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PART 1: Advising your patients Uterine fibroids: Childbearing, cancer, and hormone effects
The author reports no financial relationships relevant to this article.
CASE 1 Rapid growth=cancer?
Mrs. G., 47 years old, has had uterine fibroids the size of a 12-week pregnancy for about 6 years. At today’s examination, however, her uterus feels about the size of a 16-week pregnancy.
She is aware that her abdomen is bigger, and she complains of some abdominal pressure and urinary frequency. She reports no abnormal bleeding and no abdominal pain.
Mrs. G. is upset because another physician told her she might have cancer and needs a hysterectomy immediately. She tells you that she does not want a hysterectomy unless “it’s absolutely necessary.”
Ultrasonography at this visit reveals that two of the three fibroids noted on a previous sonogram have grown—one from 6 cm to 9 cm in diameter; the other from 5 cm to 8 cm.
What do you tell Mrs. G.?
Understanding myomas
Uterine fibroids, also called myomas, are benign, monoclonal tumors of the myometrium that contain collagen, fibronectin, and proteoglycan. The collagen fibrils are abnormally formed and in disarray; they look like the collagen found in keloids.1 Although the precise causes of fibroids are unknown, hormonal, genetic, and growth factors appear to be involved in their development and growth.2,3
About 40% of fibroids are chromosomally abnormal; the remaining 60% may have undetected mutations. More than 100 genes have been found to be up-regulated or down-regulated in fibroid cells. Many of these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis.
- A myoma is benign tumor of the myometrium
- In a premenopausal woman, rapid uterine growth almost never indicates the presence of uterine sarcoma
- In an older woman who experiences uterine growth, abdominal pain, and irregular vaginal bleeding, pelvic malignancy may be suspected; an increased level of LDH isoenzyme 3 with increased gadolinium uptake on MRI within 40 to 60 seconds suggests a diagnosis of leiomyosarcoma
- Most fibroids have no impact on fertility, but submucosal fibroids that distort the uterine cavity decrease fertility; removing them increases fertility
- Location, size, number, and extent of myoma penetration into the myometrium can be evaluated by pelvic MRI, with coronal, axial, and sagittal images without gadolinium contrast
- Given the risks associated with surgery and the lack of proof of efficacy, myomectomy to improve fertility should be undertaken with caution
- Most myomas do not grow during pregnancy. Unfavorable pregnancy outcomes are very rare in women with myomas.
- Oral contraceptives and postmenopausal hormone therapy almost never influence fibroid growth. Women with fibroids can usually use these therapies safely.
Differentiating benign myoma from uterine sarcoma
Myomas have chromosomal rearrangements similar to other benign lesions, whereas leiomyosarcomas are undifferentiated and have complex chromosomal rearrangements not seen in myomas.4 Genetic differences between myomas and leiomyosarcomas indicate they most likely have distinct origins, and that leiomyosarcomas do not result from malignant degeneration of myomas.2
In premenopausal women, rapid uterine growth almost never indicates uterine sarcoma: One study found only one sarcoma among 371 (0.26%) women operated on for rapid growth of a presumed myoma, and no sarcomas were found in the 198 women who had a 6-week-pregnancy-equivalent increase in uterine size over 1 year.5
Clinical indications. The clinical signs that would lead to suspicion of pelvic malignancy are:
- older age
- abdominal pain
- irregular vaginal bleeding.6
The average age of 2,098 women with uterine sarcoma reported in the SEER (Surveillance Epidemiology and End Results) cancer database from 1989 to 1999 was 63 years, whereas a review of the literature found a mean age of 36 years in women subjected to myomectomy who did not have sarcoma.3,7
Diagnostic tests. The distinction between benign myoma and leiomyosarcoma need not be based on clinical signs alone. Preoperative diagnosis of leiomyosarcoma may be possible, using laboratory values of total serum lactate dehydrogenase (LDH) and LDH isoenzyme 3 plus gadolinium-enhanced magnetic resonance imaging (MRI) scan (Gd-DTPA), with initial images taken 40 to 60 seconds after injection of gadolinium. A study of 87 women with fibroids, 10 women with leiomyosarcoma, and 130 women with degenerating fibroids reported 100% specificity, 100% positive predictive value, 100% negative predictive value, and 100% diagnostic accuracy for leiomyosarcoma with this combination diagnostic procedure.8
CASE 1 RESOLVED What advice for Mrs. G.?
You order a gadolinium-enhanced, dynamic MRI scan and have blood drawn for total LDH and LDH isoenzymes. Total LDH and isoenzyme 3 are normal. MRI shows no increased enhancement of the fibroids on images taken 40 to 60 seconds after injection of gadolinium. You advise the patient that there is no evidence of cancer (sarcoma) and no urgent need for hysterectomy. You also tell her that, because she is symptomatic, myomectomy is an option that will preserve her uterus.
CASE 2 Fibroids, and contemplating childbearing
Mrs. H., a 35-year-old nulligravida, comes to the office for her first visit with you. She has no complaints, but your pelvic examination reveals a 10 week-size enlarged uterus. A sonogram shows a 6-cm subserosal fibroid and a 3-cm intramural fibroid near the endometrial cavity (see FIGURE). This patient was recently married and wants to become pregnant within the coming year.
When you tell Mrs. H. that she has fibroids, she grows concerned. She asks: “Will this affect my fertility, or a pregnancy?” and “Do I need surgery?”
You explain that the larger, subserosal fibroid is not a concern. The smaller, intramural fibroid could, however, have an impact on fertility and pregnancy if it distorts the uterine cavity.
To find out if that is the case, you order a saline infusion sonogram, which demonstrates, clearly, a normal cavity without distortion by the fibroid.
What is your advice to this woman?
Submucous fibroids that distort the uterine cavity decrease fertility; removal increases fertility. Otherwise, neither intramural nor subserosal fibroids appear to affect the fertility rate; removal has not been shown to increase fertility. Meta-analysis of 11 studies found that submucous myomas that distort the uterine cavity appear to decrease the pregnancy rate by 70% (relative risk [RR], 0.32; confidence interval [CI], 0.13–0.70).9
Assessing the uterine cavity. Evaluating a woman with fibroids for fertility requires reliable assessment of the uterine cavity. Hysteroscopy and saline infusion sonography have been shown to be far superior to transvaginal sonography or hysterosalpingography for detecting submucosal fibroids.10
The best modality for determining the extent of submucosal penetration of a myoma into the myometrium is MRI. It is also an excellent modality for evaluating the size, position, and number of multiple fibroids.11 The drawback to using MRI? It is more costly than other modalities.
Note: Classification of submucosal fibroids is based on the fraction of the mass within the cavity:
- Class 0 myomas are entirely intracavitary
- Class I myomas have 50% or more of the fibroid within the cavity
- Class II myomas have less than 50% within the cavity.12
Resection and fertility. Submucous fibroids can often be removed hysteroscopically. Systematic review of the evidence found that resection-restored fertility is equal to that of infertile controls undergoing in vitro fertilization who do not have fibroids (RR, 1.72; CI, 1.13–2.58).9 In that review, the presence of neither intramural nor subserosal fibroids decreased fertility (intramural: RR, 0.94, and CI, 0.73–1.20; subserosal: RR, 1.1, and CI, 0.06–1.72). Furthermore, removal of intramural and subserosal myomas by abdominal or laparoscopic myomectomy did not improve fertility. An updated unpublished meta-analysis, including studies published after 2001, came to the same conclusion (Pritts E, personal communication, 2008).
CASE 2: Subserosal, intramural myomas cause concern
In a woman contemplating childbearing, does a subserosal (left) or intramural (right) myoma present a problem because of potential to distort the uterine cavity?
Fibroids and pregnancy
The incidence of sonographically detected fibroids during pregnancy is low.13 Among 12,600 women at a prenatal clinic, routine second-trimester sonography identified myomas in 183 (mean age, 33 years)—an incidence of 1.5%.
Pregnancy has a variable and unpredictable effect on myoma growth, likely dependent on individual differences in genetics, circulating growth factors, and myoma-localized receptors. Most myomas do not, however, grow during pregnancy. A prospective study of pregnant women who had a single myoma found that 69% had no increase in volume throughout their pregnancy. In women who were noted to have an increase in the volume of their myoma, the greatest growth occurred before 10 weeks’ gestation. No relationship was found between initial myoma volume and myoma growth during the gestational period. 14
Do myomas complicate pregnancy?
Very rarely. Two studies reported on outcomes in large populations of pregnant women who were examined with routine second-trimester ultrasonography, with follow-up and delivery at the same institution.
In one of those studies, 12,600 pregnant women were evaluated, and the outcome in 167 women who were given a diagnosis of myoma was compared with the outcome in women who did not have a myoma.15 Despite similar clinical management between the two groups, no significant differences were seen in regard to the incidence of:
- preterm delivery
- premature rupture of membranes
- fetal growth restriction
- placenta previa
- placental abruption
- postpartum hemorrhage
- retained placenta.
Only cesarean section was more common among women with fibroids (23% vs 12%).
The second study reviewed 15,104 pregnancies and compared 401 women found to have myomas and the remaining women who did not.16 Although the presence of myoma did not increase the risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis, or endomyometritis, there was some increased risk of pre-term delivery (19.2% vs 12.7%), placenta previa (3.5% vs 1.8%), and post-partum hemorrhage (8.3% vs 2.9%). Cesarean section was, again, more common (49.1% vs 21.4%).
Do myomas injure the fetus?
Fetal injury as a consequence of fibroids has been reported very infrequently. A review of the literature from 1980 to 2005 revealed only four cases—one each of:
- fetal head anomalies with fetal growth restriction
- postural deformity
- limb reduction
- fetal head deformation with torticollis.17-19
CASE 2 RESOLVED Should Mrs. H. have a myomectomy?
Probably not. Abdominal and laparoscopic myomectomy involve substantial operative and anesthetic risks, including infection, postoperative adhesions, a very small risk of uterine rupture during pregnancy, and increased likelihood of cesarean section. Costs are also substantial, involving not only the expense of surgery, but also patient discomfort and time for recovery. Therefore, until it is proved that intramural myomas decrease fertility and myomectomy increases fertility, surgery should be undertaken with caution. As far as the effects of myoma on pregnancy are concerned, no data are available by which to compare pregnancy outcomes following myomectomy with pregnancy outcomes in women whose myomas are untreated. Randomized studies are needed to clarify these important issues.
CASES 3 & 4 The effects of oral contraceptives and hormone replacement therapy
Mrs. J. is a 32-year-old G0P0 woman who has a 5-cm fundal myoma. She is sexually active and wants to use an oral contraceptive (OC). She has heard from friends, however, that taking an OC makes fibroids grow, and she asks for your advice.
The same day, you see Mrs. K., a 54-year-old, recently menopausal woman. She complains of severe hot flashes and night sweats that disturb her sleep. She has had asymptomatic uterine fibroids for about 10 years and, although she would like to take menopausal hormone therapy, she is worried that the medication will make the fibroids larger.
How do you advise these two women?
OCs. OCs do not appear to influence the growth of fibroids. One study found a slightly increased risk of fibroids, another study found no increased risk, and a third found a decreased risk.18,19 These studies are retrospective, however, and may be marked by selection bias.
Postmenopausal hormone replacement therapy. Postmenopausal hormone therapy does not ordinarily cause fibroid growth. After 3 years, only three of 34 (8%) post-menopausal women who had fibroids and were treated with 0.625 mg of conjugated equine estrogen (CEE) and 5 mg of medroxyprogesterone acetate (MPA) a day had any increase in the size of fibroids.20 If any increase in the size of the uterus is noted, it is likely related to progestins.
A study found that 23% of women taking oral estrogen plus 2.5 mg of MPA a day for 1 year had a slight increase in the size of fibroids, whereas 50% of women taking 5 mg of MPA had an increase in size (mean increase in diameter, 3.2 cm).21 Transdermal estrogen plus oral MPA was shown, after 1 year, to cause, on average, a 0.5-cm increase in the diameter of fibroids; oral estrogen and MPA caused no increase in size.22
CASES RESOLVED Rx: Reassurance
Advise Mrs. J. that taking an OC is unlikely to make her fibroids grow larger.
Mrs. K., who is older, can seek relief from postmenopausal symptoms by taking hormone therapy without fear of her fibroids being stimulated to grow.
1. Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab. 1994;79:900-906.
2. Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111:1037-1054.
3. Parker W. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87:725-736.
4. Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004;40:97-108.
5. Parker WH, Fu YS, Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol. 1994;83:414-418.
6. Boutselis JG, Ullery JC. Sarcoma of the uterus. Obstet Gynecol. 1962;20:23-35.
7. Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol. 2004;93:204-208.
8. Goto A, Takeuchi S, Sugimura K, Maruo T. Usefulness of Gd-DTPA contrast-enhanced dynamic MRI and serum determination of LDH and its isozymes in the differential diagnosis of leiomyosarcoma from degenerated leiomyoma of the uterus. Int J Gynecol Cancer. 2002;12:354-361.
9. Pritts EA. Fibroids and infertility: a systematic review of the evidence. Obstet Gynecol Surv. 2001;56:483-491.
10. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Evaluation of the uterine cavity with magnetic resonance imaging, transvaginal sonography, hysterosonographic examination, and diagnostic hysteroscopy. Fertil Steril. 2001;76:350-357.
11. Dueholm M, Lundorf E, Olesen F. Imaging techniques for evaluation of the uterine cavity and endometrium in premenopausal patients before minimally invasive surgery. Obstet Gynecol Surv. 2002;57:388-403.
12. Cohen LS, Valle RF. Role of vaginal sonography and hysterosonography in the endoscopic treatment of uterine myomas. Fertil Steril. 2000;73:197-204.
13. Cooper NP, Okolo S. Fibroids in pregnancy—common but poorly understood. Obstet Gynecol Surv. 2005;60:132-138.
14. Rosati P, Exacoustos C, Mancuso S. Longitudinal evaluation of uterine myoma growth during pregnancy. A sonographic study. J Ultrasound Med. 1992;11:511-515.
15. Vergani P, Ghidini A, Strobelt N, et al. Do uterine leiomyomas influence pregnancy outcome? Am J Perinatol. 1994;11:356-358.
16. Qidwai GI, Caughey AB, Jacoby AF. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol. 2006;107:376-382.
17. Joo JG, Inovay J, Silhavy M, Papp Z. Successful enucleation of a necrotizing fibroid causing oligohydramnios and fetal postural deformity in the 25th week of gestation. A case report. J Reprod Med. 2001;46:923-925.
18. Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (Clin Res Ed). 1986;293:359-362.
19. Ratner H. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (Clin Res Ed). 1986;293:1027.-
20. Yang CH, Lee JN, Hsu SC, Kuo CH, Tsai EM. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women—a 3-year study. Maturitas. 2002;43:35-39.
21. Palomba S, Sena T, Morelli M, Noia R, Zullo F, Mastrantonio P. Effect of different doses of progestin on uterine leiomyomas in postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2002;102:199-201.
22. Sener AB, Seçkin NC, Ozmen S, Gökmen O, Dogu N, Ekici E. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril. 1996;65:354-357.
The author reports no financial relationships relevant to this article.
CASE 1 Rapid growth=cancer?
Mrs. G., 47 years old, has had uterine fibroids the size of a 12-week pregnancy for about 6 years. At today’s examination, however, her uterus feels about the size of a 16-week pregnancy.
She is aware that her abdomen is bigger, and she complains of some abdominal pressure and urinary frequency. She reports no abnormal bleeding and no abdominal pain.
Mrs. G. is upset because another physician told her she might have cancer and needs a hysterectomy immediately. She tells you that she does not want a hysterectomy unless “it’s absolutely necessary.”
Ultrasonography at this visit reveals that two of the three fibroids noted on a previous sonogram have grown—one from 6 cm to 9 cm in diameter; the other from 5 cm to 8 cm.
What do you tell Mrs. G.?
Understanding myomas
Uterine fibroids, also called myomas, are benign, monoclonal tumors of the myometrium that contain collagen, fibronectin, and proteoglycan. The collagen fibrils are abnormally formed and in disarray; they look like the collagen found in keloids.1 Although the precise causes of fibroids are unknown, hormonal, genetic, and growth factors appear to be involved in their development and growth.2,3
About 40% of fibroids are chromosomally abnormal; the remaining 60% may have undetected mutations. More than 100 genes have been found to be up-regulated or down-regulated in fibroid cells. Many of these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis.
- A myoma is benign tumor of the myometrium
- In a premenopausal woman, rapid uterine growth almost never indicates the presence of uterine sarcoma
- In an older woman who experiences uterine growth, abdominal pain, and irregular vaginal bleeding, pelvic malignancy may be suspected; an increased level of LDH isoenzyme 3 with increased gadolinium uptake on MRI within 40 to 60 seconds suggests a diagnosis of leiomyosarcoma
- Most fibroids have no impact on fertility, but submucosal fibroids that distort the uterine cavity decrease fertility; removing them increases fertility
- Location, size, number, and extent of myoma penetration into the myometrium can be evaluated by pelvic MRI, with coronal, axial, and sagittal images without gadolinium contrast
- Given the risks associated with surgery and the lack of proof of efficacy, myomectomy to improve fertility should be undertaken with caution
- Most myomas do not grow during pregnancy. Unfavorable pregnancy outcomes are very rare in women with myomas.
- Oral contraceptives and postmenopausal hormone therapy almost never influence fibroid growth. Women with fibroids can usually use these therapies safely.
Differentiating benign myoma from uterine sarcoma
Myomas have chromosomal rearrangements similar to other benign lesions, whereas leiomyosarcomas are undifferentiated and have complex chromosomal rearrangements not seen in myomas.4 Genetic differences between myomas and leiomyosarcomas indicate they most likely have distinct origins, and that leiomyosarcomas do not result from malignant degeneration of myomas.2
In premenopausal women, rapid uterine growth almost never indicates uterine sarcoma: One study found only one sarcoma among 371 (0.26%) women operated on for rapid growth of a presumed myoma, and no sarcomas were found in the 198 women who had a 6-week-pregnancy-equivalent increase in uterine size over 1 year.5
Clinical indications. The clinical signs that would lead to suspicion of pelvic malignancy are:
- older age
- abdominal pain
- irregular vaginal bleeding.6
The average age of 2,098 women with uterine sarcoma reported in the SEER (Surveillance Epidemiology and End Results) cancer database from 1989 to 1999 was 63 years, whereas a review of the literature found a mean age of 36 years in women subjected to myomectomy who did not have sarcoma.3,7
Diagnostic tests. The distinction between benign myoma and leiomyosarcoma need not be based on clinical signs alone. Preoperative diagnosis of leiomyosarcoma may be possible, using laboratory values of total serum lactate dehydrogenase (LDH) and LDH isoenzyme 3 plus gadolinium-enhanced magnetic resonance imaging (MRI) scan (Gd-DTPA), with initial images taken 40 to 60 seconds after injection of gadolinium. A study of 87 women with fibroids, 10 women with leiomyosarcoma, and 130 women with degenerating fibroids reported 100% specificity, 100% positive predictive value, 100% negative predictive value, and 100% diagnostic accuracy for leiomyosarcoma with this combination diagnostic procedure.8
CASE 1 RESOLVED What advice for Mrs. G.?
You order a gadolinium-enhanced, dynamic MRI scan and have blood drawn for total LDH and LDH isoenzymes. Total LDH and isoenzyme 3 are normal. MRI shows no increased enhancement of the fibroids on images taken 40 to 60 seconds after injection of gadolinium. You advise the patient that there is no evidence of cancer (sarcoma) and no urgent need for hysterectomy. You also tell her that, because she is symptomatic, myomectomy is an option that will preserve her uterus.
CASE 2 Fibroids, and contemplating childbearing
Mrs. H., a 35-year-old nulligravida, comes to the office for her first visit with you. She has no complaints, but your pelvic examination reveals a 10 week-size enlarged uterus. A sonogram shows a 6-cm subserosal fibroid and a 3-cm intramural fibroid near the endometrial cavity (see FIGURE). This patient was recently married and wants to become pregnant within the coming year.
When you tell Mrs. H. that she has fibroids, she grows concerned. She asks: “Will this affect my fertility, or a pregnancy?” and “Do I need surgery?”
You explain that the larger, subserosal fibroid is not a concern. The smaller, intramural fibroid could, however, have an impact on fertility and pregnancy if it distorts the uterine cavity.
To find out if that is the case, you order a saline infusion sonogram, which demonstrates, clearly, a normal cavity without distortion by the fibroid.
What is your advice to this woman?
Submucous fibroids that distort the uterine cavity decrease fertility; removal increases fertility. Otherwise, neither intramural nor subserosal fibroids appear to affect the fertility rate; removal has not been shown to increase fertility. Meta-analysis of 11 studies found that submucous myomas that distort the uterine cavity appear to decrease the pregnancy rate by 70% (relative risk [RR], 0.32; confidence interval [CI], 0.13–0.70).9
Assessing the uterine cavity. Evaluating a woman with fibroids for fertility requires reliable assessment of the uterine cavity. Hysteroscopy and saline infusion sonography have been shown to be far superior to transvaginal sonography or hysterosalpingography for detecting submucosal fibroids.10
The best modality for determining the extent of submucosal penetration of a myoma into the myometrium is MRI. It is also an excellent modality for evaluating the size, position, and number of multiple fibroids.11 The drawback to using MRI? It is more costly than other modalities.
Note: Classification of submucosal fibroids is based on the fraction of the mass within the cavity:
- Class 0 myomas are entirely intracavitary
- Class I myomas have 50% or more of the fibroid within the cavity
- Class II myomas have less than 50% within the cavity.12
Resection and fertility. Submucous fibroids can often be removed hysteroscopically. Systematic review of the evidence found that resection-restored fertility is equal to that of infertile controls undergoing in vitro fertilization who do not have fibroids (RR, 1.72; CI, 1.13–2.58).9 In that review, the presence of neither intramural nor subserosal fibroids decreased fertility (intramural: RR, 0.94, and CI, 0.73–1.20; subserosal: RR, 1.1, and CI, 0.06–1.72). Furthermore, removal of intramural and subserosal myomas by abdominal or laparoscopic myomectomy did not improve fertility. An updated unpublished meta-analysis, including studies published after 2001, came to the same conclusion (Pritts E, personal communication, 2008).
CASE 2: Subserosal, intramural myomas cause concern
In a woman contemplating childbearing, does a subserosal (left) or intramural (right) myoma present a problem because of potential to distort the uterine cavity?
Fibroids and pregnancy
The incidence of sonographically detected fibroids during pregnancy is low.13 Among 12,600 women at a prenatal clinic, routine second-trimester sonography identified myomas in 183 (mean age, 33 years)—an incidence of 1.5%.
Pregnancy has a variable and unpredictable effect on myoma growth, likely dependent on individual differences in genetics, circulating growth factors, and myoma-localized receptors. Most myomas do not, however, grow during pregnancy. A prospective study of pregnant women who had a single myoma found that 69% had no increase in volume throughout their pregnancy. In women who were noted to have an increase in the volume of their myoma, the greatest growth occurred before 10 weeks’ gestation. No relationship was found between initial myoma volume and myoma growth during the gestational period. 14
Do myomas complicate pregnancy?
Very rarely. Two studies reported on outcomes in large populations of pregnant women who were examined with routine second-trimester ultrasonography, with follow-up and delivery at the same institution.
In one of those studies, 12,600 pregnant women were evaluated, and the outcome in 167 women who were given a diagnosis of myoma was compared with the outcome in women who did not have a myoma.15 Despite similar clinical management between the two groups, no significant differences were seen in regard to the incidence of:
- preterm delivery
- premature rupture of membranes
- fetal growth restriction
- placenta previa
- placental abruption
- postpartum hemorrhage
- retained placenta.
Only cesarean section was more common among women with fibroids (23% vs 12%).
The second study reviewed 15,104 pregnancies and compared 401 women found to have myomas and the remaining women who did not.16 Although the presence of myoma did not increase the risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis, or endomyometritis, there was some increased risk of pre-term delivery (19.2% vs 12.7%), placenta previa (3.5% vs 1.8%), and post-partum hemorrhage (8.3% vs 2.9%). Cesarean section was, again, more common (49.1% vs 21.4%).
Do myomas injure the fetus?
Fetal injury as a consequence of fibroids has been reported very infrequently. A review of the literature from 1980 to 2005 revealed only four cases—one each of:
- fetal head anomalies with fetal growth restriction
- postural deformity
- limb reduction
- fetal head deformation with torticollis.17-19
CASE 2 RESOLVED Should Mrs. H. have a myomectomy?
Probably not. Abdominal and laparoscopic myomectomy involve substantial operative and anesthetic risks, including infection, postoperative adhesions, a very small risk of uterine rupture during pregnancy, and increased likelihood of cesarean section. Costs are also substantial, involving not only the expense of surgery, but also patient discomfort and time for recovery. Therefore, until it is proved that intramural myomas decrease fertility and myomectomy increases fertility, surgery should be undertaken with caution. As far as the effects of myoma on pregnancy are concerned, no data are available by which to compare pregnancy outcomes following myomectomy with pregnancy outcomes in women whose myomas are untreated. Randomized studies are needed to clarify these important issues.
CASES 3 & 4 The effects of oral contraceptives and hormone replacement therapy
Mrs. J. is a 32-year-old G0P0 woman who has a 5-cm fundal myoma. She is sexually active and wants to use an oral contraceptive (OC). She has heard from friends, however, that taking an OC makes fibroids grow, and she asks for your advice.
The same day, you see Mrs. K., a 54-year-old, recently menopausal woman. She complains of severe hot flashes and night sweats that disturb her sleep. She has had asymptomatic uterine fibroids for about 10 years and, although she would like to take menopausal hormone therapy, she is worried that the medication will make the fibroids larger.
How do you advise these two women?
OCs. OCs do not appear to influence the growth of fibroids. One study found a slightly increased risk of fibroids, another study found no increased risk, and a third found a decreased risk.18,19 These studies are retrospective, however, and may be marked by selection bias.
Postmenopausal hormone replacement therapy. Postmenopausal hormone therapy does not ordinarily cause fibroid growth. After 3 years, only three of 34 (8%) post-menopausal women who had fibroids and were treated with 0.625 mg of conjugated equine estrogen (CEE) and 5 mg of medroxyprogesterone acetate (MPA) a day had any increase in the size of fibroids.20 If any increase in the size of the uterus is noted, it is likely related to progestins.
A study found that 23% of women taking oral estrogen plus 2.5 mg of MPA a day for 1 year had a slight increase in the size of fibroids, whereas 50% of women taking 5 mg of MPA had an increase in size (mean increase in diameter, 3.2 cm).21 Transdermal estrogen plus oral MPA was shown, after 1 year, to cause, on average, a 0.5-cm increase in the diameter of fibroids; oral estrogen and MPA caused no increase in size.22
CASES RESOLVED Rx: Reassurance
Advise Mrs. J. that taking an OC is unlikely to make her fibroids grow larger.
Mrs. K., who is older, can seek relief from postmenopausal symptoms by taking hormone therapy without fear of her fibroids being stimulated to grow.
The author reports no financial relationships relevant to this article.
CASE 1 Rapid growth=cancer?
Mrs. G., 47 years old, has had uterine fibroids the size of a 12-week pregnancy for about 6 years. At today’s examination, however, her uterus feels about the size of a 16-week pregnancy.
She is aware that her abdomen is bigger, and she complains of some abdominal pressure and urinary frequency. She reports no abnormal bleeding and no abdominal pain.
Mrs. G. is upset because another physician told her she might have cancer and needs a hysterectomy immediately. She tells you that she does not want a hysterectomy unless “it’s absolutely necessary.”
Ultrasonography at this visit reveals that two of the three fibroids noted on a previous sonogram have grown—one from 6 cm to 9 cm in diameter; the other from 5 cm to 8 cm.
What do you tell Mrs. G.?
Understanding myomas
Uterine fibroids, also called myomas, are benign, monoclonal tumors of the myometrium that contain collagen, fibronectin, and proteoglycan. The collagen fibrils are abnormally formed and in disarray; they look like the collagen found in keloids.1 Although the precise causes of fibroids are unknown, hormonal, genetic, and growth factors appear to be involved in their development and growth.2,3
About 40% of fibroids are chromosomally abnormal; the remaining 60% may have undetected mutations. More than 100 genes have been found to be up-regulated or down-regulated in fibroid cells. Many of these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis.
- A myoma is benign tumor of the myometrium
- In a premenopausal woman, rapid uterine growth almost never indicates the presence of uterine sarcoma
- In an older woman who experiences uterine growth, abdominal pain, and irregular vaginal bleeding, pelvic malignancy may be suspected; an increased level of LDH isoenzyme 3 with increased gadolinium uptake on MRI within 40 to 60 seconds suggests a diagnosis of leiomyosarcoma
- Most fibroids have no impact on fertility, but submucosal fibroids that distort the uterine cavity decrease fertility; removing them increases fertility
- Location, size, number, and extent of myoma penetration into the myometrium can be evaluated by pelvic MRI, with coronal, axial, and sagittal images without gadolinium contrast
- Given the risks associated with surgery and the lack of proof of efficacy, myomectomy to improve fertility should be undertaken with caution
- Most myomas do not grow during pregnancy. Unfavorable pregnancy outcomes are very rare in women with myomas.
- Oral contraceptives and postmenopausal hormone therapy almost never influence fibroid growth. Women with fibroids can usually use these therapies safely.
Differentiating benign myoma from uterine sarcoma
Myomas have chromosomal rearrangements similar to other benign lesions, whereas leiomyosarcomas are undifferentiated and have complex chromosomal rearrangements not seen in myomas.4 Genetic differences between myomas and leiomyosarcomas indicate they most likely have distinct origins, and that leiomyosarcomas do not result from malignant degeneration of myomas.2
In premenopausal women, rapid uterine growth almost never indicates uterine sarcoma: One study found only one sarcoma among 371 (0.26%) women operated on for rapid growth of a presumed myoma, and no sarcomas were found in the 198 women who had a 6-week-pregnancy-equivalent increase in uterine size over 1 year.5
Clinical indications. The clinical signs that would lead to suspicion of pelvic malignancy are:
- older age
- abdominal pain
- irregular vaginal bleeding.6
The average age of 2,098 women with uterine sarcoma reported in the SEER (Surveillance Epidemiology and End Results) cancer database from 1989 to 1999 was 63 years, whereas a review of the literature found a mean age of 36 years in women subjected to myomectomy who did not have sarcoma.3,7
Diagnostic tests. The distinction between benign myoma and leiomyosarcoma need not be based on clinical signs alone. Preoperative diagnosis of leiomyosarcoma may be possible, using laboratory values of total serum lactate dehydrogenase (LDH) and LDH isoenzyme 3 plus gadolinium-enhanced magnetic resonance imaging (MRI) scan (Gd-DTPA), with initial images taken 40 to 60 seconds after injection of gadolinium. A study of 87 women with fibroids, 10 women with leiomyosarcoma, and 130 women with degenerating fibroids reported 100% specificity, 100% positive predictive value, 100% negative predictive value, and 100% diagnostic accuracy for leiomyosarcoma with this combination diagnostic procedure.8
CASE 1 RESOLVED What advice for Mrs. G.?
You order a gadolinium-enhanced, dynamic MRI scan and have blood drawn for total LDH and LDH isoenzymes. Total LDH and isoenzyme 3 are normal. MRI shows no increased enhancement of the fibroids on images taken 40 to 60 seconds after injection of gadolinium. You advise the patient that there is no evidence of cancer (sarcoma) and no urgent need for hysterectomy. You also tell her that, because she is symptomatic, myomectomy is an option that will preserve her uterus.
CASE 2 Fibroids, and contemplating childbearing
Mrs. H., a 35-year-old nulligravida, comes to the office for her first visit with you. She has no complaints, but your pelvic examination reveals a 10 week-size enlarged uterus. A sonogram shows a 6-cm subserosal fibroid and a 3-cm intramural fibroid near the endometrial cavity (see FIGURE). This patient was recently married and wants to become pregnant within the coming year.
When you tell Mrs. H. that she has fibroids, she grows concerned. She asks: “Will this affect my fertility, or a pregnancy?” and “Do I need surgery?”
You explain that the larger, subserosal fibroid is not a concern. The smaller, intramural fibroid could, however, have an impact on fertility and pregnancy if it distorts the uterine cavity.
To find out if that is the case, you order a saline infusion sonogram, which demonstrates, clearly, a normal cavity without distortion by the fibroid.
What is your advice to this woman?
Submucous fibroids that distort the uterine cavity decrease fertility; removal increases fertility. Otherwise, neither intramural nor subserosal fibroids appear to affect the fertility rate; removal has not been shown to increase fertility. Meta-analysis of 11 studies found that submucous myomas that distort the uterine cavity appear to decrease the pregnancy rate by 70% (relative risk [RR], 0.32; confidence interval [CI], 0.13–0.70).9
Assessing the uterine cavity. Evaluating a woman with fibroids for fertility requires reliable assessment of the uterine cavity. Hysteroscopy and saline infusion sonography have been shown to be far superior to transvaginal sonography or hysterosalpingography for detecting submucosal fibroids.10
The best modality for determining the extent of submucosal penetration of a myoma into the myometrium is MRI. It is also an excellent modality for evaluating the size, position, and number of multiple fibroids.11 The drawback to using MRI? It is more costly than other modalities.
Note: Classification of submucosal fibroids is based on the fraction of the mass within the cavity:
- Class 0 myomas are entirely intracavitary
- Class I myomas have 50% or more of the fibroid within the cavity
- Class II myomas have less than 50% within the cavity.12
Resection and fertility. Submucous fibroids can often be removed hysteroscopically. Systematic review of the evidence found that resection-restored fertility is equal to that of infertile controls undergoing in vitro fertilization who do not have fibroids (RR, 1.72; CI, 1.13–2.58).9 In that review, the presence of neither intramural nor subserosal fibroids decreased fertility (intramural: RR, 0.94, and CI, 0.73–1.20; subserosal: RR, 1.1, and CI, 0.06–1.72). Furthermore, removal of intramural and subserosal myomas by abdominal or laparoscopic myomectomy did not improve fertility. An updated unpublished meta-analysis, including studies published after 2001, came to the same conclusion (Pritts E, personal communication, 2008).
CASE 2: Subserosal, intramural myomas cause concern
In a woman contemplating childbearing, does a subserosal (left) or intramural (right) myoma present a problem because of potential to distort the uterine cavity?
Fibroids and pregnancy
The incidence of sonographically detected fibroids during pregnancy is low.13 Among 12,600 women at a prenatal clinic, routine second-trimester sonography identified myomas in 183 (mean age, 33 years)—an incidence of 1.5%.
Pregnancy has a variable and unpredictable effect on myoma growth, likely dependent on individual differences in genetics, circulating growth factors, and myoma-localized receptors. Most myomas do not, however, grow during pregnancy. A prospective study of pregnant women who had a single myoma found that 69% had no increase in volume throughout their pregnancy. In women who were noted to have an increase in the volume of their myoma, the greatest growth occurred before 10 weeks’ gestation. No relationship was found between initial myoma volume and myoma growth during the gestational period. 14
Do myomas complicate pregnancy?
Very rarely. Two studies reported on outcomes in large populations of pregnant women who were examined with routine second-trimester ultrasonography, with follow-up and delivery at the same institution.
In one of those studies, 12,600 pregnant women were evaluated, and the outcome in 167 women who were given a diagnosis of myoma was compared with the outcome in women who did not have a myoma.15 Despite similar clinical management between the two groups, no significant differences were seen in regard to the incidence of:
- preterm delivery
- premature rupture of membranes
- fetal growth restriction
- placenta previa
- placental abruption
- postpartum hemorrhage
- retained placenta.
Only cesarean section was more common among women with fibroids (23% vs 12%).
The second study reviewed 15,104 pregnancies and compared 401 women found to have myomas and the remaining women who did not.16 Although the presence of myoma did not increase the risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis, or endomyometritis, there was some increased risk of pre-term delivery (19.2% vs 12.7%), placenta previa (3.5% vs 1.8%), and post-partum hemorrhage (8.3% vs 2.9%). Cesarean section was, again, more common (49.1% vs 21.4%).
Do myomas injure the fetus?
Fetal injury as a consequence of fibroids has been reported very infrequently. A review of the literature from 1980 to 2005 revealed only four cases—one each of:
- fetal head anomalies with fetal growth restriction
- postural deformity
- limb reduction
- fetal head deformation with torticollis.17-19
CASE 2 RESOLVED Should Mrs. H. have a myomectomy?
Probably not. Abdominal and laparoscopic myomectomy involve substantial operative and anesthetic risks, including infection, postoperative adhesions, a very small risk of uterine rupture during pregnancy, and increased likelihood of cesarean section. Costs are also substantial, involving not only the expense of surgery, but also patient discomfort and time for recovery. Therefore, until it is proved that intramural myomas decrease fertility and myomectomy increases fertility, surgery should be undertaken with caution. As far as the effects of myoma on pregnancy are concerned, no data are available by which to compare pregnancy outcomes following myomectomy with pregnancy outcomes in women whose myomas are untreated. Randomized studies are needed to clarify these important issues.
CASES 3 & 4 The effects of oral contraceptives and hormone replacement therapy
Mrs. J. is a 32-year-old G0P0 woman who has a 5-cm fundal myoma. She is sexually active and wants to use an oral contraceptive (OC). She has heard from friends, however, that taking an OC makes fibroids grow, and she asks for your advice.
The same day, you see Mrs. K., a 54-year-old, recently menopausal woman. She complains of severe hot flashes and night sweats that disturb her sleep. She has had asymptomatic uterine fibroids for about 10 years and, although she would like to take menopausal hormone therapy, she is worried that the medication will make the fibroids larger.
How do you advise these two women?
OCs. OCs do not appear to influence the growth of fibroids. One study found a slightly increased risk of fibroids, another study found no increased risk, and a third found a decreased risk.18,19 These studies are retrospective, however, and may be marked by selection bias.
Postmenopausal hormone replacement therapy. Postmenopausal hormone therapy does not ordinarily cause fibroid growth. After 3 years, only three of 34 (8%) post-menopausal women who had fibroids and were treated with 0.625 mg of conjugated equine estrogen (CEE) and 5 mg of medroxyprogesterone acetate (MPA) a day had any increase in the size of fibroids.20 If any increase in the size of the uterus is noted, it is likely related to progestins.
A study found that 23% of women taking oral estrogen plus 2.5 mg of MPA a day for 1 year had a slight increase in the size of fibroids, whereas 50% of women taking 5 mg of MPA had an increase in size (mean increase in diameter, 3.2 cm).21 Transdermal estrogen plus oral MPA was shown, after 1 year, to cause, on average, a 0.5-cm increase in the diameter of fibroids; oral estrogen and MPA caused no increase in size.22
CASES RESOLVED Rx: Reassurance
Advise Mrs. J. that taking an OC is unlikely to make her fibroids grow larger.
Mrs. K., who is older, can seek relief from postmenopausal symptoms by taking hormone therapy without fear of her fibroids being stimulated to grow.
1. Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab. 1994;79:900-906.
2. Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111:1037-1054.
3. Parker W. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87:725-736.
4. Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004;40:97-108.
5. Parker WH, Fu YS, Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol. 1994;83:414-418.
6. Boutselis JG, Ullery JC. Sarcoma of the uterus. Obstet Gynecol. 1962;20:23-35.
7. Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol. 2004;93:204-208.
8. Goto A, Takeuchi S, Sugimura K, Maruo T. Usefulness of Gd-DTPA contrast-enhanced dynamic MRI and serum determination of LDH and its isozymes in the differential diagnosis of leiomyosarcoma from degenerated leiomyoma of the uterus. Int J Gynecol Cancer. 2002;12:354-361.
9. Pritts EA. Fibroids and infertility: a systematic review of the evidence. Obstet Gynecol Surv. 2001;56:483-491.
10. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Evaluation of the uterine cavity with magnetic resonance imaging, transvaginal sonography, hysterosonographic examination, and diagnostic hysteroscopy. Fertil Steril. 2001;76:350-357.
11. Dueholm M, Lundorf E, Olesen F. Imaging techniques for evaluation of the uterine cavity and endometrium in premenopausal patients before minimally invasive surgery. Obstet Gynecol Surv. 2002;57:388-403.
12. Cohen LS, Valle RF. Role of vaginal sonography and hysterosonography in the endoscopic treatment of uterine myomas. Fertil Steril. 2000;73:197-204.
13. Cooper NP, Okolo S. Fibroids in pregnancy—common but poorly understood. Obstet Gynecol Surv. 2005;60:132-138.
14. Rosati P, Exacoustos C, Mancuso S. Longitudinal evaluation of uterine myoma growth during pregnancy. A sonographic study. J Ultrasound Med. 1992;11:511-515.
15. Vergani P, Ghidini A, Strobelt N, et al. Do uterine leiomyomas influence pregnancy outcome? Am J Perinatol. 1994;11:356-358.
16. Qidwai GI, Caughey AB, Jacoby AF. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol. 2006;107:376-382.
17. Joo JG, Inovay J, Silhavy M, Papp Z. Successful enucleation of a necrotizing fibroid causing oligohydramnios and fetal postural deformity in the 25th week of gestation. A case report. J Reprod Med. 2001;46:923-925.
18. Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (Clin Res Ed). 1986;293:359-362.
19. Ratner H. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (Clin Res Ed). 1986;293:1027.-
20. Yang CH, Lee JN, Hsu SC, Kuo CH, Tsai EM. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women—a 3-year study. Maturitas. 2002;43:35-39.
21. Palomba S, Sena T, Morelli M, Noia R, Zullo F, Mastrantonio P. Effect of different doses of progestin on uterine leiomyomas in postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2002;102:199-201.
22. Sener AB, Seçkin NC, Ozmen S, Gökmen O, Dogu N, Ekici E. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril. 1996;65:354-357.
1. Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab. 1994;79:900-906.
2. Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111:1037-1054.
3. Parker W. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87:725-736.
4. Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004;40:97-108.
5. Parker WH, Fu YS, Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol. 1994;83:414-418.
6. Boutselis JG, Ullery JC. Sarcoma of the uterus. Obstet Gynecol. 1962;20:23-35.
7. Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol. 2004;93:204-208.
8. Goto A, Takeuchi S, Sugimura K, Maruo T. Usefulness of Gd-DTPA contrast-enhanced dynamic MRI and serum determination of LDH and its isozymes in the differential diagnosis of leiomyosarcoma from degenerated leiomyoma of the uterus. Int J Gynecol Cancer. 2002;12:354-361.
9. Pritts EA. Fibroids and infertility: a systematic review of the evidence. Obstet Gynecol Surv. 2001;56:483-491.
10. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Evaluation of the uterine cavity with magnetic resonance imaging, transvaginal sonography, hysterosonographic examination, and diagnostic hysteroscopy. Fertil Steril. 2001;76:350-357.
11. Dueholm M, Lundorf E, Olesen F. Imaging techniques for evaluation of the uterine cavity and endometrium in premenopausal patients before minimally invasive surgery. Obstet Gynecol Surv. 2002;57:388-403.
12. Cohen LS, Valle RF. Role of vaginal sonography and hysterosonography in the endoscopic treatment of uterine myomas. Fertil Steril. 2000;73:197-204.
13. Cooper NP, Okolo S. Fibroids in pregnancy—common but poorly understood. Obstet Gynecol Surv. 2005;60:132-138.
14. Rosati P, Exacoustos C, Mancuso S. Longitudinal evaluation of uterine myoma growth during pregnancy. A sonographic study. J Ultrasound Med. 1992;11:511-515.
15. Vergani P, Ghidini A, Strobelt N, et al. Do uterine leiomyomas influence pregnancy outcome? Am J Perinatol. 1994;11:356-358.
16. Qidwai GI, Caughey AB, Jacoby AF. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol. 2006;107:376-382.
17. Joo JG, Inovay J, Silhavy M, Papp Z. Successful enucleation of a necrotizing fibroid causing oligohydramnios and fetal postural deformity in the 25th week of gestation. A case report. J Reprod Med. 2001;46:923-925.
18. Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (Clin Res Ed). 1986;293:359-362.
19. Ratner H. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (Clin Res Ed). 1986;293:1027.-
20. Yang CH, Lee JN, Hsu SC, Kuo CH, Tsai EM. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women—a 3-year study. Maturitas. 2002;43:35-39.
21. Palomba S, Sena T, Morelli M, Noia R, Zullo F, Mastrantonio P. Effect of different doses of progestin on uterine leiomyomas in postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2002;102:199-201.
22. Sener AB, Seçkin NC, Ozmen S, Gökmen O, Dogu N, Ekici E. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril. 1996;65:354-357.
IN THIS ARTICLE
“Doctor, I want a C-section.” How should you respond?
In general, when a patient inquires about elective primary C-section, it is best to consider the “6 C’s of elective cesarean” in a careful discussion with her. That approach entails consideration of the following:
- Clarification of her request
- Comorbidities in maternal health or surgical history
- number of Children planned overall
- clear Consent for the procedure
- Correct determination of gestational age at the time of planned delivery
- Confirmation of coverage by her insurance carrier.
One trend is clear: Maternal requests for primary cesarean delivery are on the rise in the United States, although we lack precise data on exactly how fast the rate is rising. Many experts estimate it to be 4% to 18%.1 In Brazil, the rate of elective C-section for women in private hospitals is thought to be as high as 80% to 90%.2
As more celebrities and other prominent figures undergo elective C-section, more American women are beginning to ask for the same “privilege.” In this article, I lay out an evidence-based and ethically sensitive approach to counseling patients who request C-section on an elective basis.
In 2004, the United States saw 4.1 million births, 18% of which—or nearly 750,000—involved primary C-section.13 However, it is difficult to discern how many of these primary C-sections were performed for nonobstetric, or elective, indications, because such data are not routinely collected.
Birth certificates are changing
Efforts to improve birth certificate data have begun. In 2003, the revised US Standard Certificate of Live Birth was adopted by seven states, allowing for a more detailed description of births. The new certificate provides for more robust information in several areas, including
- risk factors in the index pregnancy
- obstetric procedures performed
- characteristics of labor and delivery
- method of delivery
- normal conditions of the newborn
- congenital anomalies in the newborn.
It also specifies whether or not a trial of labor was attempted before cesarean delivery, but it is limited by the inclusion of breech presentation in the statistics.14
Data collection remains an inexact science
Even with the new birth certificate data, it remains difficult to accurately quantify the number of nonobstetrically indicated primary C-sections, although many experts have estimated the rate at 4% to 28%.1
The points raised in the list that begins this article are all discussed here.
The difficulty of calculating the rate of primary C-section
We are limited by terminology and data-collection practices, as well as a multitude of confounding obstetric factors. Practicing providers recognize the inherent difference between a planned C-section at term without the onset of labor and an unplanned C-section at term after the onset of labor—as well as every scenario in between.
Unplanned C-section can be performed to address fetal compromise or an unsuccessful attempt at vaginal delivery—each scenario replete with its own risks and potential complications. The urgency of C-section also confounds subsequent maternal and fetal complications. Underlying maternal factors such as obesity and medical and surgical history further complicate the scenario.
For these reasons, the discussion of elective C-section is best managed by limiting the parameters considered to the requested, scheduled, elective C-section at term without maternal or fetal indications. Most patients have this paradigm in mind when they make their request, even though physicians and midwives understand that this is the ideal and not generally the reality.
Medicolegal and ethical considerations
The ethical principles surrounding cesarean delivery upon maternal request balance on the tension between beneficence and patient autonomy. The former requires the promotion of the patient’s overall health and well-being, along with attention to the closely related dictum, primum non nocere, or “first do no harm.”
Patient autonomy requires respectful consideration of the patient and her world view when making a medical decision. The ethical principle of patient autonomy is usually understood as a right to decline medical intervention—not necessarily to demand dangerous or unproven intervention.1
This raises the question: Is a scheduled C-section in the absence of obstetric indications dangerous? Harmful? Imprudent? The medical community has accepted these inherent tensions in the field of aesthetic plastic surgery, but societies in obstetrics and gynecology continue to struggle with the ethical principles involved in maternal-choice cesarean.
FIGO: C-section for nonmedical reasons is not justified
The International Federation of Gynecology and Obstetrics (FIGO) Committee for the Ethical Aspects of Human Reproduction and Women’s Health bases its guidelines on the use of cesarean delivery for nonmedical reasons on the principles of beneficence and social justice. It concludes: “Cesarean section is a surgical intervention with potential hazards for both mother and child. It also uses more health-care resources than normal vaginal delivery…performing cesarean section for nonmedical reasons is ethically not justified.”3
ACOG: Individualize the decision consistent with ethical principles
The American College of Obstetricians and Gynecologists (ACOG), in a recent Committee Opinion, acknowledged the paucity of research data directly comparing cesarean delivery on maternal request with planned vaginal delivery. The document reviews the National Institutes of Health (NIH) State-of-the-Science Conference on Cesarean Delivery on Maternal Request (see below), which was convened in 2006, and notes the panel’s conclusion that the available body of evidence does not allow for a conclusive recommendation of one mode of delivery over another.4 The ACOG Committee Opinion states: “Any decision to perform a cesarean delivery on maternal request should be carefully individualized and consistent with ethical principles.”5
Different world views likely account for different conclusions
The difference in the FIGO and ACOG positions may arise from differences in cultural contexts between a general world health view and a highly patient-centered Western perspective. The former view bases the decision on universal good and the utilization of scarce health-care resources; the latter view recognizes the individual within an ethical context.
Both views acknowledge the limited data available to inform the decision. So what do the data say, and how can we help our patients understand it?
NIH State-of-the-Science Conference
In March of 2006, an independent panel of experts from a range of medical fields reviewed the scientific literature regarding cesarean delivery on maternal request at the NIH in Bethesda, Maryland. Although the panel found no Level I, or strong, evidence within the literature, it was able to characterize the risks and benefits of maternal-request C-section based on Level II (moderate), Level III (weak), and Level IV (absent) evidence.
Moderate evidence was scarce
From a maternal perspective, the panel found that “the frequency of postpartum hemorrhage associated with planned cesarean delivery is lower than that reported with the combination of planned vaginal delivery and unplanned cesarean delivery,”5 although hospital stay is longer than with vaginal delivery.
From a neonatal perspective, moderate evidence favors vaginal delivery because of a decreased incidence of respiratory morbidity, such as transient tachypnea of the newborn and respiratory distress syndrome. Respiratory morbidity is directly related to gestational age, and there is a risk of iatrogenic prematurity with scheduled C-section. The possibility of incorrect obstetric dating would seem to favor awaiting the spontaneous onset of labor at term and an attempt at vaginal delivery to reduce the risk of respiratory complications due to iatrogenic prematurity.
Weak evidence goes both ways
Weakly supported evidence favored both cesarean section and vaginal delivery for either the mother or fetus. Weak evidence favoring vaginal delivery for maternal interests included:
- decreased maternal infectious morbidity and anesthetic complications, compared with C-section
- greater ease establishing breastfeeding, due to logistical challenges surrounding mother–infant bonding after C-section
- greater freedom in planning family size because increasing numbers of repeat C-sections with subsequent pregnancies increase risk of uterine rupture, cesarean hysterectomy, and abnormal placentation.
- lower rate of postpartum stress urinary incontinence, compared with women undergoing vaginal delivery, in the short term
- lower risk of surgical morbidity and traumatic obstetric lacerations with elective C-section, compared with the injuries that can occur at the time of unscheduled C-section or vaginal delivery.
Weak evidence of neonatal benefit
From the neonatal perspective, the NIH Consensus Committee found weak evidence favoring C-section. A scheduled C-section protects the neonate from stillbirth arising from postdates intrauterine fetal demise, because, with elective cesarean, a pregnancy is not usually allowed to continue post-term.
The Committee also documented protection from intracranial hemorrhage, neonatal asphyxia, encephalopathy, birth injury, and neonatal infection with C-section, compared with vaginal delivery.5
The socioeconomic picture matters
From a socioeconomic standpoint, women who request C-section may have financial concerns such as the amount of time off from work that may be necessary for both themselves and their partners. The availability of family support may be relevant and improved if a specific time frame for delivery is anticipated.
In many cultures, “lucky days” exist, and women may have preferences or aspirations for their child to be born on one of them.
Last, although it may be more cost-effective for a patient to undergo vaginal delivery, we, as health-care providers, cannot predict who will be successful in that regard. A complicated labor that necessitates unscheduled, urgent, or emergent C-section costs more in health-care dollars than does a C-section without labor.
Canadian researchers in 2005 examined the hospital care costs over 18 years in 27,614 pregnancies associated with varying types of delivery and found that the cost of delivery was highest for a C-section performed after the onset of labor ($2,137). The lowest cost was for spontaneous vaginal delivery ($1,340), followed by C-section without labor ($1,532).6 Therefore, some could argue that the overall cost to the patient and system is lower with a scheduled cesarean delivery because it avoids the other possible comorbidities and utilization of resources.
TABLE
Risks and benefits of planned cesarean delivery
| BENEFIT | RISK | UNCLEAR EFFECTS |
|---|---|---|
| The mother | ||
| Protection against urinary incontinence Decreased surgical complications Decreased risk of postpartum hemorrhage Cultural factors Availability of social support Economic advantage | Increased length of stay Infection Anesthetic risk Subsequent placentation Difficulty breastfeeding Complication from future cesarean section Comorbidities related to obesity | Anorectal function Sexual function Pelvic organ prolapse Maternal mortality Postpartum pain Postpartum depression Thromboembolism |
| The child | ||
| Reduced mortality Decreased risk of intracranial hemorrhage Decreased risk of neonatal asphyxia Decreased risk of neonatal encephalopathy Decreased risk of brachial plexus injury | Iatrogenic prematurity Increased hospitalization Increased risk of respiratory complication | Breastfeeding Fetal laceration |
When a patient raises the subject
Your first responsibility is to clarify her request. Key to this discussion is the patient’s reason for requesting a scheduled C-section. Many women—especially primiparous women—have a fear of labor itself, not to mention concerns about their safety and the safety of their baby.7 Another major concern to many women is the risk of injury to their perineum and pelvic floor.1 These fears and concerns may motivate their request.
Educating patients about labor and discussing options for pain relief during labor can help soothe the patients’ fears. Clarifying long-term risks and benefits in regard to pelvic floor dysfunction also is important. Patients may have an unrealistic understanding of C-section and its potential complications. Often, education about the birth process and mode of delivery can alleviate a patient’s fears and change her hopes for delivery.
Explore any comorbidities
Because C-section is a major abdominal surgical procedure, maternal factors such as weight, age, surgical history, and medical comorbidities are relevant considerations when discussing the risks and benefits of cesarean in the absence of obstetric indications. Even in the absence of such comorbidities, certain risks of surgery should be clarified, including the risk of hemorrhage, infection, wound complication, thromboembolism, need for future surgery, and postoperative recovery.
The risks and benefits of vaginal delivery also should be discussed, including the factors that may lead up to an un-scheduled cesarean delivery despite the desire for a vaginal delivery.
How many children are planned?
Given the reluctance of health-care providers to manage attempted vaginal birth after C-section, women who opt for elective C-section for their first delivery may be committing themselves to C-section with subsequent pregnancies, too.8 Data suggest that an increasing number of C-sections place women at increasing risk of placenta accreta or previa, hysterectomy, blood transfusion, cystotomy, endometritis, prolonged operative time, and longer hospital stays. That said, overall maternal mortality from C-section remains low.9
Therefore, if a patient plans to have more than one or two children, she needs to understand the ramifications of repeat C-section at the time of her next delivery as well as in any additional pregnancies. Although a successful vaginal delivery cannot be guaranteed for any parturient, an attempt at vaginal delivery might be preferable for a woman hoping for a larger family.
Ensure clear consent
Chervenak and McCullough have provided an algorithm for offering C-section that balances the ethical concepts of autonomy and beneficence; that model is described above.10
If the patient requests C-section, but the clinician is uncomfortable performing one under the circumstances, referral is reasonable.
A patient’s thoughtful request can be considered out of respect for autonomy and supported by thorough counseling.
The decision to perform cesarean delivery is one of the most common clinical ethical challenges in obstetric practice today—“a challenge that will only increase with the growing influence of managed care,” observe Frank A. Chervenak, MD, and Laurence B. McCullough, PhD, who have written widely about ethical challenges in obstetrics and gynecology.10
In 1996, they proposed a model to help guide practitioners through the decision-making process of choosing cesarean delivery. According to that model, C-section is justified in four situations:
- when C-section is the only reasonable option based on clinical judgment, such as in a patient with a previous classical uterine incision. In this case, the clinician does not offer vaginal delivery but recommends only C-section based on beneficence
- when either C-section or vaginal delivery may be appropriate. This scenario warrants a clear discussion with the patient about the risks, benefits, and inherent controversy between delivery modes when all choices are equal in one’s best clinical judgment. An example might be the vertex/breech presentation of twins
- when vaginal delivery is preferable but C-section would also be indicated, such as in attempted vaginal birth after C-section
- when cesarean delivery is not generally supported over vaginal delivery, but the patient requests C-section and that request is based solely on autonomous principles. This is the case of cesarean delivery by maternal request, which necessitates clear counseling and education of the patient. Fear of pain is not a justifiable reason for cesarean delivery, because we can offer options for adequate pain management in labor.
Ensuring a correct gestational age
Once the decision to proceed with scheduled C-section is made, accurate determination of gestational age is crucial to avoid iatrogenic prematurity.
ACOG Educational Bulletin No. 230 (November 1996) lists a number of criteria by which to infer gestational age and, therefore, fetal lung maturity. The criteria include:
- documented fetal heart tone for 30 weeks by Doppler ultrasound
- 36 weeks having passed since reliable documentation of a positive urine or serum human chorionic gonadotropin pregnancy test
- crown–rump measurement by ultrasonography (US) at 6 to 11 weeks of gestation that supports the current gestational age of 39 weeks or more
- US measurement at 12 to 20 weeks’ gestation that supports the clinically determined estimated gestational age above 39 weeks.
Insurance concerns are vital to the decision
The Newborns’ and Mothers’ Health Protection Act (NMHPA) was passed in 1996. The law delineates a minimum requirement of coverage by insurers for hospital stays of 48 hours after vaginal delivery or 96 hours after C-section, thereby preventing health insurance plans from restricting hospital stays after delivery.11 The law was passed as a response to political concerns about “drive-thru deliveries.”
The NMHPA also allows for provider discretion regarding the length of stay required after childbirth, meaning that, if an attending-level provider deems discharge feasible in less than 48 or 96 hours, the insurer is not mandated to continue coverage beyond discharge.
The law, however, does not mandate coverage by health insurance plans for prenatal care, delivery, and postpartum care. Confounding the actions of health insurance companies are state laws governing the care of newborns and mothers, as these laws superceded the NMHPA. So, although most states have mandated benefit laws regarding a variety of services, as of 2002, only 18 states had laws mandating specific maternity services.12 Some states specifically mention elective C-sections as nonmandated services, meaning that a patient who elects a scheduled C-section at term without obstetric indications may be required to pay for her obstetric care.
1. Wax JR, Cartin A, Pinette MG, Blackstone J. Patient choice cesarean: an evidence-based review. Obstet Gynecol Surv. 2004;59:601-616.
2. Hopkins K. Are Brazilian women really choosing to deliver by cesarean? Soc Sci Med. 2000;51:725-740.
3. FIGO Committee for the Study of Ethical Aspects of Human Reproduction and Women’s Health. Ethical Issues in Obstetrics and Gynecology. November 2006. Available at www.figo.org/docs/Ethics%20Guidelines%20-%20English%20version%202006%20-2009.pdf. Accessed April 3, 2008.
4. ACOG Committee Opinion No 386: Cesarean delivery on maternal request. November 2007. Available at www.acog.org/publications/committee_opinions/co386.cfm. Accessed April 3, 2008.
5. National Institutes of Health state-of-the-science conference statement. Cesarean delivery on maternal request March 27-29, 2006. Obstet Gynecol. 2006;107:1386-1397.
6. Allen VM, O’Connell CM, Farrell SA, Baskett TF. Economic implications of method of delivery. Am J Obstet Gynecol. 2005;193:192-197.
7. McCourt C, Weaver J, Statham H, Beake S, Gamble J, Creedy DK. Elective cesarean section and decision making: a critical review of the literature. Birth. 2007;34:65-79.
8. Roberts RG, Deutchman M, King VJ, Fryer GE, Miyoshi TJ. Changing policies on vaginal birth after cesarean: impact on access. Birth. 2007;34:316-322.
9. Silver RM, Landon MB, Rouse DJ, et al. Maternal morbidity associated with multiple repeat cesarean deliveries. National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network. Obstet Gynecol. 2006;107:1226-1232.
10. Chervenak FA, McCullough LB. An ethically justified algorithm for offering, recommending, and performing cesarean delivery and its application in managed care practice. Obstet Gynecol. 1996;87:302-305.
11. Newborns’ and Mothers’ Health Protection Act of 1996, 29 U S.C.S. §1185.
12. Laugesen MJ, Paul RR, Luft HS, Aubry W, Ganiats TG. A comparative analysis of mandated benefit laws, 1949-2002. Health Serv Res. 2006;41(3 pt 2):1081-1103.
13. National Center for Health Statistics Technical Appendix. Vital statistics of the United States, 2004. Vol. I: Natality. US Department of Heath and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Hyattsville, Md. Available at www.cdc.gov/nchs/nvss.htm. Accessed April 3, 2008.
14. National Vital Statistics Reports. Vol. 55, No. 12, April 19, 2007. Available at www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_12.pdf. Accessed April 3, 2008.
In general, when a patient inquires about elective primary C-section, it is best to consider the “6 C’s of elective cesarean” in a careful discussion with her. That approach entails consideration of the following:
- Clarification of her request
- Comorbidities in maternal health or surgical history
- number of Children planned overall
- clear Consent for the procedure
- Correct determination of gestational age at the time of planned delivery
- Confirmation of coverage by her insurance carrier.
One trend is clear: Maternal requests for primary cesarean delivery are on the rise in the United States, although we lack precise data on exactly how fast the rate is rising. Many experts estimate it to be 4% to 18%.1 In Brazil, the rate of elective C-section for women in private hospitals is thought to be as high as 80% to 90%.2
As more celebrities and other prominent figures undergo elective C-section, more American women are beginning to ask for the same “privilege.” In this article, I lay out an evidence-based and ethically sensitive approach to counseling patients who request C-section on an elective basis.
In 2004, the United States saw 4.1 million births, 18% of which—or nearly 750,000—involved primary C-section.13 However, it is difficult to discern how many of these primary C-sections were performed for nonobstetric, or elective, indications, because such data are not routinely collected.
Birth certificates are changing
Efforts to improve birth certificate data have begun. In 2003, the revised US Standard Certificate of Live Birth was adopted by seven states, allowing for a more detailed description of births. The new certificate provides for more robust information in several areas, including
- risk factors in the index pregnancy
- obstetric procedures performed
- characteristics of labor and delivery
- method of delivery
- normal conditions of the newborn
- congenital anomalies in the newborn.
It also specifies whether or not a trial of labor was attempted before cesarean delivery, but it is limited by the inclusion of breech presentation in the statistics.14
Data collection remains an inexact science
Even with the new birth certificate data, it remains difficult to accurately quantify the number of nonobstetrically indicated primary C-sections, although many experts have estimated the rate at 4% to 28%.1
The points raised in the list that begins this article are all discussed here.
The difficulty of calculating the rate of primary C-section
We are limited by terminology and data-collection practices, as well as a multitude of confounding obstetric factors. Practicing providers recognize the inherent difference between a planned C-section at term without the onset of labor and an unplanned C-section at term after the onset of labor—as well as every scenario in between.
Unplanned C-section can be performed to address fetal compromise or an unsuccessful attempt at vaginal delivery—each scenario replete with its own risks and potential complications. The urgency of C-section also confounds subsequent maternal and fetal complications. Underlying maternal factors such as obesity and medical and surgical history further complicate the scenario.
For these reasons, the discussion of elective C-section is best managed by limiting the parameters considered to the requested, scheduled, elective C-section at term without maternal or fetal indications. Most patients have this paradigm in mind when they make their request, even though physicians and midwives understand that this is the ideal and not generally the reality.
Medicolegal and ethical considerations
The ethical principles surrounding cesarean delivery upon maternal request balance on the tension between beneficence and patient autonomy. The former requires the promotion of the patient’s overall health and well-being, along with attention to the closely related dictum, primum non nocere, or “first do no harm.”
Patient autonomy requires respectful consideration of the patient and her world view when making a medical decision. The ethical principle of patient autonomy is usually understood as a right to decline medical intervention—not necessarily to demand dangerous or unproven intervention.1
This raises the question: Is a scheduled C-section in the absence of obstetric indications dangerous? Harmful? Imprudent? The medical community has accepted these inherent tensions in the field of aesthetic plastic surgery, but societies in obstetrics and gynecology continue to struggle with the ethical principles involved in maternal-choice cesarean.
FIGO: C-section for nonmedical reasons is not justified
The International Federation of Gynecology and Obstetrics (FIGO) Committee for the Ethical Aspects of Human Reproduction and Women’s Health bases its guidelines on the use of cesarean delivery for nonmedical reasons on the principles of beneficence and social justice. It concludes: “Cesarean section is a surgical intervention with potential hazards for both mother and child. It also uses more health-care resources than normal vaginal delivery…performing cesarean section for nonmedical reasons is ethically not justified.”3
ACOG: Individualize the decision consistent with ethical principles
The American College of Obstetricians and Gynecologists (ACOG), in a recent Committee Opinion, acknowledged the paucity of research data directly comparing cesarean delivery on maternal request with planned vaginal delivery. The document reviews the National Institutes of Health (NIH) State-of-the-Science Conference on Cesarean Delivery on Maternal Request (see below), which was convened in 2006, and notes the panel’s conclusion that the available body of evidence does not allow for a conclusive recommendation of one mode of delivery over another.4 The ACOG Committee Opinion states: “Any decision to perform a cesarean delivery on maternal request should be carefully individualized and consistent with ethical principles.”5
Different world views likely account for different conclusions
The difference in the FIGO and ACOG positions may arise from differences in cultural contexts between a general world health view and a highly patient-centered Western perspective. The former view bases the decision on universal good and the utilization of scarce health-care resources; the latter view recognizes the individual within an ethical context.
Both views acknowledge the limited data available to inform the decision. So what do the data say, and how can we help our patients understand it?
NIH State-of-the-Science Conference
In March of 2006, an independent panel of experts from a range of medical fields reviewed the scientific literature regarding cesarean delivery on maternal request at the NIH in Bethesda, Maryland. Although the panel found no Level I, or strong, evidence within the literature, it was able to characterize the risks and benefits of maternal-request C-section based on Level II (moderate), Level III (weak), and Level IV (absent) evidence.
Moderate evidence was scarce
From a maternal perspective, the panel found that “the frequency of postpartum hemorrhage associated with planned cesarean delivery is lower than that reported with the combination of planned vaginal delivery and unplanned cesarean delivery,”5 although hospital stay is longer than with vaginal delivery.
From a neonatal perspective, moderate evidence favors vaginal delivery because of a decreased incidence of respiratory morbidity, such as transient tachypnea of the newborn and respiratory distress syndrome. Respiratory morbidity is directly related to gestational age, and there is a risk of iatrogenic prematurity with scheduled C-section. The possibility of incorrect obstetric dating would seem to favor awaiting the spontaneous onset of labor at term and an attempt at vaginal delivery to reduce the risk of respiratory complications due to iatrogenic prematurity.
Weak evidence goes both ways
Weakly supported evidence favored both cesarean section and vaginal delivery for either the mother or fetus. Weak evidence favoring vaginal delivery for maternal interests included:
- decreased maternal infectious morbidity and anesthetic complications, compared with C-section
- greater ease establishing breastfeeding, due to logistical challenges surrounding mother–infant bonding after C-section
- greater freedom in planning family size because increasing numbers of repeat C-sections with subsequent pregnancies increase risk of uterine rupture, cesarean hysterectomy, and abnormal placentation.
- lower rate of postpartum stress urinary incontinence, compared with women undergoing vaginal delivery, in the short term
- lower risk of surgical morbidity and traumatic obstetric lacerations with elective C-section, compared with the injuries that can occur at the time of unscheduled C-section or vaginal delivery.
Weak evidence of neonatal benefit
From the neonatal perspective, the NIH Consensus Committee found weak evidence favoring C-section. A scheduled C-section protects the neonate from stillbirth arising from postdates intrauterine fetal demise, because, with elective cesarean, a pregnancy is not usually allowed to continue post-term.
The Committee also documented protection from intracranial hemorrhage, neonatal asphyxia, encephalopathy, birth injury, and neonatal infection with C-section, compared with vaginal delivery.5
The socioeconomic picture matters
From a socioeconomic standpoint, women who request C-section may have financial concerns such as the amount of time off from work that may be necessary for both themselves and their partners. The availability of family support may be relevant and improved if a specific time frame for delivery is anticipated.
In many cultures, “lucky days” exist, and women may have preferences or aspirations for their child to be born on one of them.
Last, although it may be more cost-effective for a patient to undergo vaginal delivery, we, as health-care providers, cannot predict who will be successful in that regard. A complicated labor that necessitates unscheduled, urgent, or emergent C-section costs more in health-care dollars than does a C-section without labor.
Canadian researchers in 2005 examined the hospital care costs over 18 years in 27,614 pregnancies associated with varying types of delivery and found that the cost of delivery was highest for a C-section performed after the onset of labor ($2,137). The lowest cost was for spontaneous vaginal delivery ($1,340), followed by C-section without labor ($1,532).6 Therefore, some could argue that the overall cost to the patient and system is lower with a scheduled cesarean delivery because it avoids the other possible comorbidities and utilization of resources.
TABLE
Risks and benefits of planned cesarean delivery
| BENEFIT | RISK | UNCLEAR EFFECTS |
|---|---|---|
| The mother | ||
| Protection against urinary incontinence Decreased surgical complications Decreased risk of postpartum hemorrhage Cultural factors Availability of social support Economic advantage | Increased length of stay Infection Anesthetic risk Subsequent placentation Difficulty breastfeeding Complication from future cesarean section Comorbidities related to obesity | Anorectal function Sexual function Pelvic organ prolapse Maternal mortality Postpartum pain Postpartum depression Thromboembolism |
| The child | ||
| Reduced mortality Decreased risk of intracranial hemorrhage Decreased risk of neonatal asphyxia Decreased risk of neonatal encephalopathy Decreased risk of brachial plexus injury | Iatrogenic prematurity Increased hospitalization Increased risk of respiratory complication | Breastfeeding Fetal laceration |
When a patient raises the subject
Your first responsibility is to clarify her request. Key to this discussion is the patient’s reason for requesting a scheduled C-section. Many women—especially primiparous women—have a fear of labor itself, not to mention concerns about their safety and the safety of their baby.7 Another major concern to many women is the risk of injury to their perineum and pelvic floor.1 These fears and concerns may motivate their request.
Educating patients about labor and discussing options for pain relief during labor can help soothe the patients’ fears. Clarifying long-term risks and benefits in regard to pelvic floor dysfunction also is important. Patients may have an unrealistic understanding of C-section and its potential complications. Often, education about the birth process and mode of delivery can alleviate a patient’s fears and change her hopes for delivery.
Explore any comorbidities
Because C-section is a major abdominal surgical procedure, maternal factors such as weight, age, surgical history, and medical comorbidities are relevant considerations when discussing the risks and benefits of cesarean in the absence of obstetric indications. Even in the absence of such comorbidities, certain risks of surgery should be clarified, including the risk of hemorrhage, infection, wound complication, thromboembolism, need for future surgery, and postoperative recovery.
The risks and benefits of vaginal delivery also should be discussed, including the factors that may lead up to an un-scheduled cesarean delivery despite the desire for a vaginal delivery.
How many children are planned?
Given the reluctance of health-care providers to manage attempted vaginal birth after C-section, women who opt for elective C-section for their first delivery may be committing themselves to C-section with subsequent pregnancies, too.8 Data suggest that an increasing number of C-sections place women at increasing risk of placenta accreta or previa, hysterectomy, blood transfusion, cystotomy, endometritis, prolonged operative time, and longer hospital stays. That said, overall maternal mortality from C-section remains low.9
Therefore, if a patient plans to have more than one or two children, she needs to understand the ramifications of repeat C-section at the time of her next delivery as well as in any additional pregnancies. Although a successful vaginal delivery cannot be guaranteed for any parturient, an attempt at vaginal delivery might be preferable for a woman hoping for a larger family.
Ensure clear consent
Chervenak and McCullough have provided an algorithm for offering C-section that balances the ethical concepts of autonomy and beneficence; that model is described above.10
If the patient requests C-section, but the clinician is uncomfortable performing one under the circumstances, referral is reasonable.
A patient’s thoughtful request can be considered out of respect for autonomy and supported by thorough counseling.
The decision to perform cesarean delivery is one of the most common clinical ethical challenges in obstetric practice today—“a challenge that will only increase with the growing influence of managed care,” observe Frank A. Chervenak, MD, and Laurence B. McCullough, PhD, who have written widely about ethical challenges in obstetrics and gynecology.10
In 1996, they proposed a model to help guide practitioners through the decision-making process of choosing cesarean delivery. According to that model, C-section is justified in four situations:
- when C-section is the only reasonable option based on clinical judgment, such as in a patient with a previous classical uterine incision. In this case, the clinician does not offer vaginal delivery but recommends only C-section based on beneficence
- when either C-section or vaginal delivery may be appropriate. This scenario warrants a clear discussion with the patient about the risks, benefits, and inherent controversy between delivery modes when all choices are equal in one’s best clinical judgment. An example might be the vertex/breech presentation of twins
- when vaginal delivery is preferable but C-section would also be indicated, such as in attempted vaginal birth after C-section
- when cesarean delivery is not generally supported over vaginal delivery, but the patient requests C-section and that request is based solely on autonomous principles. This is the case of cesarean delivery by maternal request, which necessitates clear counseling and education of the patient. Fear of pain is not a justifiable reason for cesarean delivery, because we can offer options for adequate pain management in labor.
Ensuring a correct gestational age
Once the decision to proceed with scheduled C-section is made, accurate determination of gestational age is crucial to avoid iatrogenic prematurity.
ACOG Educational Bulletin No. 230 (November 1996) lists a number of criteria by which to infer gestational age and, therefore, fetal lung maturity. The criteria include:
- documented fetal heart tone for 30 weeks by Doppler ultrasound
- 36 weeks having passed since reliable documentation of a positive urine or serum human chorionic gonadotropin pregnancy test
- crown–rump measurement by ultrasonography (US) at 6 to 11 weeks of gestation that supports the current gestational age of 39 weeks or more
- US measurement at 12 to 20 weeks’ gestation that supports the clinically determined estimated gestational age above 39 weeks.
Insurance concerns are vital to the decision
The Newborns’ and Mothers’ Health Protection Act (NMHPA) was passed in 1996. The law delineates a minimum requirement of coverage by insurers for hospital stays of 48 hours after vaginal delivery or 96 hours after C-section, thereby preventing health insurance plans from restricting hospital stays after delivery.11 The law was passed as a response to political concerns about “drive-thru deliveries.”
The NMHPA also allows for provider discretion regarding the length of stay required after childbirth, meaning that, if an attending-level provider deems discharge feasible in less than 48 or 96 hours, the insurer is not mandated to continue coverage beyond discharge.
The law, however, does not mandate coverage by health insurance plans for prenatal care, delivery, and postpartum care. Confounding the actions of health insurance companies are state laws governing the care of newborns and mothers, as these laws superceded the NMHPA. So, although most states have mandated benefit laws regarding a variety of services, as of 2002, only 18 states had laws mandating specific maternity services.12 Some states specifically mention elective C-sections as nonmandated services, meaning that a patient who elects a scheduled C-section at term without obstetric indications may be required to pay for her obstetric care.
In general, when a patient inquires about elective primary C-section, it is best to consider the “6 C’s of elective cesarean” in a careful discussion with her. That approach entails consideration of the following:
- Clarification of her request
- Comorbidities in maternal health or surgical history
- number of Children planned overall
- clear Consent for the procedure
- Correct determination of gestational age at the time of planned delivery
- Confirmation of coverage by her insurance carrier.
One trend is clear: Maternal requests for primary cesarean delivery are on the rise in the United States, although we lack precise data on exactly how fast the rate is rising. Many experts estimate it to be 4% to 18%.1 In Brazil, the rate of elective C-section for women in private hospitals is thought to be as high as 80% to 90%.2
As more celebrities and other prominent figures undergo elective C-section, more American women are beginning to ask for the same “privilege.” In this article, I lay out an evidence-based and ethically sensitive approach to counseling patients who request C-section on an elective basis.
In 2004, the United States saw 4.1 million births, 18% of which—or nearly 750,000—involved primary C-section.13 However, it is difficult to discern how many of these primary C-sections were performed for nonobstetric, or elective, indications, because such data are not routinely collected.
Birth certificates are changing
Efforts to improve birth certificate data have begun. In 2003, the revised US Standard Certificate of Live Birth was adopted by seven states, allowing for a more detailed description of births. The new certificate provides for more robust information in several areas, including
- risk factors in the index pregnancy
- obstetric procedures performed
- characteristics of labor and delivery
- method of delivery
- normal conditions of the newborn
- congenital anomalies in the newborn.
It also specifies whether or not a trial of labor was attempted before cesarean delivery, but it is limited by the inclusion of breech presentation in the statistics.14
Data collection remains an inexact science
Even with the new birth certificate data, it remains difficult to accurately quantify the number of nonobstetrically indicated primary C-sections, although many experts have estimated the rate at 4% to 28%.1
The points raised in the list that begins this article are all discussed here.
The difficulty of calculating the rate of primary C-section
We are limited by terminology and data-collection practices, as well as a multitude of confounding obstetric factors. Practicing providers recognize the inherent difference between a planned C-section at term without the onset of labor and an unplanned C-section at term after the onset of labor—as well as every scenario in between.
Unplanned C-section can be performed to address fetal compromise or an unsuccessful attempt at vaginal delivery—each scenario replete with its own risks and potential complications. The urgency of C-section also confounds subsequent maternal and fetal complications. Underlying maternal factors such as obesity and medical and surgical history further complicate the scenario.
For these reasons, the discussion of elective C-section is best managed by limiting the parameters considered to the requested, scheduled, elective C-section at term without maternal or fetal indications. Most patients have this paradigm in mind when they make their request, even though physicians and midwives understand that this is the ideal and not generally the reality.
Medicolegal and ethical considerations
The ethical principles surrounding cesarean delivery upon maternal request balance on the tension between beneficence and patient autonomy. The former requires the promotion of the patient’s overall health and well-being, along with attention to the closely related dictum, primum non nocere, or “first do no harm.”
Patient autonomy requires respectful consideration of the patient and her world view when making a medical decision. The ethical principle of patient autonomy is usually understood as a right to decline medical intervention—not necessarily to demand dangerous or unproven intervention.1
This raises the question: Is a scheduled C-section in the absence of obstetric indications dangerous? Harmful? Imprudent? The medical community has accepted these inherent tensions in the field of aesthetic plastic surgery, but societies in obstetrics and gynecology continue to struggle with the ethical principles involved in maternal-choice cesarean.
FIGO: C-section for nonmedical reasons is not justified
The International Federation of Gynecology and Obstetrics (FIGO) Committee for the Ethical Aspects of Human Reproduction and Women’s Health bases its guidelines on the use of cesarean delivery for nonmedical reasons on the principles of beneficence and social justice. It concludes: “Cesarean section is a surgical intervention with potential hazards for both mother and child. It also uses more health-care resources than normal vaginal delivery…performing cesarean section for nonmedical reasons is ethically not justified.”3
ACOG: Individualize the decision consistent with ethical principles
The American College of Obstetricians and Gynecologists (ACOG), in a recent Committee Opinion, acknowledged the paucity of research data directly comparing cesarean delivery on maternal request with planned vaginal delivery. The document reviews the National Institutes of Health (NIH) State-of-the-Science Conference on Cesarean Delivery on Maternal Request (see below), which was convened in 2006, and notes the panel’s conclusion that the available body of evidence does not allow for a conclusive recommendation of one mode of delivery over another.4 The ACOG Committee Opinion states: “Any decision to perform a cesarean delivery on maternal request should be carefully individualized and consistent with ethical principles.”5
Different world views likely account for different conclusions
The difference in the FIGO and ACOG positions may arise from differences in cultural contexts between a general world health view and a highly patient-centered Western perspective. The former view bases the decision on universal good and the utilization of scarce health-care resources; the latter view recognizes the individual within an ethical context.
Both views acknowledge the limited data available to inform the decision. So what do the data say, and how can we help our patients understand it?
NIH State-of-the-Science Conference
In March of 2006, an independent panel of experts from a range of medical fields reviewed the scientific literature regarding cesarean delivery on maternal request at the NIH in Bethesda, Maryland. Although the panel found no Level I, or strong, evidence within the literature, it was able to characterize the risks and benefits of maternal-request C-section based on Level II (moderate), Level III (weak), and Level IV (absent) evidence.
Moderate evidence was scarce
From a maternal perspective, the panel found that “the frequency of postpartum hemorrhage associated with planned cesarean delivery is lower than that reported with the combination of planned vaginal delivery and unplanned cesarean delivery,”5 although hospital stay is longer than with vaginal delivery.
From a neonatal perspective, moderate evidence favors vaginal delivery because of a decreased incidence of respiratory morbidity, such as transient tachypnea of the newborn and respiratory distress syndrome. Respiratory morbidity is directly related to gestational age, and there is a risk of iatrogenic prematurity with scheduled C-section. The possibility of incorrect obstetric dating would seem to favor awaiting the spontaneous onset of labor at term and an attempt at vaginal delivery to reduce the risk of respiratory complications due to iatrogenic prematurity.
Weak evidence goes both ways
Weakly supported evidence favored both cesarean section and vaginal delivery for either the mother or fetus. Weak evidence favoring vaginal delivery for maternal interests included:
- decreased maternal infectious morbidity and anesthetic complications, compared with C-section
- greater ease establishing breastfeeding, due to logistical challenges surrounding mother–infant bonding after C-section
- greater freedom in planning family size because increasing numbers of repeat C-sections with subsequent pregnancies increase risk of uterine rupture, cesarean hysterectomy, and abnormal placentation.
- lower rate of postpartum stress urinary incontinence, compared with women undergoing vaginal delivery, in the short term
- lower risk of surgical morbidity and traumatic obstetric lacerations with elective C-section, compared with the injuries that can occur at the time of unscheduled C-section or vaginal delivery.
Weak evidence of neonatal benefit
From the neonatal perspective, the NIH Consensus Committee found weak evidence favoring C-section. A scheduled C-section protects the neonate from stillbirth arising from postdates intrauterine fetal demise, because, with elective cesarean, a pregnancy is not usually allowed to continue post-term.
The Committee also documented protection from intracranial hemorrhage, neonatal asphyxia, encephalopathy, birth injury, and neonatal infection with C-section, compared with vaginal delivery.5
The socioeconomic picture matters
From a socioeconomic standpoint, women who request C-section may have financial concerns such as the amount of time off from work that may be necessary for both themselves and their partners. The availability of family support may be relevant and improved if a specific time frame for delivery is anticipated.
In many cultures, “lucky days” exist, and women may have preferences or aspirations for their child to be born on one of them.
Last, although it may be more cost-effective for a patient to undergo vaginal delivery, we, as health-care providers, cannot predict who will be successful in that regard. A complicated labor that necessitates unscheduled, urgent, or emergent C-section costs more in health-care dollars than does a C-section without labor.
Canadian researchers in 2005 examined the hospital care costs over 18 years in 27,614 pregnancies associated with varying types of delivery and found that the cost of delivery was highest for a C-section performed after the onset of labor ($2,137). The lowest cost was for spontaneous vaginal delivery ($1,340), followed by C-section without labor ($1,532).6 Therefore, some could argue that the overall cost to the patient and system is lower with a scheduled cesarean delivery because it avoids the other possible comorbidities and utilization of resources.
TABLE
Risks and benefits of planned cesarean delivery
| BENEFIT | RISK | UNCLEAR EFFECTS |
|---|---|---|
| The mother | ||
| Protection against urinary incontinence Decreased surgical complications Decreased risk of postpartum hemorrhage Cultural factors Availability of social support Economic advantage | Increased length of stay Infection Anesthetic risk Subsequent placentation Difficulty breastfeeding Complication from future cesarean section Comorbidities related to obesity | Anorectal function Sexual function Pelvic organ prolapse Maternal mortality Postpartum pain Postpartum depression Thromboembolism |
| The child | ||
| Reduced mortality Decreased risk of intracranial hemorrhage Decreased risk of neonatal asphyxia Decreased risk of neonatal encephalopathy Decreased risk of brachial plexus injury | Iatrogenic prematurity Increased hospitalization Increased risk of respiratory complication | Breastfeeding Fetal laceration |
When a patient raises the subject
Your first responsibility is to clarify her request. Key to this discussion is the patient’s reason for requesting a scheduled C-section. Many women—especially primiparous women—have a fear of labor itself, not to mention concerns about their safety and the safety of their baby.7 Another major concern to many women is the risk of injury to their perineum and pelvic floor.1 These fears and concerns may motivate their request.
Educating patients about labor and discussing options for pain relief during labor can help soothe the patients’ fears. Clarifying long-term risks and benefits in regard to pelvic floor dysfunction also is important. Patients may have an unrealistic understanding of C-section and its potential complications. Often, education about the birth process and mode of delivery can alleviate a patient’s fears and change her hopes for delivery.
Explore any comorbidities
Because C-section is a major abdominal surgical procedure, maternal factors such as weight, age, surgical history, and medical comorbidities are relevant considerations when discussing the risks and benefits of cesarean in the absence of obstetric indications. Even in the absence of such comorbidities, certain risks of surgery should be clarified, including the risk of hemorrhage, infection, wound complication, thromboembolism, need for future surgery, and postoperative recovery.
The risks and benefits of vaginal delivery also should be discussed, including the factors that may lead up to an un-scheduled cesarean delivery despite the desire for a vaginal delivery.
How many children are planned?
Given the reluctance of health-care providers to manage attempted vaginal birth after C-section, women who opt for elective C-section for their first delivery may be committing themselves to C-section with subsequent pregnancies, too.8 Data suggest that an increasing number of C-sections place women at increasing risk of placenta accreta or previa, hysterectomy, blood transfusion, cystotomy, endometritis, prolonged operative time, and longer hospital stays. That said, overall maternal mortality from C-section remains low.9
Therefore, if a patient plans to have more than one or two children, she needs to understand the ramifications of repeat C-section at the time of her next delivery as well as in any additional pregnancies. Although a successful vaginal delivery cannot be guaranteed for any parturient, an attempt at vaginal delivery might be preferable for a woman hoping for a larger family.
Ensure clear consent
Chervenak and McCullough have provided an algorithm for offering C-section that balances the ethical concepts of autonomy and beneficence; that model is described above.10
If the patient requests C-section, but the clinician is uncomfortable performing one under the circumstances, referral is reasonable.
A patient’s thoughtful request can be considered out of respect for autonomy and supported by thorough counseling.
The decision to perform cesarean delivery is one of the most common clinical ethical challenges in obstetric practice today—“a challenge that will only increase with the growing influence of managed care,” observe Frank A. Chervenak, MD, and Laurence B. McCullough, PhD, who have written widely about ethical challenges in obstetrics and gynecology.10
In 1996, they proposed a model to help guide practitioners through the decision-making process of choosing cesarean delivery. According to that model, C-section is justified in four situations:
- when C-section is the only reasonable option based on clinical judgment, such as in a patient with a previous classical uterine incision. In this case, the clinician does not offer vaginal delivery but recommends only C-section based on beneficence
- when either C-section or vaginal delivery may be appropriate. This scenario warrants a clear discussion with the patient about the risks, benefits, and inherent controversy between delivery modes when all choices are equal in one’s best clinical judgment. An example might be the vertex/breech presentation of twins
- when vaginal delivery is preferable but C-section would also be indicated, such as in attempted vaginal birth after C-section
- when cesarean delivery is not generally supported over vaginal delivery, but the patient requests C-section and that request is based solely on autonomous principles. This is the case of cesarean delivery by maternal request, which necessitates clear counseling and education of the patient. Fear of pain is not a justifiable reason for cesarean delivery, because we can offer options for adequate pain management in labor.
Ensuring a correct gestational age
Once the decision to proceed with scheduled C-section is made, accurate determination of gestational age is crucial to avoid iatrogenic prematurity.
ACOG Educational Bulletin No. 230 (November 1996) lists a number of criteria by which to infer gestational age and, therefore, fetal lung maturity. The criteria include:
- documented fetal heart tone for 30 weeks by Doppler ultrasound
- 36 weeks having passed since reliable documentation of a positive urine or serum human chorionic gonadotropin pregnancy test
- crown–rump measurement by ultrasonography (US) at 6 to 11 weeks of gestation that supports the current gestational age of 39 weeks or more
- US measurement at 12 to 20 weeks’ gestation that supports the clinically determined estimated gestational age above 39 weeks.
Insurance concerns are vital to the decision
The Newborns’ and Mothers’ Health Protection Act (NMHPA) was passed in 1996. The law delineates a minimum requirement of coverage by insurers for hospital stays of 48 hours after vaginal delivery or 96 hours after C-section, thereby preventing health insurance plans from restricting hospital stays after delivery.11 The law was passed as a response to political concerns about “drive-thru deliveries.”
The NMHPA also allows for provider discretion regarding the length of stay required after childbirth, meaning that, if an attending-level provider deems discharge feasible in less than 48 or 96 hours, the insurer is not mandated to continue coverage beyond discharge.
The law, however, does not mandate coverage by health insurance plans for prenatal care, delivery, and postpartum care. Confounding the actions of health insurance companies are state laws governing the care of newborns and mothers, as these laws superceded the NMHPA. So, although most states have mandated benefit laws regarding a variety of services, as of 2002, only 18 states had laws mandating specific maternity services.12 Some states specifically mention elective C-sections as nonmandated services, meaning that a patient who elects a scheduled C-section at term without obstetric indications may be required to pay for her obstetric care.
1. Wax JR, Cartin A, Pinette MG, Blackstone J. Patient choice cesarean: an evidence-based review. Obstet Gynecol Surv. 2004;59:601-616.
2. Hopkins K. Are Brazilian women really choosing to deliver by cesarean? Soc Sci Med. 2000;51:725-740.
3. FIGO Committee for the Study of Ethical Aspects of Human Reproduction and Women’s Health. Ethical Issues in Obstetrics and Gynecology. November 2006. Available at www.figo.org/docs/Ethics%20Guidelines%20-%20English%20version%202006%20-2009.pdf. Accessed April 3, 2008.
4. ACOG Committee Opinion No 386: Cesarean delivery on maternal request. November 2007. Available at www.acog.org/publications/committee_opinions/co386.cfm. Accessed April 3, 2008.
5. National Institutes of Health state-of-the-science conference statement. Cesarean delivery on maternal request March 27-29, 2006. Obstet Gynecol. 2006;107:1386-1397.
6. Allen VM, O’Connell CM, Farrell SA, Baskett TF. Economic implications of method of delivery. Am J Obstet Gynecol. 2005;193:192-197.
7. McCourt C, Weaver J, Statham H, Beake S, Gamble J, Creedy DK. Elective cesarean section and decision making: a critical review of the literature. Birth. 2007;34:65-79.
8. Roberts RG, Deutchman M, King VJ, Fryer GE, Miyoshi TJ. Changing policies on vaginal birth after cesarean: impact on access. Birth. 2007;34:316-322.
9. Silver RM, Landon MB, Rouse DJ, et al. Maternal morbidity associated with multiple repeat cesarean deliveries. National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network. Obstet Gynecol. 2006;107:1226-1232.
10. Chervenak FA, McCullough LB. An ethically justified algorithm for offering, recommending, and performing cesarean delivery and its application in managed care practice. Obstet Gynecol. 1996;87:302-305.
11. Newborns’ and Mothers’ Health Protection Act of 1996, 29 U S.C.S. §1185.
12. Laugesen MJ, Paul RR, Luft HS, Aubry W, Ganiats TG. A comparative analysis of mandated benefit laws, 1949-2002. Health Serv Res. 2006;41(3 pt 2):1081-1103.
13. National Center for Health Statistics Technical Appendix. Vital statistics of the United States, 2004. Vol. I: Natality. US Department of Heath and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Hyattsville, Md. Available at www.cdc.gov/nchs/nvss.htm. Accessed April 3, 2008.
14. National Vital Statistics Reports. Vol. 55, No. 12, April 19, 2007. Available at www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_12.pdf. Accessed April 3, 2008.
1. Wax JR, Cartin A, Pinette MG, Blackstone J. Patient choice cesarean: an evidence-based review. Obstet Gynecol Surv. 2004;59:601-616.
2. Hopkins K. Are Brazilian women really choosing to deliver by cesarean? Soc Sci Med. 2000;51:725-740.
3. FIGO Committee for the Study of Ethical Aspects of Human Reproduction and Women’s Health. Ethical Issues in Obstetrics and Gynecology. November 2006. Available at www.figo.org/docs/Ethics%20Guidelines%20-%20English%20version%202006%20-2009.pdf. Accessed April 3, 2008.
4. ACOG Committee Opinion No 386: Cesarean delivery on maternal request. November 2007. Available at www.acog.org/publications/committee_opinions/co386.cfm. Accessed April 3, 2008.
5. National Institutes of Health state-of-the-science conference statement. Cesarean delivery on maternal request March 27-29, 2006. Obstet Gynecol. 2006;107:1386-1397.
6. Allen VM, O’Connell CM, Farrell SA, Baskett TF. Economic implications of method of delivery. Am J Obstet Gynecol. 2005;193:192-197.
7. McCourt C, Weaver J, Statham H, Beake S, Gamble J, Creedy DK. Elective cesarean section and decision making: a critical review of the literature. Birth. 2007;34:65-79.
8. Roberts RG, Deutchman M, King VJ, Fryer GE, Miyoshi TJ. Changing policies on vaginal birth after cesarean: impact on access. Birth. 2007;34:316-322.
9. Silver RM, Landon MB, Rouse DJ, et al. Maternal morbidity associated with multiple repeat cesarean deliveries. National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network. Obstet Gynecol. 2006;107:1226-1232.
10. Chervenak FA, McCullough LB. An ethically justified algorithm for offering, recommending, and performing cesarean delivery and its application in managed care practice. Obstet Gynecol. 1996;87:302-305.
11. Newborns’ and Mothers’ Health Protection Act of 1996, 29 U S.C.S. §1185.
12. Laugesen MJ, Paul RR, Luft HS, Aubry W, Ganiats TG. A comparative analysis of mandated benefit laws, 1949-2002. Health Serv Res. 2006;41(3 pt 2):1081-1103.
13. National Center for Health Statistics Technical Appendix. Vital statistics of the United States, 2004. Vol. I: Natality. US Department of Heath and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Hyattsville, Md. Available at www.cdc.gov/nchs/nvss.htm. Accessed April 3, 2008.
14. National Vital Statistics Reports. Vol. 55, No. 12, April 19, 2007. Available at www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_12.pdf. Accessed April 3, 2008.
Detecting Depression in Older Veterans: Impact of Cultural Diversity on Test Validity
Preventing Falls in Older Adults with Dementia
Distal Biceps Brachii Tendon Tear
Neurologic Injuries After Total Hip Arthroplasty
CHRONIC PELVIC PAIN
The author reports no financial relationships relevant to this article.
A common thread ties together the studies and developments highlighted here: the notion that maladaptive changes in the neurologic supply to pelvic organs may contribute to chronic pain to a greater extent than do stimuli from damaged tissue. This understanding is consistent with the general lack of any obvious relationship between the degree (i.e., volume) of tissue change in disease (e.g., endometriosis) and the intensity of associated pain. It may also open new avenues to the prevention and treatment of chronic pain.
In the future, treatments for painful conditions seen in gynecology are likely to expand beyond nonsteroidal analgesics and narcotics to include
- neuromodulatory drugs
- local anesthetics applied in novel ways
- nerve-stimulation procedures that are less invasive than methods used so far.
Furthermore, the art of treatment will involve an understanding of the most effective ways to mix and sequence these methods.
Preoperative preemptive analgesia may reduce long-term incisional pain
Mathiesen O, Moiniche S, Dahl JB. Gabapentin and post-operative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007;7:6.
Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141.
The study of preemptive analgesia over the past 20 or more years has focused almost exclusively on one goal: reducing immediate postoperative pain, usually with narcotic consumption as the primary outcome measure. Results have been mixed, with few studies showing clear and clinically meaningful benefit.
More recently, several studies have focused on what may be a more important longer-term clinical outcome measure: incisional pain long after surgery. Multiple studies document an incidence of 10% to 25% of patients reporting incisional pain long after their surgery.1 Thoracotomy, reconstructive breast procedures, and abdominal incisions have all been associated with this problem. The study by Fassoulaki and associates shows that one dose of gabapentin before abdominal hysterectomy was associated with less incisional pain a full month after surgery.
Implications for patients in chronic pain
Patients who suffer chronic pain and who undergo surgery require a higher dosage of narcotic analgesics during postoperative care than other patients might. This need is usually attributed to accelerated metabolism of the drugs, brought about by longstanding use before surgery. An alternative hypothesis that would unite these observations is that pain pathways in the central nervous system are activated when surgical trauma is inflicted and that they affect the intensity of pain after surgery. For example, if the spinal cord segments associated with the pelvic reproductive organs have been involved in conducting nociceptive (pain) signals for the months or years leading to surgery, superimposed stimulus of surgery may be less well tolerated.
This hypothesis gives rise to several tantalizing questions:
- Would preoperative medication with drugs used to treat neuropathic pain reduce both visceral and somatic components of postoperative pain?
- Would these medications, given early in the clinical course, help prevent the chronic pain associated with pelvic infection and endometriosis?
- Would this approach be an avenue to reduce long-term postoperative pain in women with chronic pain before surgery?
Observations from research into preemptive analgesia are providing the impetus for what promises to be a productive and exciting area of clinical research in the treatment of pain in a variety of clinical situations in gynecology.
In chronic pain, changes in innervation may extend to peripheral organs
Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol. 2005;193:1650–1655.
One widely accepted hypothesis is that chronic pain states are accompanied by changes in spinal cord neurophysiology at both neurochemical and neuroanatomic levels. Indeed, in animal models of chronic pain, neuronal connections are altered in the spinal cord such that touch and pressure excite true central pain fibers. New evidence suggests that changes in innervation associated with chronic pain may also affect peripheral organs (FIGURE).
For example, in the study by Atwal and associates, the uterus of women undergoing hysterectomy was stained for unmyelinated nerve fibers of the type commonly involved in visceral pain signals. Women undergoing surgery for painless conditions had a low density of pain fibers in the lower uterine segment compared with women who had chronic pain before surgery, who had a higher density of pain fibers. This was true for women who had otherwise normal pelvic anatomy, as well as for those who had endometriosis. These findings may explain the puzzling observation that hysterectomy relieves central pelvic pain in 78% of women undergoing the procedure (and improves pain in 22% of women with persistent pain) even when the uterus is histologically normal on routine pathologic examination.2
Perhaps even more intriguing is the notion that pelvic pain may ultimately be elucidated through the study of changes in neurologic systems rather than changes in gynecologic end organs themselves. If pain, initially triggered by alterations in end organs, becomes chronic and intractable by virtue of neurologic changes, this perspective may lead to entirely new approaches to preventing chronic pain.
Chronic pain may alter spinal cord neurophysiology
Under physiologic conditions, the nerves of the central nervous system guide the uterus and other organs through their respective functions. In some women, however, spinal cord neuronal circuitry becomes distorted, eliciting a pain response even when no trigger is present.
Less invasive nerve-stimulation method holds promise for pelvic pain
Nerve stimulation in a wide variety of forms has long been used to block nociceptive signals. Examples include sacral nerve root stimulators, spinal cord implants, and transcutaneous electrical nerve stimulation (TENS) units. Their efficacy varies across pain syndromes, and the duration of impact (even in successfully treated women) is uncertain. The invasive nature of the implanted devices adds to the risk and often relegates them to the bottom of the list of treatment options.
Another method of peripheral nerve stimulation—posterior tibial nerve stimulation—was recently approved by the Food and Drug Administration for treatment of bladder irritability, and may also improve urge incontinence and pelvic pain.3,4 It involves application of electrical stimuli to a very fine (acupuncture-like) needle placed next to the posterior tibial nerve, just posterior to the medial maleolus. The nerve is generally stimulated for 30 minutes a week for a series of 12 treatments. Other protocols are bound to emerge as this method is applied more broadly.
In the case of irritability, bladder pain is also often relieved. The treatment is now being tried in women with interstitial cystitis. Even though the nerve supplies of the various pelvic and vulvar organs do not all arise from the same spinal cord segments, communications within the cord may explain the broader impact of techniques like posterior tibial nerve stimulation.
1. Kehlet H, Jensen TS, Woolf CJ. Persistent post-surgical pain: risk factors and prevention. Lancet. 2006;367:1618-1625.
2. Stovall TG, Ling FW, Crawford DA. Hysterectomy for chronic pelvic pain of presumed uterine etiology. Obstet Gynecol. 1990;75:676-679.
3. Congregado RB, Pena OXM, Campoy MP, Leon DE, Leal LA. Peripheral afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur Urol. 2004;45:65-69.
4. van Balken MR, Vandoninck V, Messelink BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43:158-163.
The author reports no financial relationships relevant to this article.
A common thread ties together the studies and developments highlighted here: the notion that maladaptive changes in the neurologic supply to pelvic organs may contribute to chronic pain to a greater extent than do stimuli from damaged tissue. This understanding is consistent with the general lack of any obvious relationship between the degree (i.e., volume) of tissue change in disease (e.g., endometriosis) and the intensity of associated pain. It may also open new avenues to the prevention and treatment of chronic pain.
In the future, treatments for painful conditions seen in gynecology are likely to expand beyond nonsteroidal analgesics and narcotics to include
- neuromodulatory drugs
- local anesthetics applied in novel ways
- nerve-stimulation procedures that are less invasive than methods used so far.
Furthermore, the art of treatment will involve an understanding of the most effective ways to mix and sequence these methods.
Preoperative preemptive analgesia may reduce long-term incisional pain
Mathiesen O, Moiniche S, Dahl JB. Gabapentin and post-operative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007;7:6.
Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141.
The study of preemptive analgesia over the past 20 or more years has focused almost exclusively on one goal: reducing immediate postoperative pain, usually with narcotic consumption as the primary outcome measure. Results have been mixed, with few studies showing clear and clinically meaningful benefit.
More recently, several studies have focused on what may be a more important longer-term clinical outcome measure: incisional pain long after surgery. Multiple studies document an incidence of 10% to 25% of patients reporting incisional pain long after their surgery.1 Thoracotomy, reconstructive breast procedures, and abdominal incisions have all been associated with this problem. The study by Fassoulaki and associates shows that one dose of gabapentin before abdominal hysterectomy was associated with less incisional pain a full month after surgery.
Implications for patients in chronic pain
Patients who suffer chronic pain and who undergo surgery require a higher dosage of narcotic analgesics during postoperative care than other patients might. This need is usually attributed to accelerated metabolism of the drugs, brought about by longstanding use before surgery. An alternative hypothesis that would unite these observations is that pain pathways in the central nervous system are activated when surgical trauma is inflicted and that they affect the intensity of pain after surgery. For example, if the spinal cord segments associated with the pelvic reproductive organs have been involved in conducting nociceptive (pain) signals for the months or years leading to surgery, superimposed stimulus of surgery may be less well tolerated.
This hypothesis gives rise to several tantalizing questions:
- Would preoperative medication with drugs used to treat neuropathic pain reduce both visceral and somatic components of postoperative pain?
- Would these medications, given early in the clinical course, help prevent the chronic pain associated with pelvic infection and endometriosis?
- Would this approach be an avenue to reduce long-term postoperative pain in women with chronic pain before surgery?
Observations from research into preemptive analgesia are providing the impetus for what promises to be a productive and exciting area of clinical research in the treatment of pain in a variety of clinical situations in gynecology.
In chronic pain, changes in innervation may extend to peripheral organs
Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol. 2005;193:1650–1655.
One widely accepted hypothesis is that chronic pain states are accompanied by changes in spinal cord neurophysiology at both neurochemical and neuroanatomic levels. Indeed, in animal models of chronic pain, neuronal connections are altered in the spinal cord such that touch and pressure excite true central pain fibers. New evidence suggests that changes in innervation associated with chronic pain may also affect peripheral organs (FIGURE).
For example, in the study by Atwal and associates, the uterus of women undergoing hysterectomy was stained for unmyelinated nerve fibers of the type commonly involved in visceral pain signals. Women undergoing surgery for painless conditions had a low density of pain fibers in the lower uterine segment compared with women who had chronic pain before surgery, who had a higher density of pain fibers. This was true for women who had otherwise normal pelvic anatomy, as well as for those who had endometriosis. These findings may explain the puzzling observation that hysterectomy relieves central pelvic pain in 78% of women undergoing the procedure (and improves pain in 22% of women with persistent pain) even when the uterus is histologically normal on routine pathologic examination.2
Perhaps even more intriguing is the notion that pelvic pain may ultimately be elucidated through the study of changes in neurologic systems rather than changes in gynecologic end organs themselves. If pain, initially triggered by alterations in end organs, becomes chronic and intractable by virtue of neurologic changes, this perspective may lead to entirely new approaches to preventing chronic pain.
Chronic pain may alter spinal cord neurophysiology
Under physiologic conditions, the nerves of the central nervous system guide the uterus and other organs through their respective functions. In some women, however, spinal cord neuronal circuitry becomes distorted, eliciting a pain response even when no trigger is present.
Less invasive nerve-stimulation method holds promise for pelvic pain
Nerve stimulation in a wide variety of forms has long been used to block nociceptive signals. Examples include sacral nerve root stimulators, spinal cord implants, and transcutaneous electrical nerve stimulation (TENS) units. Their efficacy varies across pain syndromes, and the duration of impact (even in successfully treated women) is uncertain. The invasive nature of the implanted devices adds to the risk and often relegates them to the bottom of the list of treatment options.
Another method of peripheral nerve stimulation—posterior tibial nerve stimulation—was recently approved by the Food and Drug Administration for treatment of bladder irritability, and may also improve urge incontinence and pelvic pain.3,4 It involves application of electrical stimuli to a very fine (acupuncture-like) needle placed next to the posterior tibial nerve, just posterior to the medial maleolus. The nerve is generally stimulated for 30 minutes a week for a series of 12 treatments. Other protocols are bound to emerge as this method is applied more broadly.
In the case of irritability, bladder pain is also often relieved. The treatment is now being tried in women with interstitial cystitis. Even though the nerve supplies of the various pelvic and vulvar organs do not all arise from the same spinal cord segments, communications within the cord may explain the broader impact of techniques like posterior tibial nerve stimulation.
The author reports no financial relationships relevant to this article.
A common thread ties together the studies and developments highlighted here: the notion that maladaptive changes in the neurologic supply to pelvic organs may contribute to chronic pain to a greater extent than do stimuli from damaged tissue. This understanding is consistent with the general lack of any obvious relationship between the degree (i.e., volume) of tissue change in disease (e.g., endometriosis) and the intensity of associated pain. It may also open new avenues to the prevention and treatment of chronic pain.
In the future, treatments for painful conditions seen in gynecology are likely to expand beyond nonsteroidal analgesics and narcotics to include
- neuromodulatory drugs
- local anesthetics applied in novel ways
- nerve-stimulation procedures that are less invasive than methods used so far.
Furthermore, the art of treatment will involve an understanding of the most effective ways to mix and sequence these methods.
Preoperative preemptive analgesia may reduce long-term incisional pain
Mathiesen O, Moiniche S, Dahl JB. Gabapentin and post-operative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007;7:6.
Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141.
The study of preemptive analgesia over the past 20 or more years has focused almost exclusively on one goal: reducing immediate postoperative pain, usually with narcotic consumption as the primary outcome measure. Results have been mixed, with few studies showing clear and clinically meaningful benefit.
More recently, several studies have focused on what may be a more important longer-term clinical outcome measure: incisional pain long after surgery. Multiple studies document an incidence of 10% to 25% of patients reporting incisional pain long after their surgery.1 Thoracotomy, reconstructive breast procedures, and abdominal incisions have all been associated with this problem. The study by Fassoulaki and associates shows that one dose of gabapentin before abdominal hysterectomy was associated with less incisional pain a full month after surgery.
Implications for patients in chronic pain
Patients who suffer chronic pain and who undergo surgery require a higher dosage of narcotic analgesics during postoperative care than other patients might. This need is usually attributed to accelerated metabolism of the drugs, brought about by longstanding use before surgery. An alternative hypothesis that would unite these observations is that pain pathways in the central nervous system are activated when surgical trauma is inflicted and that they affect the intensity of pain after surgery. For example, if the spinal cord segments associated with the pelvic reproductive organs have been involved in conducting nociceptive (pain) signals for the months or years leading to surgery, superimposed stimulus of surgery may be less well tolerated.
This hypothesis gives rise to several tantalizing questions:
- Would preoperative medication with drugs used to treat neuropathic pain reduce both visceral and somatic components of postoperative pain?
- Would these medications, given early in the clinical course, help prevent the chronic pain associated with pelvic infection and endometriosis?
- Would this approach be an avenue to reduce long-term postoperative pain in women with chronic pain before surgery?
Observations from research into preemptive analgesia are providing the impetus for what promises to be a productive and exciting area of clinical research in the treatment of pain in a variety of clinical situations in gynecology.
In chronic pain, changes in innervation may extend to peripheral organs
Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol. 2005;193:1650–1655.
One widely accepted hypothesis is that chronic pain states are accompanied by changes in spinal cord neurophysiology at both neurochemical and neuroanatomic levels. Indeed, in animal models of chronic pain, neuronal connections are altered in the spinal cord such that touch and pressure excite true central pain fibers. New evidence suggests that changes in innervation associated with chronic pain may also affect peripheral organs (FIGURE).
For example, in the study by Atwal and associates, the uterus of women undergoing hysterectomy was stained for unmyelinated nerve fibers of the type commonly involved in visceral pain signals. Women undergoing surgery for painless conditions had a low density of pain fibers in the lower uterine segment compared with women who had chronic pain before surgery, who had a higher density of pain fibers. This was true for women who had otherwise normal pelvic anatomy, as well as for those who had endometriosis. These findings may explain the puzzling observation that hysterectomy relieves central pelvic pain in 78% of women undergoing the procedure (and improves pain in 22% of women with persistent pain) even when the uterus is histologically normal on routine pathologic examination.2
Perhaps even more intriguing is the notion that pelvic pain may ultimately be elucidated through the study of changes in neurologic systems rather than changes in gynecologic end organs themselves. If pain, initially triggered by alterations in end organs, becomes chronic and intractable by virtue of neurologic changes, this perspective may lead to entirely new approaches to preventing chronic pain.
Chronic pain may alter spinal cord neurophysiology
Under physiologic conditions, the nerves of the central nervous system guide the uterus and other organs through their respective functions. In some women, however, spinal cord neuronal circuitry becomes distorted, eliciting a pain response even when no trigger is present.
Less invasive nerve-stimulation method holds promise for pelvic pain
Nerve stimulation in a wide variety of forms has long been used to block nociceptive signals. Examples include sacral nerve root stimulators, spinal cord implants, and transcutaneous electrical nerve stimulation (TENS) units. Their efficacy varies across pain syndromes, and the duration of impact (even in successfully treated women) is uncertain. The invasive nature of the implanted devices adds to the risk and often relegates them to the bottom of the list of treatment options.
Another method of peripheral nerve stimulation—posterior tibial nerve stimulation—was recently approved by the Food and Drug Administration for treatment of bladder irritability, and may also improve urge incontinence and pelvic pain.3,4 It involves application of electrical stimuli to a very fine (acupuncture-like) needle placed next to the posterior tibial nerve, just posterior to the medial maleolus. The nerve is generally stimulated for 30 minutes a week for a series of 12 treatments. Other protocols are bound to emerge as this method is applied more broadly.
In the case of irritability, bladder pain is also often relieved. The treatment is now being tried in women with interstitial cystitis. Even though the nerve supplies of the various pelvic and vulvar organs do not all arise from the same spinal cord segments, communications within the cord may explain the broader impact of techniques like posterior tibial nerve stimulation.
1. Kehlet H, Jensen TS, Woolf CJ. Persistent post-surgical pain: risk factors and prevention. Lancet. 2006;367:1618-1625.
2. Stovall TG, Ling FW, Crawford DA. Hysterectomy for chronic pelvic pain of presumed uterine etiology. Obstet Gynecol. 1990;75:676-679.
3. Congregado RB, Pena OXM, Campoy MP, Leon DE, Leal LA. Peripheral afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur Urol. 2004;45:65-69.
4. van Balken MR, Vandoninck V, Messelink BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43:158-163.
1. Kehlet H, Jensen TS, Woolf CJ. Persistent post-surgical pain: risk factors and prevention. Lancet. 2006;367:1618-1625.
2. Stovall TG, Ling FW, Crawford DA. Hysterectomy for chronic pelvic pain of presumed uterine etiology. Obstet Gynecol. 1990;75:676-679.
3. Congregado RB, Pena OXM, Campoy MP, Leon DE, Leal LA. Peripheral afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur Urol. 2004;45:65-69.
4. van Balken MR, Vandoninck V, Messelink BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43:158-163.
Managing preterm birth to lower the risk of cerebral palsy
The author reports no financial relationships relevant to this article.
- Intrapartum hypoxia, once considered an important cause of cerebral palsy (CP), is responsible for only 8% to 10% of cases.
- Increasingly, evidence suggests that the primary cause of CP lies in the relationship among intrauterine infection and inflammation, preterm labor, preterm premature rupture of membranes (pPROM), and neonatal white matter disease.
- This review focuses on that relationship and its implications for managing preterm birth with intact membranes or pPROM.
Cerebral palsy is a complex disease characterized by aberrant control of movement or posture that results from an insult to the developing central nervous system (CNS). In addition to motor abnormalities, some patients have seizures, cognitive impairment, and extrapyramidal abnormalities.
Clinical and epidemiologic evidence points to white matter lesions and severe intraventricular hemorrhage (IVH)—detected by neonatal neurosonography—as the key determinants of CP. The lesions are the sonographic antecedent or counterpart of periventricular leukomalacia (PVL), a cerebral lesion characterized by foci of necrosis in the white matter near the ventricles (FIGURE).
The principal risk factor is prematurity
A precise cause for CP has not been identified in more than 75% of cases. The leading identifiable risk factor is prematurity. The prevalence of CP at 3 years of age is 4.4% among infants born earlier than 27 weeks of gestation, compared with 0.06% among babies born at term.1
FIGURE Periventricular leukomalacia
Four axial magnetic resonance images of the brain of an infant show the usual appearance of this cerebral lesion, characterized by foci of necrosis of white matter near the ventricles.
How inflammation leads to premature birth
Any condition that increases the incidence of prematurity can be expected to increase the incidence of CP. More than 80% of premature births follow preterm labor or pPROM. Clinical and experimental evidence suggests that most of these births reflect one or more of four major pathogenic processes, which lead to uterine contractions and cervical changes, with or without premature rupture of membranes2:
- local or systemic inflammatory immune response
- activation of the maternal or fetal hypothalamic–pituitary–adrenal axis
- decidual hemorrhage (abruption)
- pathologic distention of the uterus.
Two or more of these processes often occur simultaneously, ultimately converging on a final common biochemical pathway that leads to degradation of the extracellular matrix in the cervix and fetal membranes and activation of the uterine myometrium. This process leads in turn to cervical dilation, rupture of membranes, and uterine contractions.
The “inflammatory pathway” is activated in most cases of spontaneous preterm labor and pPROM. As many as 50% of women with preterm labor and intact membranes have histologic chorioamnionitis; the rate is even higher in pPROM. The incidence of chorioamnionitis increases with decreasing gestational age.
Invading microorganisms in gestational tissues often cause intrauterine inflammation and preterm birth. Highly sensitive molecular techniques detect bacteria in the amniotic fluid of as many as half of patients with preterm labor with intact membranes3 and even more women with pPROM. As with chorioamnionitis, the lower the gestational age, the higher the bacterial isolation rates—45% at 23 to 26 weeks compared with 17% at 27 to 30 weeks.4 The microorganisms isolated are often those colonizing the vagina—most commonly anaerobes, gram-negative rods, Gardnerella vaginalis, group B streptococci, Mycoplasma hominis, and Ureaplasma urealyticum.
Infection doesn’t always lead to inflammation
Bacterial products—particularly endotoxin, a major constituent of gram-negative bacteria—bind to a specific pattern-recognition receptor, known as a toll-like receptor, on cell surfaces. This activates innate immunity and stimulates a proinflammatory immune response. Endotoxin is a potent stimulant for proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which promote the release of chemoattractant cytokines such as IL-6 and IL-8. Different white blood cells migrate into the inflamed tissue and become activated at the same time.
The uterine cavity is thought to be sterile, and microorganisms there are universally associated with inflammation. Recent studies challenge this assumption. One found bacteria in as many as 90% of endometrial samples from nonpregnant women, but histologic endometritis in only 40%.5 Another noted bacteria in as many as 80% of gestational tissues delivered electively by cesarean section at term or before 32 weeks because of preeclampsia, but histologic assessment showed no or minimal inflammation.6
Why don’t all women develop inflammation?
A critical question is why some pregnant women with microbial invasion of gestational tissues develop inflammation, whereas others do not. Susceptibility depends, in part, on the pathogenicity and amount of invading bacteria. Endotoxin-containing gram-negative bacteria elicit an especially potent inflammatory response. The strength of the response correlates with the amount of endotoxin-containing bacteria in the environment.7
The isolation rate of bacteria from the intrauterine cavity is higher in women with bacterial vaginosis (BV), a condition characterized by malodorous vaginal discharge, vaginal pH higher than 4.5, and a shift from a Lactobacilli-dominant vaginal flora toward predominance of G vaginalis, anaerobic bacteria, and M hominis. The greater number of bacteria may account, in part, for a twofold greater risk of preterm delivery among women diagnosed with BV during pregnancy.8
Genetics may also play a role. Intrauterine inflammation and morbidity are partly influenced by common variations (polymorphisms) in immunoregulatory genes. Preliminary evidence suggests that some women who carry a variant of the TNF-α gene can mount an exaggerated immune response to BV-related organisms (hyper-responders),9 increasing their risk of preterm delivery.10
Inflammation alone is a risk factor for CP
Growing evidence suggests that intrauterine inflammation increases the risk of neonatal white matter disease and subsequent development of CP beyond the risk conferred by gestational age at birth. The relative risk (RR) for CP in preterm infants born after intrauterine infection and inflammation or inflammation alone is 1.9 and 1.6, respectively.11
The association between inflammation, neonatal white matter disease, and CP is strongest in fetuses with funisitis and a plasma IL-6 level greater than 11 ng/mL12—a condition known as fetal inflammatory response syndrome (FIRS). FIRS is also associated with other sequelae of prematurity, including bronchopulmonary dysplasia, respiratory distress syndrome, and myocardial dysfunction.
Can we diagnose subacute inflammation and infection?
Diagnosing and treating intrauterine inflammation promptly may decrease the risk of CP. No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient. Maternal signs and symptoms such as fundal tenderness, tachycardia, and fever, along with laboratory findings such as an elevated C-reactive protein level and an elevated white blood cell (WBC) count in peripheral blood, indicate overt chorioamnionitis and systemic maternal infection. However, these tests are not especially useful for diagnosing subacute intrauterine infection and inflammation in patients with preterm labor and intact membranes or pPROM. Some authorities advocate amniocentesis for these patients.
- Prematurity is the leading risk factor for cerebral palsy (CP)
- Subacute intrauterine infection and inflammation are common causes of preterm delivery
- Intrauterine inflammation may lower the threshold at which hypoxia becomes neurotoxic in the fetus
- No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient
- A biophysical profile (BPP) score of 7 or lower predicts infection-related neonatal outcomes better than any single component of the BPP
- In a pregnancy complicated by pPROM, adjunctive antibiotics prolong pregnancy for as long as 10 days, but do not affect neonatal neurologic outcome
- Adjunctive antibiotics have no proven benefit in managing preterm labor with intact membranes
- Screening for and treating bacterial vaginosis during pregnancy are not useful
- Prophylactic antibiotic treatment during the periconceptional period has no proven benefit
- A single course of antenatal steroids in preterm labor with intact membranes or pPROM significantly decreases neonatal mortality and neurologic morbidity without raising the risk of neonatal sepsis—even in the presence of intrauterine infection
- Tocolysis with magnesium sulfate or a calcium-channel blocker to stop preterm labor with intact membranes may decrease neurologic morbidity in neonates
- Consider delivery after 32 weeks if fetal lung maturity is confirmed because 1) expectant management of pPROM beyond 32 completed weeks of gestation does not have a clear benefit and 2) intrauterine inflammation associated with white matter disease is common in pPROM
A positive bacterial culture or gram-stained slide of amniotic fluid confirms intra-amniotic infection but detects fewer than 50% of cases. Other diagnostic criteria, such as an elevated WBC count, high level of lactate dehydrogenase activity, high protein level, and low glucose concentration in amniotic fluid, are more sensitive, but nonspecific, for amniotic infection and inflammation.
Elevated inflammatory cytokines such as IL-6 in amniotic fluid and fetal blood have been associated with intrauterine inflammation and neonatal white matter disease in women with preterm labor and intact membranes or pPROM, but they are not significantly more accurate than the previously mentioned biomarkers.13,14 An amniotic fluid pocket may not be accessible by the abdominal approach in most patients with pPROM because of significant oligohydramnios. Testing amniotic fluid from the vagina is an alternative. Low glucose in vaginal samples is a specific, but not a sensitive, marker for intra-amniotic infection.15
Using the BPP. The biophysical profile has been used to identify fetuses at risk of FIRS in the presence of pPROM. Oligohydramnios—especially when the largest vertical amniotic fluid pocket is smaller than 1 cm—and diminished fetal breathing and body movement are associated with chorioamnionitis and suspected or proven neonatal sepsis. A nonreactive nonstress test is specific but not sensitive.
Although each component of the BPP provides useful information, a BPP score of 7 or lower predicts infection-related outcome much better than any single finding. In a population with an infection-related outcome of 30%, a BPP score of 7 or lower within 24 hours of delivery had a positive predictive value of 95% and a negative predictive value of 97%.16 A retrospective case-control study found that women who were followed with daily BPP and delivered within 24 hours after a BPP score of 7 or lower on two examinations 2 hours apart had a lower rate of neonatal sepsis than women who were managed expectantly or had a single amniocentesis on admission to the hospital.17
How management tactics affect neurologic outcome
Options for women in preterm labor with intact membranes or pPROM include antibiotics, antenatal steroids, tocolytics, or early delivery.
Antibiotics in cases of pPROM only
The findings of two large clinical trials powerful enough to evaluate adjunctive antibiotics in women with pPROM are in agreement: Such treatment prolongs the pregnancy briefly (as long as 10 days).18,19
NICHD-MFMU study. In a trial conducted by the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (NICHD-MFMU) Research Network, 48 hours of intravenous therapy with ampicillin and erythromycin followed by 5 days of oral amoxicillin and enteric-coated erythromycin given to 614 women between 24 and 32 weeks’ gestation decreased the number of infants who died or suffered a major morbidity, including respiratory distress syndrome, early sepsis, severe IVH, or severe necrotizing enterocolitis.18
ORACLE I. The results of the larger ORACLE I trial, which included 4,826 women, were less impressive.19 Patients who developed pPROM before 37 weeks’ gestation received erythromycin, amoxicillin-clavulanic acid, or both, or placebo for up to 10 days. Although antibiotic therapy prolonged pregnancy briefly, it did not have a major impact on neonatal mortality or any major morbidity, including cerebral abnormality on ultrasonography (US). In contrast to the NICHD-MFMU Research Network study, treatment with oral amoxicillin-clavulanic acid increased the risk of necrotizing enterocolitis.
ORACLE II. The ORACLE II trial evaluated the benefit of adjunctive antibiotics for 6,295 women in spontaneous preterm labor before 37 weeks’ gestation who had intact membranes and no evidence of clinical infection.20 The women received erythromycin, amoxicillin-clavulanic acid, or both, or placebo for as long as 10 days. Compared with placebo, none of the antibiotics was associated with a lower rate of the composite primary outcome, which included major cerebral abnormality on US before discharge from the hospital.
Prophylaxis. It has been suggested that antibiotics are more likely to prevent preterm birth if they are given long before contractions start or membranes rupture. Studies of antibiotic prophylaxis to prevent preterm birth and related sequelae don’t support this notion. A Cochrane meta-analysis of six randomized clinical trials involving 2,184 asymptomatic women who received prophylactic antibiotics in the second or third trimester found no reduction in the risk of subsequent preterm birth.21 In fact, intervention increased the risk of neonatal sepsis (odds ratio [OR]=8.07, 95% confidence interval [CI], 1.36 to 47.77). Another meta-analysis of the effect of antibiotics on BV during pregnancy drew similar conclusions.22 This analysis of 15 randomized clinical trials with a total of 5,888 patients showed that treating BV did not reduce the risk of preterm birth. The trials reported very few perinatal deaths, and none reported substantive neonatal morbidity.
Another hypothesis argues that the events leading to preterm birth begin in very early stages of pregnancy, including conception and implantation of the embryo. To test this hypothesis, 241 women with a history of spontaneous preterm birth or pPROM between 16 and 34 weeks’ gestation were randomized to receive an oral course of azithromycin and metronidazole or placebo every 4 months until conception.23 The 124 women who conceived and were available for follow-up showed no difference in the rate of preterm birth between the treatment and placebo groups. In fact, women who received an antibiotic tended to have a shorter pregnancy and a lower-birth-weight baby than those given placebo.
Several mechanisms have been proposed to explain the role of inflammation in neonatal white matter disease. Microorganisms and microbial products can gain access to the fetus and activate inflammatory cytokines, increasing the permeability of the blood–brain barrier and facilitating passage of the cytokines into the brain.
Microbial products stimulate human fetal microglia (the central nervous system [CNS] equivalent of macrophages) to produce interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which, in turn, stimulate proliferation of astrocytes (the CNS equivalent of fibroblasts) and production of TNF. Leviton proposed that TNF-α can damage white matter by four mechanisms:33
- inducing hypotension and brain ischemia
- stimulating the production of a tissue factor, which can activate the hemostatic system and contribute to coagulation necrosis of white matter
- inducing the release of platelet-activating factor, which can act as a membrane detergent, causing direct brain damage
- producing a direct cytotoxic effect on oligodendrocytes.
Polymorphisms in immunomodulatory genes, such as the gene encoding TNF-α, modify the immune response and the risk for white matter disease in preterm infants.34
Based on available data, treatment with a short course of antibiotics such as erythromycin or ampicillin, or both, is recommended only in cases of pPROM.
Antenatal steroids improve outcome
Antenatal steroids reduce neonatal mortality and morbidity, including IVH and PVL, in infants born between 24 and 34 weeks’ gestation. One concern raised about antenatal steroid use is whether it increases the risk of neonatal infection and morbidity when intrauterine infection and inflammation are present. A retrospective analysis of infants who weighed 1,750 g or more at birth concluded that antenatal steroids significantly decreased neonatal mortality and morbidity—including IVH, PVL, and major brain lesions—without increasing neonatal sepsis in babies delivered following preterm labor or pPROM.24
In another retrospective analysis of 457 consecutive 23- to 32-week live-born singletons, antenatal steroids weren’t associated with significant worsening of any neonatal outcome. Steroids were associated with significant reductions in respiratory distress syndrome and neonatal systemic inflammatory response syndrome in infants with positive placental cultures and elevated cord blood IL-6 levels.25
These data suggest that antenatal steroids may not be contraindicated in the face of inflammation and infection; they may, in fact, be beneficial. In women with pPROM, weekly administration of ante-natal steroids doesn’t seem to improve neonatal outcomes more than single-course therapy and may increase the risk of chorioamnionitis.26
Some tocolytics may help
Tocolytic agents are often given to women with preterm contractions to delay delivery long enough to administer a course of antenatal corticosteroids.
Magnesium sulfate is commonly used in the United States. A 2007 Cochrane meta-analysis of four trials (3,701 babies) found that antenatal magnesium sulfate had no statistically significant effect on any major pediatric outcome, including death and neurologic problems such as CP in the first few years of life.27 Nor did antenatal magnesium therapy significantly affect combined rates of mortality and neurologic outcomes. Two trials involving 2,848 infants found a significant reduction in substantial gross motor dysfunction (RR=0.56; 95% CI, 0.33 to 0.97).
Betamimetics are also widely used for tocolysis, especially in resource-poor countries. Eleven randomized controlled trials, involving 1,332 women, compared betamimetics with placebo.28 Although betamimetics decreased the number of women in preterm labor who gave birth within 48 hours, they didn’t reduce perinatal or neonatal death. Data on CP were too sparse to allow comment. Because these drugs cause many maternal side effects, they aren’t considered first-line tocolytics.
Calcium-channel blockers are attracting growing interest as potentially effective and well-tolerated tocolytic agents. A meta-analysis of 12 randomized controlled trials involving 1,029 women suggests that calcium-channel blockers reduce the number of women giving birth within 7 days of receiving treatment, compared with other tocolytic agents (mainly betamimetics).29 They also decrease the frequency of neonatal morbidity, including IVH (RR, 0.59; 95% CI, 0.36 to 0.98).
Cyclooxygenase (COX) inhibitors are easy to administer and cause fewer maternal side effects than conventional tocolytics. A 2005 Cochrane meta-analysis includes outcome data from 13 trials with a total of 713 women.30 Indomethacin, a non-selective COX inhibitor, was used in 10 trials. COX inhibition reduced birth before 37 weeks’ gestation more effectively than other tocolytic agents, but data were insufficient to comment on neonatal outcomes.
In women with pPROM, starting tocolysis before onset of contractions prolongs latency. However, the utility of tocolytic therapy after pPROM remains controversial pending more powerful randomized trials.
Early delivery is an option
It has been suggested that exposure to infection, especially proinflammatory cytokines, reduces the threshold at which hypoxia becomes neurotoxic, making the brain much more vulnerable to even mild hypoxic insults. A recent study found that infants with encephalopathy were more than 90 times more likely to have experienced both neonatal intrapartum acidosis and maternal intrapartum fever than infants with no encephalopathy; maternal fever or neonatal acidosis increased the risk six- and 12-fold, respectively.31 Lack of interaction between maternal fever and acidosis suggests that these are separate causal pathways to adverse neonatal outcomes. Although intrapartum fever doesn’t always correlate with intrauterine inflammation, the findings of this study suggest that fetal acidosis should be avoided when intrauterine infection and inflammation are suspected.
Conservative management of pPROM remote from term has been shown to prolong pregnancy significantly and reduce complications in the infant when prophylactic antibiotics and ante-natal steroids are given concurrently. The benefit of this strategy is less clear after 32 weeks of gestation because:
- The efficacy of antenatal steroids after 32 weeks is unclear
- Beyond 32 weeks, the risk of severe complications of prematurity, including CP, is low if fetal lung maturity has been established by amniotic fluid samples collected vaginally or by amniocentesis.
For these reasons and because sub-acute intrauterine inflammation may harm the fetus, delivery can be considered after 32 completed weeks of gestation if fetal lung maturity is confirmed. A meta-analysis of four randomized controlled trials that compared intentional delivery with expectant management after pPROM between 30 and 36 weeks of gestation found no difference in neonatal outcomes.32
1. Cummins SK, Nelson KB, Grether JK, Velie EM. Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr. 1993;123:230-237.
2. Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol. 2001;15 Suppl 2:78-89.
3. Gardella C, Riley DE, Hitti J, Agnew K, Krieger JN, Eschenbach D. Identification and sequencing of bacterial rDNAs in culture-negative amniotic fluid from women in premature labor. Am J Perinatol. 2004;21:319-323.
4. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol. 1992;79:351-357.
5. Andrews WW, Hauth JC, Cliver SP, Conner MG, Goldenberg RL, Goepfert AR. Association of asymptomatic bacterial vaginosis with endometrial microbial colonization and plasma cell endometritis in nonpregnant women. Am J Obstet Gynecol. 2006;195:1611-1616.
6. Steele JH, Malatos S, Kennea N, et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res. 2005;57:404-411.
7. Genc MR, Witkin SS, Delaney ML, et al. A disproportionate increase in IL-1beta over IL-1ra in cervicovaginal secretions of pregnant women with vaginal microflora correlates with preterm birth. Am J Obstet Gynecol. 2004;190:1191-1197.
8. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol. 2003;189:139-147.
9. Genc MR, Vardhana S, Delaney ML, Witkin SS, Onderdonk AB. MAP Study Group. TNFA-308G>A polymorphism influences the TNF-alpha response to altered vaginal flora. Eur J Obstet Gynecol Reprod Biol. 2007;134:188-191.
10. Macones GA, Parry S, Elkousy M, et al. A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol. 2004;190:1504-1508.
11. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA. 2000;284:1417-1424.
12. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179:194-202.
13. Romero R, Yoon BH, Mazor M, et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 1993;169:839-851.
14. Romero R, Yoon BH, Mazor M, et al. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 1993;169:805-816.
15. Buhimschi CS, Sfakianaki AK, Hamar BG, et al. A low vaginal “pool” amniotic fluid glucose measurement is a predictive but not a sensitive marker for infection in women with preterm premature rupture of membranes. Am J Obstet Gynecol. 2006;194:309-316.
16. Vintzileos AM, Campbell WA, Nochimson DJ, Connolly ME, Fuenfer MM, Hoehn GJ. The fetal biophysical profile in patients with premature rupture of the membranes—an early predictor of fetal infection. Am J Obstet Gynecol. 1985;152:510-516.
17. Vintzileos AM, Bors-Koefoed R, Pelegano JF, et al. The use of fetal biophysical profile improves pregnancy outcome in premature rupture of the membranes. Am J Obstet Gynecol. 1987;157:236-240.
18. Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA. 1997;278:989-995.
19. Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet. 2001;357:979-988.
20. Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. Lancet. 2001;357:989-994.
21. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality. Cochrane Database Syst Rev. 2002;(4):CD002250.-
22. McDonald H, Brocklehurst P, Parsons J. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2005;(1):CD000262.-
23. Andrews WW, Goldenberg RL, Hauth JC, Cliver SP, Copper R, Conner M. Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am J Obstet Gynecol. 2006;194:617-623.
24. Elimian A, Verma U, Canterino J, Shah J, Visintainer P, Tejani N. Effectiveness of antenatal steroids in obstetric subgroups. Obstet Gynecol. 1999;93:174-179.
25. Goldenberg RL, Andrews WW, Faye-Petersen OM, Cliver SP, Goepfert AR, Hauth JC. The Alabama preterm birth study: corticosteroids and neonatal outcomes in 23- to 32-week newborns with various markers of intrauterine infection. Am J Obstet Gynecol. 2006;195:1020-1024.
26. Ghidini A, Salafia CM, Minior VK. Repeated courses of steroids in preterm membrane rupture do not increase the risk of histologic chorioamnionitis. Am J Perinatol. 1997;14:309-313.
27. Doyle LW, Crowther CA, Middleton P, Marret S. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2007;(3):CD004661.-
28. Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004;(8):CD004352.-
29. King JF, Flenady VJ, Papatsonis DN, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2002;(2):CD002255.-
30. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygen-ase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005;(2):CD001992.-
31. Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P. The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol. 2008;198:49-51.
32. Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2006;19:177-187.
33. Leviton A. Preterm birth and cerebral palsy: is tumor necrosis factor the missing link?. Dev Med Child Neurol. 1993;35:553-558.
34. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA. South Australian Cerebral Palsy Research Group. The association between inherited cytokine polymorphisms and cerebral palsy. Am J Obstet Gynecol. 2006;194:674.e1-11.
The author reports no financial relationships relevant to this article.
- Intrapartum hypoxia, once considered an important cause of cerebral palsy (CP), is responsible for only 8% to 10% of cases.
- Increasingly, evidence suggests that the primary cause of CP lies in the relationship among intrauterine infection and inflammation, preterm labor, preterm premature rupture of membranes (pPROM), and neonatal white matter disease.
- This review focuses on that relationship and its implications for managing preterm birth with intact membranes or pPROM.
Cerebral palsy is a complex disease characterized by aberrant control of movement or posture that results from an insult to the developing central nervous system (CNS). In addition to motor abnormalities, some patients have seizures, cognitive impairment, and extrapyramidal abnormalities.
Clinical and epidemiologic evidence points to white matter lesions and severe intraventricular hemorrhage (IVH)—detected by neonatal neurosonography—as the key determinants of CP. The lesions are the sonographic antecedent or counterpart of periventricular leukomalacia (PVL), a cerebral lesion characterized by foci of necrosis in the white matter near the ventricles (FIGURE).
The principal risk factor is prematurity
A precise cause for CP has not been identified in more than 75% of cases. The leading identifiable risk factor is prematurity. The prevalence of CP at 3 years of age is 4.4% among infants born earlier than 27 weeks of gestation, compared with 0.06% among babies born at term.1
FIGURE Periventricular leukomalacia
Four axial magnetic resonance images of the brain of an infant show the usual appearance of this cerebral lesion, characterized by foci of necrosis of white matter near the ventricles.
How inflammation leads to premature birth
Any condition that increases the incidence of prematurity can be expected to increase the incidence of CP. More than 80% of premature births follow preterm labor or pPROM. Clinical and experimental evidence suggests that most of these births reflect one or more of four major pathogenic processes, which lead to uterine contractions and cervical changes, with or without premature rupture of membranes2:
- local or systemic inflammatory immune response
- activation of the maternal or fetal hypothalamic–pituitary–adrenal axis
- decidual hemorrhage (abruption)
- pathologic distention of the uterus.
Two or more of these processes often occur simultaneously, ultimately converging on a final common biochemical pathway that leads to degradation of the extracellular matrix in the cervix and fetal membranes and activation of the uterine myometrium. This process leads in turn to cervical dilation, rupture of membranes, and uterine contractions.
The “inflammatory pathway” is activated in most cases of spontaneous preterm labor and pPROM. As many as 50% of women with preterm labor and intact membranes have histologic chorioamnionitis; the rate is even higher in pPROM. The incidence of chorioamnionitis increases with decreasing gestational age.
Invading microorganisms in gestational tissues often cause intrauterine inflammation and preterm birth. Highly sensitive molecular techniques detect bacteria in the amniotic fluid of as many as half of patients with preterm labor with intact membranes3 and even more women with pPROM. As with chorioamnionitis, the lower the gestational age, the higher the bacterial isolation rates—45% at 23 to 26 weeks compared with 17% at 27 to 30 weeks.4 The microorganisms isolated are often those colonizing the vagina—most commonly anaerobes, gram-negative rods, Gardnerella vaginalis, group B streptococci, Mycoplasma hominis, and Ureaplasma urealyticum.
Infection doesn’t always lead to inflammation
Bacterial products—particularly endotoxin, a major constituent of gram-negative bacteria—bind to a specific pattern-recognition receptor, known as a toll-like receptor, on cell surfaces. This activates innate immunity and stimulates a proinflammatory immune response. Endotoxin is a potent stimulant for proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which promote the release of chemoattractant cytokines such as IL-6 and IL-8. Different white blood cells migrate into the inflamed tissue and become activated at the same time.
The uterine cavity is thought to be sterile, and microorganisms there are universally associated with inflammation. Recent studies challenge this assumption. One found bacteria in as many as 90% of endometrial samples from nonpregnant women, but histologic endometritis in only 40%.5 Another noted bacteria in as many as 80% of gestational tissues delivered electively by cesarean section at term or before 32 weeks because of preeclampsia, but histologic assessment showed no or minimal inflammation.6
Why don’t all women develop inflammation?
A critical question is why some pregnant women with microbial invasion of gestational tissues develop inflammation, whereas others do not. Susceptibility depends, in part, on the pathogenicity and amount of invading bacteria. Endotoxin-containing gram-negative bacteria elicit an especially potent inflammatory response. The strength of the response correlates with the amount of endotoxin-containing bacteria in the environment.7
The isolation rate of bacteria from the intrauterine cavity is higher in women with bacterial vaginosis (BV), a condition characterized by malodorous vaginal discharge, vaginal pH higher than 4.5, and a shift from a Lactobacilli-dominant vaginal flora toward predominance of G vaginalis, anaerobic bacteria, and M hominis. The greater number of bacteria may account, in part, for a twofold greater risk of preterm delivery among women diagnosed with BV during pregnancy.8
Genetics may also play a role. Intrauterine inflammation and morbidity are partly influenced by common variations (polymorphisms) in immunoregulatory genes. Preliminary evidence suggests that some women who carry a variant of the TNF-α gene can mount an exaggerated immune response to BV-related organisms (hyper-responders),9 increasing their risk of preterm delivery.10
Inflammation alone is a risk factor for CP
Growing evidence suggests that intrauterine inflammation increases the risk of neonatal white matter disease and subsequent development of CP beyond the risk conferred by gestational age at birth. The relative risk (RR) for CP in preterm infants born after intrauterine infection and inflammation or inflammation alone is 1.9 and 1.6, respectively.11
The association between inflammation, neonatal white matter disease, and CP is strongest in fetuses with funisitis and a plasma IL-6 level greater than 11 ng/mL12—a condition known as fetal inflammatory response syndrome (FIRS). FIRS is also associated with other sequelae of prematurity, including bronchopulmonary dysplasia, respiratory distress syndrome, and myocardial dysfunction.
Can we diagnose subacute inflammation and infection?
Diagnosing and treating intrauterine inflammation promptly may decrease the risk of CP. No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient. Maternal signs and symptoms such as fundal tenderness, tachycardia, and fever, along with laboratory findings such as an elevated C-reactive protein level and an elevated white blood cell (WBC) count in peripheral blood, indicate overt chorioamnionitis and systemic maternal infection. However, these tests are not especially useful for diagnosing subacute intrauterine infection and inflammation in patients with preterm labor and intact membranes or pPROM. Some authorities advocate amniocentesis for these patients.
- Prematurity is the leading risk factor for cerebral palsy (CP)
- Subacute intrauterine infection and inflammation are common causes of preterm delivery
- Intrauterine inflammation may lower the threshold at which hypoxia becomes neurotoxic in the fetus
- No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient
- A biophysical profile (BPP) score of 7 or lower predicts infection-related neonatal outcomes better than any single component of the BPP
- In a pregnancy complicated by pPROM, adjunctive antibiotics prolong pregnancy for as long as 10 days, but do not affect neonatal neurologic outcome
- Adjunctive antibiotics have no proven benefit in managing preterm labor with intact membranes
- Screening for and treating bacterial vaginosis during pregnancy are not useful
- Prophylactic antibiotic treatment during the periconceptional period has no proven benefit
- A single course of antenatal steroids in preterm labor with intact membranes or pPROM significantly decreases neonatal mortality and neurologic morbidity without raising the risk of neonatal sepsis—even in the presence of intrauterine infection
- Tocolysis with magnesium sulfate or a calcium-channel blocker to stop preterm labor with intact membranes may decrease neurologic morbidity in neonates
- Consider delivery after 32 weeks if fetal lung maturity is confirmed because 1) expectant management of pPROM beyond 32 completed weeks of gestation does not have a clear benefit and 2) intrauterine inflammation associated with white matter disease is common in pPROM
A positive bacterial culture or gram-stained slide of amniotic fluid confirms intra-amniotic infection but detects fewer than 50% of cases. Other diagnostic criteria, such as an elevated WBC count, high level of lactate dehydrogenase activity, high protein level, and low glucose concentration in amniotic fluid, are more sensitive, but nonspecific, for amniotic infection and inflammation.
Elevated inflammatory cytokines such as IL-6 in amniotic fluid and fetal blood have been associated with intrauterine inflammation and neonatal white matter disease in women with preterm labor and intact membranes or pPROM, but they are not significantly more accurate than the previously mentioned biomarkers.13,14 An amniotic fluid pocket may not be accessible by the abdominal approach in most patients with pPROM because of significant oligohydramnios. Testing amniotic fluid from the vagina is an alternative. Low glucose in vaginal samples is a specific, but not a sensitive, marker for intra-amniotic infection.15
Using the BPP. The biophysical profile has been used to identify fetuses at risk of FIRS in the presence of pPROM. Oligohydramnios—especially when the largest vertical amniotic fluid pocket is smaller than 1 cm—and diminished fetal breathing and body movement are associated with chorioamnionitis and suspected or proven neonatal sepsis. A nonreactive nonstress test is specific but not sensitive.
Although each component of the BPP provides useful information, a BPP score of 7 or lower predicts infection-related outcome much better than any single finding. In a population with an infection-related outcome of 30%, a BPP score of 7 or lower within 24 hours of delivery had a positive predictive value of 95% and a negative predictive value of 97%.16 A retrospective case-control study found that women who were followed with daily BPP and delivered within 24 hours after a BPP score of 7 or lower on two examinations 2 hours apart had a lower rate of neonatal sepsis than women who were managed expectantly or had a single amniocentesis on admission to the hospital.17
How management tactics affect neurologic outcome
Options for women in preterm labor with intact membranes or pPROM include antibiotics, antenatal steroids, tocolytics, or early delivery.
Antibiotics in cases of pPROM only
The findings of two large clinical trials powerful enough to evaluate adjunctive antibiotics in women with pPROM are in agreement: Such treatment prolongs the pregnancy briefly (as long as 10 days).18,19
NICHD-MFMU study. In a trial conducted by the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (NICHD-MFMU) Research Network, 48 hours of intravenous therapy with ampicillin and erythromycin followed by 5 days of oral amoxicillin and enteric-coated erythromycin given to 614 women between 24 and 32 weeks’ gestation decreased the number of infants who died or suffered a major morbidity, including respiratory distress syndrome, early sepsis, severe IVH, or severe necrotizing enterocolitis.18
ORACLE I. The results of the larger ORACLE I trial, which included 4,826 women, were less impressive.19 Patients who developed pPROM before 37 weeks’ gestation received erythromycin, amoxicillin-clavulanic acid, or both, or placebo for up to 10 days. Although antibiotic therapy prolonged pregnancy briefly, it did not have a major impact on neonatal mortality or any major morbidity, including cerebral abnormality on ultrasonography (US). In contrast to the NICHD-MFMU Research Network study, treatment with oral amoxicillin-clavulanic acid increased the risk of necrotizing enterocolitis.
ORACLE II. The ORACLE II trial evaluated the benefit of adjunctive antibiotics for 6,295 women in spontaneous preterm labor before 37 weeks’ gestation who had intact membranes and no evidence of clinical infection.20 The women received erythromycin, amoxicillin-clavulanic acid, or both, or placebo for as long as 10 days. Compared with placebo, none of the antibiotics was associated with a lower rate of the composite primary outcome, which included major cerebral abnormality on US before discharge from the hospital.
Prophylaxis. It has been suggested that antibiotics are more likely to prevent preterm birth if they are given long before contractions start or membranes rupture. Studies of antibiotic prophylaxis to prevent preterm birth and related sequelae don’t support this notion. A Cochrane meta-analysis of six randomized clinical trials involving 2,184 asymptomatic women who received prophylactic antibiotics in the second or third trimester found no reduction in the risk of subsequent preterm birth.21 In fact, intervention increased the risk of neonatal sepsis (odds ratio [OR]=8.07, 95% confidence interval [CI], 1.36 to 47.77). Another meta-analysis of the effect of antibiotics on BV during pregnancy drew similar conclusions.22 This analysis of 15 randomized clinical trials with a total of 5,888 patients showed that treating BV did not reduce the risk of preterm birth. The trials reported very few perinatal deaths, and none reported substantive neonatal morbidity.
Another hypothesis argues that the events leading to preterm birth begin in very early stages of pregnancy, including conception and implantation of the embryo. To test this hypothesis, 241 women with a history of spontaneous preterm birth or pPROM between 16 and 34 weeks’ gestation were randomized to receive an oral course of azithromycin and metronidazole or placebo every 4 months until conception.23 The 124 women who conceived and were available for follow-up showed no difference in the rate of preterm birth between the treatment and placebo groups. In fact, women who received an antibiotic tended to have a shorter pregnancy and a lower-birth-weight baby than those given placebo.
Several mechanisms have been proposed to explain the role of inflammation in neonatal white matter disease. Microorganisms and microbial products can gain access to the fetus and activate inflammatory cytokines, increasing the permeability of the blood–brain barrier and facilitating passage of the cytokines into the brain.
Microbial products stimulate human fetal microglia (the central nervous system [CNS] equivalent of macrophages) to produce interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which, in turn, stimulate proliferation of astrocytes (the CNS equivalent of fibroblasts) and production of TNF. Leviton proposed that TNF-α can damage white matter by four mechanisms:33
- inducing hypotension and brain ischemia
- stimulating the production of a tissue factor, which can activate the hemostatic system and contribute to coagulation necrosis of white matter
- inducing the release of platelet-activating factor, which can act as a membrane detergent, causing direct brain damage
- producing a direct cytotoxic effect on oligodendrocytes.
Polymorphisms in immunomodulatory genes, such as the gene encoding TNF-α, modify the immune response and the risk for white matter disease in preterm infants.34
Based on available data, treatment with a short course of antibiotics such as erythromycin or ampicillin, or both, is recommended only in cases of pPROM.
Antenatal steroids improve outcome
Antenatal steroids reduce neonatal mortality and morbidity, including IVH and PVL, in infants born between 24 and 34 weeks’ gestation. One concern raised about antenatal steroid use is whether it increases the risk of neonatal infection and morbidity when intrauterine infection and inflammation are present. A retrospective analysis of infants who weighed 1,750 g or more at birth concluded that antenatal steroids significantly decreased neonatal mortality and morbidity—including IVH, PVL, and major brain lesions—without increasing neonatal sepsis in babies delivered following preterm labor or pPROM.24
In another retrospective analysis of 457 consecutive 23- to 32-week live-born singletons, antenatal steroids weren’t associated with significant worsening of any neonatal outcome. Steroids were associated with significant reductions in respiratory distress syndrome and neonatal systemic inflammatory response syndrome in infants with positive placental cultures and elevated cord blood IL-6 levels.25
These data suggest that antenatal steroids may not be contraindicated in the face of inflammation and infection; they may, in fact, be beneficial. In women with pPROM, weekly administration of ante-natal steroids doesn’t seem to improve neonatal outcomes more than single-course therapy and may increase the risk of chorioamnionitis.26
Some tocolytics may help
Tocolytic agents are often given to women with preterm contractions to delay delivery long enough to administer a course of antenatal corticosteroids.
Magnesium sulfate is commonly used in the United States. A 2007 Cochrane meta-analysis of four trials (3,701 babies) found that antenatal magnesium sulfate had no statistically significant effect on any major pediatric outcome, including death and neurologic problems such as CP in the first few years of life.27 Nor did antenatal magnesium therapy significantly affect combined rates of mortality and neurologic outcomes. Two trials involving 2,848 infants found a significant reduction in substantial gross motor dysfunction (RR=0.56; 95% CI, 0.33 to 0.97).
Betamimetics are also widely used for tocolysis, especially in resource-poor countries. Eleven randomized controlled trials, involving 1,332 women, compared betamimetics with placebo.28 Although betamimetics decreased the number of women in preterm labor who gave birth within 48 hours, they didn’t reduce perinatal or neonatal death. Data on CP were too sparse to allow comment. Because these drugs cause many maternal side effects, they aren’t considered first-line tocolytics.
Calcium-channel blockers are attracting growing interest as potentially effective and well-tolerated tocolytic agents. A meta-analysis of 12 randomized controlled trials involving 1,029 women suggests that calcium-channel blockers reduce the number of women giving birth within 7 days of receiving treatment, compared with other tocolytic agents (mainly betamimetics).29 They also decrease the frequency of neonatal morbidity, including IVH (RR, 0.59; 95% CI, 0.36 to 0.98).
Cyclooxygenase (COX) inhibitors are easy to administer and cause fewer maternal side effects than conventional tocolytics. A 2005 Cochrane meta-analysis includes outcome data from 13 trials with a total of 713 women.30 Indomethacin, a non-selective COX inhibitor, was used in 10 trials. COX inhibition reduced birth before 37 weeks’ gestation more effectively than other tocolytic agents, but data were insufficient to comment on neonatal outcomes.
In women with pPROM, starting tocolysis before onset of contractions prolongs latency. However, the utility of tocolytic therapy after pPROM remains controversial pending more powerful randomized trials.
Early delivery is an option
It has been suggested that exposure to infection, especially proinflammatory cytokines, reduces the threshold at which hypoxia becomes neurotoxic, making the brain much more vulnerable to even mild hypoxic insults. A recent study found that infants with encephalopathy were more than 90 times more likely to have experienced both neonatal intrapartum acidosis and maternal intrapartum fever than infants with no encephalopathy; maternal fever or neonatal acidosis increased the risk six- and 12-fold, respectively.31 Lack of interaction between maternal fever and acidosis suggests that these are separate causal pathways to adverse neonatal outcomes. Although intrapartum fever doesn’t always correlate with intrauterine inflammation, the findings of this study suggest that fetal acidosis should be avoided when intrauterine infection and inflammation are suspected.
Conservative management of pPROM remote from term has been shown to prolong pregnancy significantly and reduce complications in the infant when prophylactic antibiotics and ante-natal steroids are given concurrently. The benefit of this strategy is less clear after 32 weeks of gestation because:
- The efficacy of antenatal steroids after 32 weeks is unclear
- Beyond 32 weeks, the risk of severe complications of prematurity, including CP, is low if fetal lung maturity has been established by amniotic fluid samples collected vaginally or by amniocentesis.
For these reasons and because sub-acute intrauterine inflammation may harm the fetus, delivery can be considered after 32 completed weeks of gestation if fetal lung maturity is confirmed. A meta-analysis of four randomized controlled trials that compared intentional delivery with expectant management after pPROM between 30 and 36 weeks of gestation found no difference in neonatal outcomes.32
The author reports no financial relationships relevant to this article.
- Intrapartum hypoxia, once considered an important cause of cerebral palsy (CP), is responsible for only 8% to 10% of cases.
- Increasingly, evidence suggests that the primary cause of CP lies in the relationship among intrauterine infection and inflammation, preterm labor, preterm premature rupture of membranes (pPROM), and neonatal white matter disease.
- This review focuses on that relationship and its implications for managing preterm birth with intact membranes or pPROM.
Cerebral palsy is a complex disease characterized by aberrant control of movement or posture that results from an insult to the developing central nervous system (CNS). In addition to motor abnormalities, some patients have seizures, cognitive impairment, and extrapyramidal abnormalities.
Clinical and epidemiologic evidence points to white matter lesions and severe intraventricular hemorrhage (IVH)—detected by neonatal neurosonography—as the key determinants of CP. The lesions are the sonographic antecedent or counterpart of periventricular leukomalacia (PVL), a cerebral lesion characterized by foci of necrosis in the white matter near the ventricles (FIGURE).
The principal risk factor is prematurity
A precise cause for CP has not been identified in more than 75% of cases. The leading identifiable risk factor is prematurity. The prevalence of CP at 3 years of age is 4.4% among infants born earlier than 27 weeks of gestation, compared with 0.06% among babies born at term.1
FIGURE Periventricular leukomalacia
Four axial magnetic resonance images of the brain of an infant show the usual appearance of this cerebral lesion, characterized by foci of necrosis of white matter near the ventricles.
How inflammation leads to premature birth
Any condition that increases the incidence of prematurity can be expected to increase the incidence of CP. More than 80% of premature births follow preterm labor or pPROM. Clinical and experimental evidence suggests that most of these births reflect one or more of four major pathogenic processes, which lead to uterine contractions and cervical changes, with or without premature rupture of membranes2:
- local or systemic inflammatory immune response
- activation of the maternal or fetal hypothalamic–pituitary–adrenal axis
- decidual hemorrhage (abruption)
- pathologic distention of the uterus.
Two or more of these processes often occur simultaneously, ultimately converging on a final common biochemical pathway that leads to degradation of the extracellular matrix in the cervix and fetal membranes and activation of the uterine myometrium. This process leads in turn to cervical dilation, rupture of membranes, and uterine contractions.
The “inflammatory pathway” is activated in most cases of spontaneous preterm labor and pPROM. As many as 50% of women with preterm labor and intact membranes have histologic chorioamnionitis; the rate is even higher in pPROM. The incidence of chorioamnionitis increases with decreasing gestational age.
Invading microorganisms in gestational tissues often cause intrauterine inflammation and preterm birth. Highly sensitive molecular techniques detect bacteria in the amniotic fluid of as many as half of patients with preterm labor with intact membranes3 and even more women with pPROM. As with chorioamnionitis, the lower the gestational age, the higher the bacterial isolation rates—45% at 23 to 26 weeks compared with 17% at 27 to 30 weeks.4 The microorganisms isolated are often those colonizing the vagina—most commonly anaerobes, gram-negative rods, Gardnerella vaginalis, group B streptococci, Mycoplasma hominis, and Ureaplasma urealyticum.
Infection doesn’t always lead to inflammation
Bacterial products—particularly endotoxin, a major constituent of gram-negative bacteria—bind to a specific pattern-recognition receptor, known as a toll-like receptor, on cell surfaces. This activates innate immunity and stimulates a proinflammatory immune response. Endotoxin is a potent stimulant for proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which promote the release of chemoattractant cytokines such as IL-6 and IL-8. Different white blood cells migrate into the inflamed tissue and become activated at the same time.
The uterine cavity is thought to be sterile, and microorganisms there are universally associated with inflammation. Recent studies challenge this assumption. One found bacteria in as many as 90% of endometrial samples from nonpregnant women, but histologic endometritis in only 40%.5 Another noted bacteria in as many as 80% of gestational tissues delivered electively by cesarean section at term or before 32 weeks because of preeclampsia, but histologic assessment showed no or minimal inflammation.6
Why don’t all women develop inflammation?
A critical question is why some pregnant women with microbial invasion of gestational tissues develop inflammation, whereas others do not. Susceptibility depends, in part, on the pathogenicity and amount of invading bacteria. Endotoxin-containing gram-negative bacteria elicit an especially potent inflammatory response. The strength of the response correlates with the amount of endotoxin-containing bacteria in the environment.7
The isolation rate of bacteria from the intrauterine cavity is higher in women with bacterial vaginosis (BV), a condition characterized by malodorous vaginal discharge, vaginal pH higher than 4.5, and a shift from a Lactobacilli-dominant vaginal flora toward predominance of G vaginalis, anaerobic bacteria, and M hominis. The greater number of bacteria may account, in part, for a twofold greater risk of preterm delivery among women diagnosed with BV during pregnancy.8
Genetics may also play a role. Intrauterine inflammation and morbidity are partly influenced by common variations (polymorphisms) in immunoregulatory genes. Preliminary evidence suggests that some women who carry a variant of the TNF-α gene can mount an exaggerated immune response to BV-related organisms (hyper-responders),9 increasing their risk of preterm delivery.10
Inflammation alone is a risk factor for CP
Growing evidence suggests that intrauterine inflammation increases the risk of neonatal white matter disease and subsequent development of CP beyond the risk conferred by gestational age at birth. The relative risk (RR) for CP in preterm infants born after intrauterine infection and inflammation or inflammation alone is 1.9 and 1.6, respectively.11
The association between inflammation, neonatal white matter disease, and CP is strongest in fetuses with funisitis and a plasma IL-6 level greater than 11 ng/mL12—a condition known as fetal inflammatory response syndrome (FIRS). FIRS is also associated with other sequelae of prematurity, including bronchopulmonary dysplasia, respiratory distress syndrome, and myocardial dysfunction.
Can we diagnose subacute inflammation and infection?
Diagnosing and treating intrauterine inflammation promptly may decrease the risk of CP. No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient. Maternal signs and symptoms such as fundal tenderness, tachycardia, and fever, along with laboratory findings such as an elevated C-reactive protein level and an elevated white blood cell (WBC) count in peripheral blood, indicate overt chorioamnionitis and systemic maternal infection. However, these tests are not especially useful for diagnosing subacute intrauterine infection and inflammation in patients with preterm labor and intact membranes or pPROM. Some authorities advocate amniocentesis for these patients.
- Prematurity is the leading risk factor for cerebral palsy (CP)
- Subacute intrauterine infection and inflammation are common causes of preterm delivery
- Intrauterine inflammation may lower the threshold at which hypoxia becomes neurotoxic in the fetus
- No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient
- A biophysical profile (BPP) score of 7 or lower predicts infection-related neonatal outcomes better than any single component of the BPP
- In a pregnancy complicated by pPROM, adjunctive antibiotics prolong pregnancy for as long as 10 days, but do not affect neonatal neurologic outcome
- Adjunctive antibiotics have no proven benefit in managing preterm labor with intact membranes
- Screening for and treating bacterial vaginosis during pregnancy are not useful
- Prophylactic antibiotic treatment during the periconceptional period has no proven benefit
- A single course of antenatal steroids in preterm labor with intact membranes or pPROM significantly decreases neonatal mortality and neurologic morbidity without raising the risk of neonatal sepsis—even in the presence of intrauterine infection
- Tocolysis with magnesium sulfate or a calcium-channel blocker to stop preterm labor with intact membranes may decrease neurologic morbidity in neonates
- Consider delivery after 32 weeks if fetal lung maturity is confirmed because 1) expectant management of pPROM beyond 32 completed weeks of gestation does not have a clear benefit and 2) intrauterine inflammation associated with white matter disease is common in pPROM
A positive bacterial culture or gram-stained slide of amniotic fluid confirms intra-amniotic infection but detects fewer than 50% of cases. Other diagnostic criteria, such as an elevated WBC count, high level of lactate dehydrogenase activity, high protein level, and low glucose concentration in amniotic fluid, are more sensitive, but nonspecific, for amniotic infection and inflammation.
Elevated inflammatory cytokines such as IL-6 in amniotic fluid and fetal blood have been associated with intrauterine inflammation and neonatal white matter disease in women with preterm labor and intact membranes or pPROM, but they are not significantly more accurate than the previously mentioned biomarkers.13,14 An amniotic fluid pocket may not be accessible by the abdominal approach in most patients with pPROM because of significant oligohydramnios. Testing amniotic fluid from the vagina is an alternative. Low glucose in vaginal samples is a specific, but not a sensitive, marker for intra-amniotic infection.15
Using the BPP. The biophysical profile has been used to identify fetuses at risk of FIRS in the presence of pPROM. Oligohydramnios—especially when the largest vertical amniotic fluid pocket is smaller than 1 cm—and diminished fetal breathing and body movement are associated with chorioamnionitis and suspected or proven neonatal sepsis. A nonreactive nonstress test is specific but not sensitive.
Although each component of the BPP provides useful information, a BPP score of 7 or lower predicts infection-related outcome much better than any single finding. In a population with an infection-related outcome of 30%, a BPP score of 7 or lower within 24 hours of delivery had a positive predictive value of 95% and a negative predictive value of 97%.16 A retrospective case-control study found that women who were followed with daily BPP and delivered within 24 hours after a BPP score of 7 or lower on two examinations 2 hours apart had a lower rate of neonatal sepsis than women who were managed expectantly or had a single amniocentesis on admission to the hospital.17
How management tactics affect neurologic outcome
Options for women in preterm labor with intact membranes or pPROM include antibiotics, antenatal steroids, tocolytics, or early delivery.
Antibiotics in cases of pPROM only
The findings of two large clinical trials powerful enough to evaluate adjunctive antibiotics in women with pPROM are in agreement: Such treatment prolongs the pregnancy briefly (as long as 10 days).18,19
NICHD-MFMU study. In a trial conducted by the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (NICHD-MFMU) Research Network, 48 hours of intravenous therapy with ampicillin and erythromycin followed by 5 days of oral amoxicillin and enteric-coated erythromycin given to 614 women between 24 and 32 weeks’ gestation decreased the number of infants who died or suffered a major morbidity, including respiratory distress syndrome, early sepsis, severe IVH, or severe necrotizing enterocolitis.18
ORACLE I. The results of the larger ORACLE I trial, which included 4,826 women, were less impressive.19 Patients who developed pPROM before 37 weeks’ gestation received erythromycin, amoxicillin-clavulanic acid, or both, or placebo for up to 10 days. Although antibiotic therapy prolonged pregnancy briefly, it did not have a major impact on neonatal mortality or any major morbidity, including cerebral abnormality on ultrasonography (US). In contrast to the NICHD-MFMU Research Network study, treatment with oral amoxicillin-clavulanic acid increased the risk of necrotizing enterocolitis.
ORACLE II. The ORACLE II trial evaluated the benefit of adjunctive antibiotics for 6,295 women in spontaneous preterm labor before 37 weeks’ gestation who had intact membranes and no evidence of clinical infection.20 The women received erythromycin, amoxicillin-clavulanic acid, or both, or placebo for as long as 10 days. Compared with placebo, none of the antibiotics was associated with a lower rate of the composite primary outcome, which included major cerebral abnormality on US before discharge from the hospital.
Prophylaxis. It has been suggested that antibiotics are more likely to prevent preterm birth if they are given long before contractions start or membranes rupture. Studies of antibiotic prophylaxis to prevent preterm birth and related sequelae don’t support this notion. A Cochrane meta-analysis of six randomized clinical trials involving 2,184 asymptomatic women who received prophylactic antibiotics in the second or third trimester found no reduction in the risk of subsequent preterm birth.21 In fact, intervention increased the risk of neonatal sepsis (odds ratio [OR]=8.07, 95% confidence interval [CI], 1.36 to 47.77). Another meta-analysis of the effect of antibiotics on BV during pregnancy drew similar conclusions.22 This analysis of 15 randomized clinical trials with a total of 5,888 patients showed that treating BV did not reduce the risk of preterm birth. The trials reported very few perinatal deaths, and none reported substantive neonatal morbidity.
Another hypothesis argues that the events leading to preterm birth begin in very early stages of pregnancy, including conception and implantation of the embryo. To test this hypothesis, 241 women with a history of spontaneous preterm birth or pPROM between 16 and 34 weeks’ gestation were randomized to receive an oral course of azithromycin and metronidazole or placebo every 4 months until conception.23 The 124 women who conceived and were available for follow-up showed no difference in the rate of preterm birth between the treatment and placebo groups. In fact, women who received an antibiotic tended to have a shorter pregnancy and a lower-birth-weight baby than those given placebo.
Several mechanisms have been proposed to explain the role of inflammation in neonatal white matter disease. Microorganisms and microbial products can gain access to the fetus and activate inflammatory cytokines, increasing the permeability of the blood–brain barrier and facilitating passage of the cytokines into the brain.
Microbial products stimulate human fetal microglia (the central nervous system [CNS] equivalent of macrophages) to produce interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which, in turn, stimulate proliferation of astrocytes (the CNS equivalent of fibroblasts) and production of TNF. Leviton proposed that TNF-α can damage white matter by four mechanisms:33
- inducing hypotension and brain ischemia
- stimulating the production of a tissue factor, which can activate the hemostatic system and contribute to coagulation necrosis of white matter
- inducing the release of platelet-activating factor, which can act as a membrane detergent, causing direct brain damage
- producing a direct cytotoxic effect on oligodendrocytes.
Polymorphisms in immunomodulatory genes, such as the gene encoding TNF-α, modify the immune response and the risk for white matter disease in preterm infants.34
Based on available data, treatment with a short course of antibiotics such as erythromycin or ampicillin, or both, is recommended only in cases of pPROM.
Antenatal steroids improve outcome
Antenatal steroids reduce neonatal mortality and morbidity, including IVH and PVL, in infants born between 24 and 34 weeks’ gestation. One concern raised about antenatal steroid use is whether it increases the risk of neonatal infection and morbidity when intrauterine infection and inflammation are present. A retrospective analysis of infants who weighed 1,750 g or more at birth concluded that antenatal steroids significantly decreased neonatal mortality and morbidity—including IVH, PVL, and major brain lesions—without increasing neonatal sepsis in babies delivered following preterm labor or pPROM.24
In another retrospective analysis of 457 consecutive 23- to 32-week live-born singletons, antenatal steroids weren’t associated with significant worsening of any neonatal outcome. Steroids were associated with significant reductions in respiratory distress syndrome and neonatal systemic inflammatory response syndrome in infants with positive placental cultures and elevated cord blood IL-6 levels.25
These data suggest that antenatal steroids may not be contraindicated in the face of inflammation and infection; they may, in fact, be beneficial. In women with pPROM, weekly administration of ante-natal steroids doesn’t seem to improve neonatal outcomes more than single-course therapy and may increase the risk of chorioamnionitis.26
Some tocolytics may help
Tocolytic agents are often given to women with preterm contractions to delay delivery long enough to administer a course of antenatal corticosteroids.
Magnesium sulfate is commonly used in the United States. A 2007 Cochrane meta-analysis of four trials (3,701 babies) found that antenatal magnesium sulfate had no statistically significant effect on any major pediatric outcome, including death and neurologic problems such as CP in the first few years of life.27 Nor did antenatal magnesium therapy significantly affect combined rates of mortality and neurologic outcomes. Two trials involving 2,848 infants found a significant reduction in substantial gross motor dysfunction (RR=0.56; 95% CI, 0.33 to 0.97).
Betamimetics are also widely used for tocolysis, especially in resource-poor countries. Eleven randomized controlled trials, involving 1,332 women, compared betamimetics with placebo.28 Although betamimetics decreased the number of women in preterm labor who gave birth within 48 hours, they didn’t reduce perinatal or neonatal death. Data on CP were too sparse to allow comment. Because these drugs cause many maternal side effects, they aren’t considered first-line tocolytics.
Calcium-channel blockers are attracting growing interest as potentially effective and well-tolerated tocolytic agents. A meta-analysis of 12 randomized controlled trials involving 1,029 women suggests that calcium-channel blockers reduce the number of women giving birth within 7 days of receiving treatment, compared with other tocolytic agents (mainly betamimetics).29 They also decrease the frequency of neonatal morbidity, including IVH (RR, 0.59; 95% CI, 0.36 to 0.98).
Cyclooxygenase (COX) inhibitors are easy to administer and cause fewer maternal side effects than conventional tocolytics. A 2005 Cochrane meta-analysis includes outcome data from 13 trials with a total of 713 women.30 Indomethacin, a non-selective COX inhibitor, was used in 10 trials. COX inhibition reduced birth before 37 weeks’ gestation more effectively than other tocolytic agents, but data were insufficient to comment on neonatal outcomes.
In women with pPROM, starting tocolysis before onset of contractions prolongs latency. However, the utility of tocolytic therapy after pPROM remains controversial pending more powerful randomized trials.
Early delivery is an option
It has been suggested that exposure to infection, especially proinflammatory cytokines, reduces the threshold at which hypoxia becomes neurotoxic, making the brain much more vulnerable to even mild hypoxic insults. A recent study found that infants with encephalopathy were more than 90 times more likely to have experienced both neonatal intrapartum acidosis and maternal intrapartum fever than infants with no encephalopathy; maternal fever or neonatal acidosis increased the risk six- and 12-fold, respectively.31 Lack of interaction between maternal fever and acidosis suggests that these are separate causal pathways to adverse neonatal outcomes. Although intrapartum fever doesn’t always correlate with intrauterine inflammation, the findings of this study suggest that fetal acidosis should be avoided when intrauterine infection and inflammation are suspected.
Conservative management of pPROM remote from term has been shown to prolong pregnancy significantly and reduce complications in the infant when prophylactic antibiotics and ante-natal steroids are given concurrently. The benefit of this strategy is less clear after 32 weeks of gestation because:
- The efficacy of antenatal steroids after 32 weeks is unclear
- Beyond 32 weeks, the risk of severe complications of prematurity, including CP, is low if fetal lung maturity has been established by amniotic fluid samples collected vaginally or by amniocentesis.
For these reasons and because sub-acute intrauterine inflammation may harm the fetus, delivery can be considered after 32 completed weeks of gestation if fetal lung maturity is confirmed. A meta-analysis of four randomized controlled trials that compared intentional delivery with expectant management after pPROM between 30 and 36 weeks of gestation found no difference in neonatal outcomes.32
1. Cummins SK, Nelson KB, Grether JK, Velie EM. Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr. 1993;123:230-237.
2. Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol. 2001;15 Suppl 2:78-89.
3. Gardella C, Riley DE, Hitti J, Agnew K, Krieger JN, Eschenbach D. Identification and sequencing of bacterial rDNAs in culture-negative amniotic fluid from women in premature labor. Am J Perinatol. 2004;21:319-323.
4. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol. 1992;79:351-357.
5. Andrews WW, Hauth JC, Cliver SP, Conner MG, Goldenberg RL, Goepfert AR. Association of asymptomatic bacterial vaginosis with endometrial microbial colonization and plasma cell endometritis in nonpregnant women. Am J Obstet Gynecol. 2006;195:1611-1616.
6. Steele JH, Malatos S, Kennea N, et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res. 2005;57:404-411.
7. Genc MR, Witkin SS, Delaney ML, et al. A disproportionate increase in IL-1beta over IL-1ra in cervicovaginal secretions of pregnant women with vaginal microflora correlates with preterm birth. Am J Obstet Gynecol. 2004;190:1191-1197.
8. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol. 2003;189:139-147.
9. Genc MR, Vardhana S, Delaney ML, Witkin SS, Onderdonk AB. MAP Study Group. TNFA-308G>A polymorphism influences the TNF-alpha response to altered vaginal flora. Eur J Obstet Gynecol Reprod Biol. 2007;134:188-191.
10. Macones GA, Parry S, Elkousy M, et al. A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol. 2004;190:1504-1508.
11. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA. 2000;284:1417-1424.
12. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179:194-202.
13. Romero R, Yoon BH, Mazor M, et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 1993;169:839-851.
14. Romero R, Yoon BH, Mazor M, et al. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 1993;169:805-816.
15. Buhimschi CS, Sfakianaki AK, Hamar BG, et al. A low vaginal “pool” amniotic fluid glucose measurement is a predictive but not a sensitive marker for infection in women with preterm premature rupture of membranes. Am J Obstet Gynecol. 2006;194:309-316.
16. Vintzileos AM, Campbell WA, Nochimson DJ, Connolly ME, Fuenfer MM, Hoehn GJ. The fetal biophysical profile in patients with premature rupture of the membranes—an early predictor of fetal infection. Am J Obstet Gynecol. 1985;152:510-516.
17. Vintzileos AM, Bors-Koefoed R, Pelegano JF, et al. The use of fetal biophysical profile improves pregnancy outcome in premature rupture of the membranes. Am J Obstet Gynecol. 1987;157:236-240.
18. Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA. 1997;278:989-995.
19. Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet. 2001;357:979-988.
20. Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. Lancet. 2001;357:989-994.
21. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality. Cochrane Database Syst Rev. 2002;(4):CD002250.-
22. McDonald H, Brocklehurst P, Parsons J. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2005;(1):CD000262.-
23. Andrews WW, Goldenberg RL, Hauth JC, Cliver SP, Copper R, Conner M. Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am J Obstet Gynecol. 2006;194:617-623.
24. Elimian A, Verma U, Canterino J, Shah J, Visintainer P, Tejani N. Effectiveness of antenatal steroids in obstetric subgroups. Obstet Gynecol. 1999;93:174-179.
25. Goldenberg RL, Andrews WW, Faye-Petersen OM, Cliver SP, Goepfert AR, Hauth JC. The Alabama preterm birth study: corticosteroids and neonatal outcomes in 23- to 32-week newborns with various markers of intrauterine infection. Am J Obstet Gynecol. 2006;195:1020-1024.
26. Ghidini A, Salafia CM, Minior VK. Repeated courses of steroids in preterm membrane rupture do not increase the risk of histologic chorioamnionitis. Am J Perinatol. 1997;14:309-313.
27. Doyle LW, Crowther CA, Middleton P, Marret S. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2007;(3):CD004661.-
28. Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004;(8):CD004352.-
29. King JF, Flenady VJ, Papatsonis DN, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2002;(2):CD002255.-
30. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygen-ase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005;(2):CD001992.-
31. Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P. The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol. 2008;198:49-51.
32. Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2006;19:177-187.
33. Leviton A. Preterm birth and cerebral palsy: is tumor necrosis factor the missing link?. Dev Med Child Neurol. 1993;35:553-558.
34. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA. South Australian Cerebral Palsy Research Group. The association between inherited cytokine polymorphisms and cerebral palsy. Am J Obstet Gynecol. 2006;194:674.e1-11.
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15. Buhimschi CS, Sfakianaki AK, Hamar BG, et al. A low vaginal “pool” amniotic fluid glucose measurement is a predictive but not a sensitive marker for infection in women with preterm premature rupture of membranes. Am J Obstet Gynecol. 2006;194:309-316.
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17. Vintzileos AM, Bors-Koefoed R, Pelegano JF, et al. The use of fetal biophysical profile improves pregnancy outcome in premature rupture of the membranes. Am J Obstet Gynecol. 1987;157:236-240.
18. Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA. 1997;278:989-995.
19. Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet. 2001;357:979-988.
20. Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. Lancet. 2001;357:989-994.
21. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality. Cochrane Database Syst Rev. 2002;(4):CD002250.-
22. McDonald H, Brocklehurst P, Parsons J. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2005;(1):CD000262.-
23. Andrews WW, Goldenberg RL, Hauth JC, Cliver SP, Copper R, Conner M. Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am J Obstet Gynecol. 2006;194:617-623.
24. Elimian A, Verma U, Canterino J, Shah J, Visintainer P, Tejani N. Effectiveness of antenatal steroids in obstetric subgroups. Obstet Gynecol. 1999;93:174-179.
25. Goldenberg RL, Andrews WW, Faye-Petersen OM, Cliver SP, Goepfert AR, Hauth JC. The Alabama preterm birth study: corticosteroids and neonatal outcomes in 23- to 32-week newborns with various markers of intrauterine infection. Am J Obstet Gynecol. 2006;195:1020-1024.
26. Ghidini A, Salafia CM, Minior VK. Repeated courses of steroids in preterm membrane rupture do not increase the risk of histologic chorioamnionitis. Am J Perinatol. 1997;14:309-313.
27. Doyle LW, Crowther CA, Middleton P, Marret S. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2007;(3):CD004661.-
28. Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004;(8):CD004352.-
29. King JF, Flenady VJ, Papatsonis DN, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2002;(2):CD002255.-
30. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygen-ase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005;(2):CD001992.-
31. Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P. The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol. 2008;198:49-51.
32. Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2006;19:177-187.
33. Leviton A. Preterm birth and cerebral palsy: is tumor necrosis factor the missing link?. Dev Med Child Neurol. 1993;35:553-558.
34. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA. South Australian Cerebral Palsy Research Group. The association between inherited cytokine polymorphisms and cerebral palsy. Am J Obstet Gynecol. 2006;194:674.e1-11.