MD,m Atef H. Moawad, MD,h and James Roberts, MD,b for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Memphis, Tennessee, Pittsburgh, Pennsylvania, Birmingham, Alabama, Washington, D.C., Charleston, South Carolina, Bethesda, Maryland, Chicago, Illinois, Columbus and Cincinnati, Ohio, Los Angeles, California, Winston-Salem, North Carolina, and Detroit, Michigan OBJECTIVE: The purpose of this study was to compare the rates of indicated and spontaneous preterm delivery among women with chronic hypertension or pregestational diabetes mellitus with the rates among healthy women. STUDY DESIGN: This was a secondary analysis of data from healthy women with singleton gestations enrolled in a prospective observational study for prediction of preterm delivery (control group, n = 2738), women with pregestational diabetes mellitus requiring insulin therapy (n = 461), and women with chronic hypertension (n = 761). The two latter groups were enrolled in a randomized multicenter trial for prevention of preeclampsia. The main outcome measures were rates of preterm delivery, either spontaneous (preterm labor or rupture of membranes) or indicated (for maternal or fetal reasons), and neonatal outcomes. RESULTS: The overall rates of preterm delivery were significantly higher among women with diabetes mellitus (38%) and hypertension (33.1%) than among control women (13.9%). Rates were also significantly higher for delivery at <35 weeks’ gestation. Women with diabetes mellitus had significantly higher rates of both indicated preterm delivery (21.9% vs 3.4%; odds ratio, 8.1; 95% confidence interval, 6.0-10.9) and spontaneous preterm delivery (16.1% vs 10.5%; odds ratio, 1.6; 95% confidence interval, 1.2-2.2) than did women in the control group. In addition, they had significantly higher rates of both indicated preterm delivery (odds ratio, 4.8; 95% confidence interval, 3.0-7.5) and spontaneous preterm delivery (odds ratio, 2.1; 95% confidence interval, 1.4-3.0) at <35 weeks’ gestation than did control women. Compared with control women those with chronic hypertension had higher rates of indicated preterm delivery at both <37 weeks’ gestation (21.9% vs 3.4%; odds ratio, 8.1; 95% confidence interval, 6.2-10.6) and at <35 weeks’ gestation (12.1% vs 1.6%; odds ratio, 8.2; 95% confidence interval, 5.7-11.9), but there were no differences in rates of spontaneous preterm delivery. CONCLUSION: The increased rate of preterm delivery among women with chronic hypertension relative to control women was primarily an increase in indicated preterm delivery, whereas the rates of both spontaneous and indicated preterm delivery were increased among women with pregestational diabetes mellitus. (Am J Obstet Gynecol 2000;183:1520-4.)
Key words: Hypertension, indicated preterm delivery, pregestational diabetes mellitus, spontaneous preterm delivery
From the Departments of Obstetrics and Gynecology at the University of Tennessee, Memphis,a the University of Pittsburgh,b the University of Alabama,c the George Washington University Biostatistics Center,d the Medical University of South Carolina,e the National Institute of Child Health and Human Development,f the University of Chicago,g Ohio State University,h the University of Cincinnati College of Medicine,i University of Southern California,j Wake Forest University,k Wayne State University,l and the University of Oklahoma.m The members of the Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development, in addition to the authors, are listed at the end of the text.
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Supported by grants HD 19897, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, and HD36801 from the National Institute of Child Health and Human Development. Received for publication December 28, 1999; revised February 29, 2000; accepted March 20, 2000. Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, 231 Bethesda Ave, Rm 4415, Cincinnati, OH 45267. 6/1/107621 doi:10.1067/mob.2000.107621
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There is general agreement that women with pregnancies complicated by either pregestational diabetes mellitus requiring an insulin regimen or chronic hypertension are at increased risk for preterm delivery.1-10 This increased risk of preterm delivery may be related to either spontaneous (preterm labor or premature rupture of the membranes) or indicated (for maternal or fetal indications) delivery. The literature, however, is imprecise regarding the rates and the causes of preterm delivery among women with such complicated pregnancies.1-10 The Maternal-Fetal Medicine Units Network for the National Institutes of Health recently concluded a randomized trial to evaluate the ability of low-dose aspirin to prevent preeclampsia among high-risk women6 and a prospective observational study for the prediction of preterm delivery among healthy women with singleton gestations.11 These studies provided a large database of pregnant women with pregestational diabetes mellitus treated with insulin, pregnant women with chronic hypertension, and healthy (control) women studied prospectively at 13 centers.6, 11 The purpose of this study was to compare both the rates and the reasons for preterm delivery among women with either pregestational diabetes mellitus treated with insulin or chronic hypertension with the respective rates among healthy women with singleton gestations. Material and methods The study population consisted of women enrolled in protocols that were designed and carried out by members of the Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development.6, 11 The study group included women with singleton pregnancies who had pregestational diabetes mellitus requiring insulin therapy or preexisting chronic hypertension and were enrolled in a multicenter randomized trial to compare low-dose aspirin with placebo for the prevention of preeclampsia.6 Women whose pregnancies were complicated by known fetal congenital anomalies were excluded. The diagnosis of pregestational diabetes mellitus was based on the need for insulin therapy before conception (types 1 and 2). Fifty-five of these women also had chronic hypertension. These women were included in the diabetes mellitus group for analysis. Diagnosis of chronic hypertension was based on a well-documented diagnosis of hypertension before pregnancy or sustained hypertension (either systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg on at least 2 separate occasions ≥4 hours apart at <20 weeks’ gestation or use of antihypertensive medications).10 This group included 461 women with pregestational diabetes mellitus requiring insulin and 761 women with chronic hypertension whose clinical courses were followed up prospectively from random assignment at 13 to 26 weeks’ gestation until delivery. These women were randomly
assigned to receive either low-dose aspirin or a placebo. Prenatal care and management of diabetes mellitus and chronic hypertension then followed the schedule routinely used for such high-risk women at each center. Management of spontaneous preterm labor among these women was not standardized. The control group included women with singleton gestations without pregestational diabetes mellitus treated with insulin and without chronic hypertension who were enrolled in a prospective observational study for the prediction of preterm delivery.11 This group included 2738 women whose clinical courses were followed up prospectively from enrollment at 22 to 24 weeks’ gestation until delivery. The procedure used during follow-up of these women has been described in detail elsewhere.11, 12 The main outcomes analyzed were rates of preterm delivery at both <37 weeks’ gestation and <35 weeks’ gestation and the percentages of preterm deliveries that were spontaneous (preterm labor or preterm rupture of membranes) and indicated (for maternal or fetal reasons). Preterm delivery at <35 weeks’ gestation was chosen as an outcome variable because it was the primary result in the preterm prediction study.11 Other outcomes included gestational age at delivery, birth weight, delivery of a small-for-gestational-age (SGA) neonate, and neonatal outcome. An infant was considered SGA if its weight was below the 10th percentile according to the criteria of Brenner et al.13 Comparisons among groups were performed with the χ2 test or the Wilcoxon rank sum test and logistic regression. Odds ratios are reported with 95% confidence intervals. All statistics were 2-sided. Results Table I compares the baseline clinical characteristics among the 3 study groups. Women with diabetes mellitus were more likely to be white and less likely to be black than were women in the other 2 groups. On the other hand, women with chronic hypertension were more likely to be older, to have a high maternal weight, and to be multiparous. Gestational age at enrollment was significantly higher in the control group. Table II compares the total preterm delivery rates at both <37 weeks’ gestation and <35 weeks’ gestation between the women with pregestational diabetes mellitus treated with insulin and the control group. The rates of delivery at <37 weeks’ gestation and <35 weeks’ gestation were significantly higher among the women with pregestational diabetes mellitus treated with insulin than in the control group. These results remained significant after adjustment for baseline variables by means of logistic regression. In addition, the rates of preterm delivery were not affected by the use of low-dose aspirin. In addition, women with pregestational diabetes mellitus treated with insulin had significantly higher rates of
1522 Sibai et al
December 2000 Am J Obstet Gynecol
Table I. Baseline clinical characteristics among study groups Pregestational Statistical diabetes mellitus (n = 461) Chronic hypertension (n = 761) Control (n = 2738) significance Race (%) White Black Married (%) Multiparous (%) Maternal age (y, mean ± SD) Maternal weight (lb, mean ± SD) Gestational age at enrollment (wk, mean ± SD)
P < .0001 52.5 39.3 46.6 49.7 25.9 ± 6.0 163.3 ± 46.7 17.8 ± 3.8
26.8 60.8 40.9 75.3 29.8 ± 6.3 194.1 ± 58.9 19.5 ± 3.8
35.3 62.8 27.1 56.9 23.5 ± 5.4 147.9 ± 40.0 23.7 ± 5.4
P < .0001 P < .0001 P < .0001 P < .0001 P < .0001
Table II. Rates of indicated and spontaneous preterm delivery in pregestational diabetes mellitus treated with insulin group and control group Pregestational diabetes mellitus treated with insulin (n = 461)
Delivery at <37 wk Indicated Spontaneous Delivery at <35 wk Indicated Spontaneous
Control (n = 2738)
Odds ratio
No.
%
No.
%
Value
95% Confidence interval
175 101 74 75 34 41
38.0 21.9 16.1 16.3 7.4 8.9
380 92 288 167 45 122
13.9 3.4 10.5 6.1 1.6 4.5
2.7 8.1 1.6 2.7 4.8 2.1
2.3-3.2 6.0-10.9 1.2-2.2 2.1-3.4 3.0-7.5 1.4-3.0
Table III. Neonatal outcomes according to reason for preterm delivery among women with pregestational diabetes mellitus treated with insulin Delivery at <37 wk
Gestational age (wk, mean ± SD) Birth weight (g, mean ± SD) SGA (No.) Admission to neonatal intensive care unit (No.) Respiratory distress syndrome (No.) Intraventricular hemorrhage (No.)
Delivery at <35 wk
Indicated
Spontaneous
Indicated
Spontaneous
33.5 ± 4.5* 2575 ± 1037 12/94 (12.8%) 63/91 (69.2%) 24/90 (26.7%) 0/91 (0.0%)
32.1 ± 4.9* 2551 ± 928 3/67 (4.5%) 50/67 (74.6%) 17/66 (25.8%) 3/67 (4.5%)
29.1 ± 5.7 1661 ± 943 4/27 (14.8%)† 25/26 (96.2%) 11/25 (44.0%) 0/26 (0.0%)
29.4 ± 5.2 2080 ± 862 0/34 (0.0%)† 31/34 (91.2%) 13/33 (39.4%) 3/34 (8.8%)
These numbers are different from those in Table II, because this table excludes stillbirths, miscarriages, and missing data. *P = .0013. †P = .034.
both indicated and spontaneous preterm delivery than did control women. This difference remained after exclusion of 7 women who had spontaneous miscarriage (the preterm delivery rate changed only slightly). Most of the indicated preterm deliveries in this group (38%) were for preeclampsia. Table III illustrates neonatal outcomes according to type of preterm delivery among women with pregestational diabetes mellitus treated with insulin. Overall infants in this group had an extremely large frequency of admission to neonatal intensive care units, ranging from 69% to 96%. Among the women who were delivered at <37 weeks’ gestation there was a significantly lower mean gestational age at delivery among those who were delivered spontaneously (P = .0013). In addition, the preva-
lence of SGA infants was significantly higher (P = .034) among those with indicated delivery at <35 weeks’ gestation. No significant difference between the groups was found in the prevalence of respiratory distress syndrome. There was also no difference in the prevalence of intraventricular hemorrhage between indicated and spontaneous preterm deliveries. Table IV compares the rates of preterm delivery between women with chronic hypertension and control women. Women with chronic hypertension had significantly higher rates of total preterm delivery. These differences remained significant after exclusion of 8 cases of miscarriage in the hypertension group. Moreover, these women had a higher rate of indicated preterm delivery than did control women. No difference in the rate of
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Table IV. Rates of indicated and spontaneous preterm delivery in chronic hypertension group relative to control group Chronic hypertension (n = 761)
Delivery at <37 wk Indicated Spontaneous Delivery at <35 wk Indicated Spontaneous
Control (n = 2738)
Odds ratio
No.
%
No.
%
Value
95% Confidence interval
252 167 85 137 92 45
33.1 21.9 11.2 18.0 12.1 5.9
380 92 288 167 45 122
13.9 3.4 10.5 6.1 1.6 4.5
2.4 8.1 1.1 3.0 8.2 1.3
2.1-2.7 6.2-10.6 0.8-1.4 2.4-3.6 5.7-11.9 0.95-1.9
Table V. Neonatal outcomes according to reason for preterm delivery among women with chronic hypertension Delivery at <37 wk
Gestational age (wk, mean ± SD) Birth weight (g, mean ± SD) SGA (No.) Admission to neonatal intensive care unit (No.) Respiratory distress syndrome (No.) Intraventricular hemorrhage (No.)
Delivery at <35 wk
Indicated
Spontaneous
Indicated
Spontaneous
32.2 ± 4.4 1940 ± 941 38/158 (24.0) 88/150 (58.7) 51/149 (34.2) 5/148 (3.4)
31.5 ± 5.5 2017 ± 1037 11/74 (14.9) 34/75 (45.3) 19/72 (26.4) 4/74 (5.4)
29.5 ± 4.2 1341 ± 738 26/83 (31.3)* 66/75 (88.0)† 43/74 (58.1) 5/73 (6.9)
27.9 ± 5.5 1335 ± 833 5/34 (14.7)* 25/35 (71.4)† 15/33 (45.5) 3/34 (8.8)
These numbers are different from those in Table II, because this table excludes stillbirths, miscarriages, and missing data. *P = .064. †P = .055.
spontaneous preterm delivery was found. These differences remained significant after adjustment for baseline variables by means of logistic regression analysis. Moreover, the rates of preterm delivery were not affected by the use of low-dose aspirin. Table V illustrates neonatal outcomes according to the type of preterm delivery among women with chronic hypertension. Neonatal complications were similar between women with indicated and spontaneous delivery, except for a trend toward a higher prevalence of SGA infants (P = .064) and a higher frequency of admission to the neonatal intensive care unit (P = .055) associated with indicated preterm delivery at <35 weeks’ gestation. There was no difference between the indicated and spontaneous preterm delivery groups in the prevalence of intraventricular hemorrhage. Comment In this study we evaluated the rates of and the reasons for preterm delivery in a large population of women with pregestational diabetes mellitus treated with insulin or chronic hypertension and compared them with those in a healthy control woman. The rates of preterm delivery at both <37 weeks’ gestation and <35 weeks’ gestation were significantly higher in the study groups than in the control group. Among women with pregestational diabetes mellitus treated with insulin the rate of preterm delivery at <37 weeks’ gestation was 38%, which is consistent with rates of 24.6% to 31% reported in 3 recent studies involv-
ing similar women.2-4 Among women with chronic hypertension the rate of preterm delivery was 33%, which was also similar to rates reported in two recent cohort studies (24% and 34.4%).7, 8 There are few data describing the reasons for preterm delivery among women with pregestational diabetes mellitus treated with insulin. The rate of indicated preterm delivery in our study was 21.9%, which was almost 7 times higher than the respective rate among the control women (3.4%). This increased rate was primarily related to the high prevalence of early-onset preeclampsia in this population. These findings support the results of Greene et al,3 who reported a high rate of indicated preterm birth (16.5%) among women with pregestational diabetes mellitus treated with insulin and noted that 36% of all preterm births in this group were for preeclampsia. Our report is also the first to document prospectively that the rate of indicated preterm delivery at <35 weeks’ gestation among women with insulin-dependent diabetes mellitus (7.4%) was significantly increased with respect to the rate among control women (1.6%). The rate of spontaneous preterm delivery among women with pregestational diabetes mellitus treated with insulin in this series was 16.1%, which is similar to the rate of 17.7% reported by Mimouni et al2 but higher than the rate of 9.7% reported by Greene et al.3 The mechanisms leading to an increased rate of spontaneous preterm delivery in this population are unknown. Mimouni et al2 reported that this increased rate was significantly
1524 Sibai et al
associated with poor glycemic control from midpregnancy onward and with the presence of urogenital infection. A major limitation of our study is the fact that data on blood glucose concentrations, glycosylated hemoglobin concentrations, and the presence of urogenital infections among the study women were not collected at the 13 centers. Therefore future studies should address the benefits of strict glycemic control and the treatment of urogenital infections in reducing spontaneous preterm delivery rate in this population. Our data are the first to compare neonatal outcomes according to the type of preterm delivery among women with pregestational diabetes mellitus treated with insulin. Interestingly, mean gestational age at delivery was significantly lower among infants born as a result of spontaneous preterm delivery than among those born as a result of indicated delivery. On the other hand, we found that the prevalence of SGA infants was significantly higher among women with indicated delivery at <35 weeks’ gestation. In conclusion, the increased rate of preterm delivery among women with pregestational diabetes mellitus was related to higher rates of both spontaneous and indicated delivery, whereas among women with chronic hypertension the increased rates of preterm delivery were primarily related to indicated delivery. In addition, among women with either pregestational diabetes mellitus treated with insulin or chronic hypertension the prevalences of SGA infants were higher among those with indicated delivery at <35 weeks’ gestation than among those with spontaneous delivery at <35 weeks’ gestation. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network was established by the Institute in 1986. In addition to the authors, the participants in the Network were as follows: J. Harger, M. Cotroneo, and T. Kamon, Magee-Women’s Hospital, Pittsburgh; B. Mercer and R. Ramsey, University of Tennessee, Memphis; Y. Rabello, D. McCart, and E. Mueller, University of Southern California, Los Angeles; R. Goldenberg and R. Copper, University of Alabama, Birmingham; G. Norman and A. Millinder, Wayne State University, Detroit; J. Christmas, S. McCoy, and S. Elder, Medical College of Virginia, Richmond; N. Elder, B. Carter, and V. Schneider, University of Cincinnati; A. Meier and V. Minton, University of Oklahoma, Oklahoma City; M. Swain and J.M. Ernest, Wake Forest University, Winston-Salem, NC; P. Jones, University of Chicago; J. Iams, S. Meadows, and S. Brenner, Ohio State University, Columbus; B. Collins, R. Newman, and S.
December 2000 Am J Obstet Gynecol
Carter, Medical University of South Carolina, Charleston; R. Romero and V. Sabo, Yale University School of Medicine, New Haven, Conn; S. Godfrey, M. Rosen, and R. Chao, Columbia University, New York; F. Witter and L. Rocco, Johns Hopkins University, Baltimore; R. Depp and S. Tannenbaum, Thomas Jefferson University, Philadelphia; R. Bain, E. Thom, D. Johnson, and M. Fischer, the George Washington University Biostatistics Center, Washington, D.C.; and D. McNellis, C. Catz, and S. Yaffe, the National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, Md. REFERENCES
1. Roversi GD, Pedretti E, Gargiulo M, Tronconi G. Spontaneous preterm delivery in pregnant diabetics: a high risk hitherto “unrecognized”. J Perinat Med 1982;10:249-53. 2. Mimouni F, Miodovnik M, Siddiqi TA, Berk MA, Wittekind C, Tsang RC. High spontaneous premature labor rate in insulindependent diabetic pregnant women: an association with poor glycemic control and urogenital infection. Obstet Gynecol 1988; 72:175-80. 3. Greene MF, Hare JW, Krache M, Phillipe M, Barss VA, Saltzman DH, et al. Prematurity among insulin-requiring diabetic gravid women. Am J Obstet Gynecol 1989;161:106-11. 4. Hanson U, Persson B. Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol 1993;10:330-3. 5. Reece EA, Coustan DR, Hayslett JP, Holford T, Coulehan J, O’Connor TZ, et al. Diabetic nephropathy: pregnancy performance and fetomaternal outcome. Am J Obstet Gynecol 1988;159:56-66. 6. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-5. 7. Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994;171:410-6. 8. McCowan LM, Buist RG, North RA, Gamble G. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996;103: 123-9. 9. Samadi AR, Mayberry RM. Maternal hypertension and spontaneous preterm births among black women. Obstet Gynecol 1998;91:899-904. 10. Sibai BM, Lindheimer M, Hauth J, Caritis S, VanDorsten P, Klebanoff M, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;339:667-71. 11. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 1996;87:643-8. 12. Meis PJ, Goldenberg RL, Mercer BM, Iams JD, Moawad AH, Miodovnik M, et al. The preterm prediction study: risk factors for indicated preterm births. Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development. Am J Obstet Gynecol 1998;178:562-7. 13. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126:555-64.
Key words: Hypertension, indicated preterm delivery, pregestational diabetes mellitus, spontaneous preterm delivery
From the Departments of Obstetrics and Gynecology at the University of Tennessee, Memphis,a the University of Pittsburgh,b the University of Alabama,c the George Washington University Biostatistics Center,d the Medical University of South Carolina,e the National Institute of Child Health and Human Development,f the University of Chicago,g Ohio State University,h the University of Cincinnati College of Medicine,i University of Southern California,j Wake Forest University,k Wayne State University,l and the University of Oklahoma.m The members of the Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development, in addition to the authors, are listed at the end of the text.
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Supported by grants HD 19897, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, and HD36801 from the National Institute of Child Health and Human Development. Received for publication December 28, 1999; revised February 29, 2000; accepted March 20, 2000. Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, 231 Bethesda Ave, Rm 4415, Cincinnati, OH 45267. 6/1/107621 doi:10.1067/mob.2000.107621
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There is general agreement that women with pregnancies complicated by either pregestational diabetes mellitus requiring an insulin regimen or chronic hypertension are at increased risk for preterm delivery.1-10 This increased risk of preterm delivery may be related to either spontaneous (preterm labor or premature rupture of the membranes) or indicated (for maternal or fetal indications) delivery. The literature, however, is imprecise regarding the rates and the causes of preterm delivery among women with such complicated pregnancies.1-10 The Maternal-Fetal Medicine Units Network for the National Institutes of Health recently concluded a randomized trial to evaluate the ability of low-dose aspirin to prevent preeclampsia among high-risk women6 and a prospective observational study for the prediction of preterm delivery among healthy women with singleton gestations.11 These studies provided a large database of pregnant women with pregestational diabetes mellitus treated with insulin, pregnant women with chronic hypertension, and healthy (control) women studied prospectively at 13 centers.6, 11 The purpose of this study was to compare both the rates and the reasons for preterm delivery among women with either pregestational diabetes mellitus treated with insulin or chronic hypertension with the respective rates among healthy women with singleton gestations. Material and methods The study population consisted of women enrolled in protocols that were designed and carried out by members of the Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development.6, 11 The study group included women with singleton pregnancies who had pregestational diabetes mellitus requiring insulin therapy or preexisting chronic hypertension and were enrolled in a multicenter randomized trial to compare low-dose aspirin with placebo for the prevention of preeclampsia.6 Women whose pregnancies were complicated by known fetal congenital anomalies were excluded. The diagnosis of pregestational diabetes mellitus was based on the need for insulin therapy before conception (types 1 and 2). Fifty-five of these women also had chronic hypertension. These women were included in the diabetes mellitus group for analysis. Diagnosis of chronic hypertension was based on a well-documented diagnosis of hypertension before pregnancy or sustained hypertension (either systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg on at least 2 separate occasions ≥4 hours apart at <20 weeks’ gestation or use of antihypertensive medications).10 This group included 461 women with pregestational diabetes mellitus requiring insulin and 761 women with chronic hypertension whose clinical courses were followed up prospectively from random assignment at 13 to 26 weeks’ gestation until delivery. These women were randomly
assigned to receive either low-dose aspirin or a placebo. Prenatal care and management of diabetes mellitus and chronic hypertension then followed the schedule routinely used for such high-risk women at each center. Management of spontaneous preterm labor among these women was not standardized. The control group included women with singleton gestations without pregestational diabetes mellitus treated with insulin and without chronic hypertension who were enrolled in a prospective observational study for the prediction of preterm delivery.11 This group included 2738 women whose clinical courses were followed up prospectively from enrollment at 22 to 24 weeks’ gestation until delivery. The procedure used during follow-up of these women has been described in detail elsewhere.11, 12 The main outcomes analyzed were rates of preterm delivery at both <37 weeks’ gestation and <35 weeks’ gestation and the percentages of preterm deliveries that were spontaneous (preterm labor or preterm rupture of membranes) and indicated (for maternal or fetal reasons). Preterm delivery at <35 weeks’ gestation was chosen as an outcome variable because it was the primary result in the preterm prediction study.11 Other outcomes included gestational age at delivery, birth weight, delivery of a small-for-gestational-age (SGA) neonate, and neonatal outcome. An infant was considered SGA if its weight was below the 10th percentile according to the criteria of Brenner et al.13 Comparisons among groups were performed with the χ2 test or the Wilcoxon rank sum test and logistic regression. Odds ratios are reported with 95% confidence intervals. All statistics were 2-sided. Results Table I compares the baseline clinical characteristics among the 3 study groups. Women with diabetes mellitus were more likely to be white and less likely to be black than were women in the other 2 groups. On the other hand, women with chronic hypertension were more likely to be older, to have a high maternal weight, and to be multiparous. Gestational age at enrollment was significantly higher in the control group. Table II compares the total preterm delivery rates at both <37 weeks’ gestation and <35 weeks’ gestation between the women with pregestational diabetes mellitus treated with insulin and the control group. The rates of delivery at <37 weeks’ gestation and <35 weeks’ gestation were significantly higher among the women with pregestational diabetes mellitus treated with insulin than in the control group. These results remained significant after adjustment for baseline variables by means of logistic regression. In addition, the rates of preterm delivery were not affected by the use of low-dose aspirin. In addition, women with pregestational diabetes mellitus treated with insulin had significantly higher rates of
1522 Sibai et al
December 2000 Am J Obstet Gynecol
Table I. Baseline clinical characteristics among study groups Pregestational Statistical diabetes mellitus (n = 461) Chronic hypertension (n = 761) Control (n = 2738) significance Race (%) White Black Married (%) Multiparous (%) Maternal age (y, mean ± SD) Maternal weight (lb, mean ± SD) Gestational age at enrollment (wk, mean ± SD)
P < .0001 52.5 39.3 46.6 49.7 25.9 ± 6.0 163.3 ± 46.7 17.8 ± 3.8
26.8 60.8 40.9 75.3 29.8 ± 6.3 194.1 ± 58.9 19.5 ± 3.8
35.3 62.8 27.1 56.9 23.5 ± 5.4 147.9 ± 40.0 23.7 ± 5.4
P < .0001 P < .0001 P < .0001 P < .0001 P < .0001
Table II. Rates of indicated and spontaneous preterm delivery in pregestational diabetes mellitus treated with insulin group and control group Pregestational diabetes mellitus treated with insulin (n = 461)
Delivery at <37 wk Indicated Spontaneous Delivery at <35 wk Indicated Spontaneous
Control (n = 2738)
Odds ratio
No.
%
No.
%
Value
95% Confidence interval
175 101 74 75 34 41
38.0 21.9 16.1 16.3 7.4 8.9
380 92 288 167 45 122
13.9 3.4 10.5 6.1 1.6 4.5
2.7 8.1 1.6 2.7 4.8 2.1
2.3-3.2 6.0-10.9 1.2-2.2 2.1-3.4 3.0-7.5 1.4-3.0
Table III. Neonatal outcomes according to reason for preterm delivery among women with pregestational diabetes mellitus treated with insulin Delivery at <37 wk
Gestational age (wk, mean ± SD) Birth weight (g, mean ± SD) SGA (No.) Admission to neonatal intensive care unit (No.) Respiratory distress syndrome (No.) Intraventricular hemorrhage (No.)
Delivery at <35 wk
Indicated
Spontaneous
Indicated
Spontaneous
33.5 ± 4.5* 2575 ± 1037 12/94 (12.8%) 63/91 (69.2%) 24/90 (26.7%) 0/91 (0.0%)
32.1 ± 4.9* 2551 ± 928 3/67 (4.5%) 50/67 (74.6%) 17/66 (25.8%) 3/67 (4.5%)
29.1 ± 5.7 1661 ± 943 4/27 (14.8%)† 25/26 (96.2%) 11/25 (44.0%) 0/26 (0.0%)
29.4 ± 5.2 2080 ± 862 0/34 (0.0%)† 31/34 (91.2%) 13/33 (39.4%) 3/34 (8.8%)
These numbers are different from those in Table II, because this table excludes stillbirths, miscarriages, and missing data. *P = .0013. †P = .034.
both indicated and spontaneous preterm delivery than did control women. This difference remained after exclusion of 7 women who had spontaneous miscarriage (the preterm delivery rate changed only slightly). Most of the indicated preterm deliveries in this group (38%) were for preeclampsia. Table III illustrates neonatal outcomes according to type of preterm delivery among women with pregestational diabetes mellitus treated with insulin. Overall infants in this group had an extremely large frequency of admission to neonatal intensive care units, ranging from 69% to 96%. Among the women who were delivered at <37 weeks’ gestation there was a significantly lower mean gestational age at delivery among those who were delivered spontaneously (P = .0013). In addition, the preva-
lence of SGA infants was significantly higher (P = .034) among those with indicated delivery at <35 weeks’ gestation. No significant difference between the groups was found in the prevalence of respiratory distress syndrome. There was also no difference in the prevalence of intraventricular hemorrhage between indicated and spontaneous preterm deliveries. Table IV compares the rates of preterm delivery between women with chronic hypertension and control women. Women with chronic hypertension had significantly higher rates of total preterm delivery. These differences remained significant after exclusion of 8 cases of miscarriage in the hypertension group. Moreover, these women had a higher rate of indicated preterm delivery than did control women. No difference in the rate of
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Volume 183, Number 6 Am J Obstet Gynecol
Table IV. Rates of indicated and spontaneous preterm delivery in chronic hypertension group relative to control group Chronic hypertension (n = 761)
Delivery at <37 wk Indicated Spontaneous Delivery at <35 wk Indicated Spontaneous
Control (n = 2738)
Odds ratio
No.
%
No.
%
Value
95% Confidence interval
252 167 85 137 92 45
33.1 21.9 11.2 18.0 12.1 5.9
380 92 288 167 45 122
13.9 3.4 10.5 6.1 1.6 4.5
2.4 8.1 1.1 3.0 8.2 1.3
2.1-2.7 6.2-10.6 0.8-1.4 2.4-3.6 5.7-11.9 0.95-1.9
Table V. Neonatal outcomes according to reason for preterm delivery among women with chronic hypertension Delivery at <37 wk
Gestational age (wk, mean ± SD) Birth weight (g, mean ± SD) SGA (No.) Admission to neonatal intensive care unit (No.) Respiratory distress syndrome (No.) Intraventricular hemorrhage (No.)
Delivery at <35 wk
Indicated
Spontaneous
Indicated
Spontaneous
32.2 ± 4.4 1940 ± 941 38/158 (24.0) 88/150 (58.7) 51/149 (34.2) 5/148 (3.4)
31.5 ± 5.5 2017 ± 1037 11/74 (14.9) 34/75 (45.3) 19/72 (26.4) 4/74 (5.4)
29.5 ± 4.2 1341 ± 738 26/83 (31.3)* 66/75 (88.0)† 43/74 (58.1) 5/73 (6.9)
27.9 ± 5.5 1335 ± 833 5/34 (14.7)* 25/35 (71.4)† 15/33 (45.5) 3/34 (8.8)
These numbers are different from those in Table II, because this table excludes stillbirths, miscarriages, and missing data. *P = .064. †P = .055.
spontaneous preterm delivery was found. These differences remained significant after adjustment for baseline variables by means of logistic regression analysis. Moreover, the rates of preterm delivery were not affected by the use of low-dose aspirin. Table V illustrates neonatal outcomes according to the type of preterm delivery among women with chronic hypertension. Neonatal complications were similar between women with indicated and spontaneous delivery, except for a trend toward a higher prevalence of SGA infants (P = .064) and a higher frequency of admission to the neonatal intensive care unit (P = .055) associated with indicated preterm delivery at <35 weeks’ gestation. There was no difference between the indicated and spontaneous preterm delivery groups in the prevalence of intraventricular hemorrhage. Comment In this study we evaluated the rates of and the reasons for preterm delivery in a large population of women with pregestational diabetes mellitus treated with insulin or chronic hypertension and compared them with those in a healthy control woman. The rates of preterm delivery at both <37 weeks’ gestation and <35 weeks’ gestation were significantly higher in the study groups than in the control group. Among women with pregestational diabetes mellitus treated with insulin the rate of preterm delivery at <37 weeks’ gestation was 38%, which is consistent with rates of 24.6% to 31% reported in 3 recent studies involv-
ing similar women.2-4 Among women with chronic hypertension the rate of preterm delivery was 33%, which was also similar to rates reported in two recent cohort studies (24% and 34.4%).7, 8 There are few data describing the reasons for preterm delivery among women with pregestational diabetes mellitus treated with insulin. The rate of indicated preterm delivery in our study was 21.9%, which was almost 7 times higher than the respective rate among the control women (3.4%). This increased rate was primarily related to the high prevalence of early-onset preeclampsia in this population. These findings support the results of Greene et al,3 who reported a high rate of indicated preterm birth (16.5%) among women with pregestational diabetes mellitus treated with insulin and noted that 36% of all preterm births in this group were for preeclampsia. Our report is also the first to document prospectively that the rate of indicated preterm delivery at <35 weeks’ gestation among women with insulin-dependent diabetes mellitus (7.4%) was significantly increased with respect to the rate among control women (1.6%). The rate of spontaneous preterm delivery among women with pregestational diabetes mellitus treated with insulin in this series was 16.1%, which is similar to the rate of 17.7% reported by Mimouni et al2 but higher than the rate of 9.7% reported by Greene et al.3 The mechanisms leading to an increased rate of spontaneous preterm delivery in this population are unknown. Mimouni et al2 reported that this increased rate was significantly
1524 Sibai et al
associated with poor glycemic control from midpregnancy onward and with the presence of urogenital infection. A major limitation of our study is the fact that data on blood glucose concentrations, glycosylated hemoglobin concentrations, and the presence of urogenital infections among the study women were not collected at the 13 centers. Therefore future studies should address the benefits of strict glycemic control and the treatment of urogenital infections in reducing spontaneous preterm delivery rate in this population. Our data are the first to compare neonatal outcomes according to the type of preterm delivery among women with pregestational diabetes mellitus treated with insulin. Interestingly, mean gestational age at delivery was significantly lower among infants born as a result of spontaneous preterm delivery than among those born as a result of indicated delivery. On the other hand, we found that the prevalence of SGA infants was significantly higher among women with indicated delivery at <35 weeks’ gestation. In conclusion, the increased rate of preterm delivery among women with pregestational diabetes mellitus was related to higher rates of both spontaneous and indicated delivery, whereas among women with chronic hypertension the increased rates of preterm delivery were primarily related to indicated delivery. In addition, among women with either pregestational diabetes mellitus treated with insulin or chronic hypertension the prevalences of SGA infants were higher among those with indicated delivery at <35 weeks’ gestation than among those with spontaneous delivery at <35 weeks’ gestation. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network was established by the Institute in 1986. In addition to the authors, the participants in the Network were as follows: J. Harger, M. Cotroneo, and T. Kamon, Magee-Women’s Hospital, Pittsburgh; B. Mercer and R. Ramsey, University of Tennessee, Memphis; Y. Rabello, D. McCart, and E. Mueller, University of Southern California, Los Angeles; R. Goldenberg and R. Copper, University of Alabama, Birmingham; G. Norman and A. Millinder, Wayne State University, Detroit; J. Christmas, S. McCoy, and S. Elder, Medical College of Virginia, Richmond; N. Elder, B. Carter, and V. Schneider, University of Cincinnati; A. Meier and V. Minton, University of Oklahoma, Oklahoma City; M. Swain and J.M. Ernest, Wake Forest University, Winston-Salem, NC; P. Jones, University of Chicago; J. Iams, S. Meadows, and S. Brenner, Ohio State University, Columbus; B. Collins, R. Newman, and S.
December 2000 Am J Obstet Gynecol
Carter, Medical University of South Carolina, Charleston; R. Romero and V. Sabo, Yale University School of Medicine, New Haven, Conn; S. Godfrey, M. Rosen, and R. Chao, Columbia University, New York; F. Witter and L. Rocco, Johns Hopkins University, Baltimore; R. Depp and S. Tannenbaum, Thomas Jefferson University, Philadelphia; R. Bain, E. Thom, D. Johnson, and M. Fischer, the George Washington University Biostatistics Center, Washington, D.C.; and D. McNellis, C. Catz, and S. Yaffe, the National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, Md. REFERENCES
1. Roversi GD, Pedretti E, Gargiulo M, Tronconi G. Spontaneous preterm delivery in pregnant diabetics: a high risk hitherto “unrecognized”. J Perinat Med 1982;10:249-53. 2. Mimouni F, Miodovnik M, Siddiqi TA, Berk MA, Wittekind C, Tsang RC. High spontaneous premature labor rate in insulindependent diabetic pregnant women: an association with poor glycemic control and urogenital infection. Obstet Gynecol 1988; 72:175-80. 3. Greene MF, Hare JW, Krache M, Phillipe M, Barss VA, Saltzman DH, et al. Prematurity among insulin-requiring diabetic gravid women. Am J Obstet Gynecol 1989;161:106-11. 4. Hanson U, Persson B. Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol 1993;10:330-3. 5. Reece EA, Coustan DR, Hayslett JP, Holford T, Coulehan J, O’Connor TZ, et al. Diabetic nephropathy: pregnancy performance and fetomaternal outcome. Am J Obstet Gynecol 1988;159:56-66. 6. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-5. 7. Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994;171:410-6. 8. McCowan LM, Buist RG, North RA, Gamble G. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996;103: 123-9. 9. Samadi AR, Mayberry RM. Maternal hypertension and spontaneous preterm births among black women. Obstet Gynecol 1998;91:899-904. 10. Sibai BM, Lindheimer M, Hauth J, Caritis S, VanDorsten P, Klebanoff M, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;339:667-71. 11. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 1996;87:643-8. 12. Meis PJ, Goldenberg RL, Mercer BM, Iams JD, Moawad AH, Miodovnik M, et al. The preterm prediction study: risk factors for indicated preterm births. Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development. Am J Obstet Gynecol 1998;178:562-7. 13. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126:555-64.