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Do dietary interventions improve ADHD symptoms in children?
PROBABLY NOT, based on available data. Insufficient evidence exists to suggest that dietary interventions improve the symptoms of attention deficit hyperactivity disorder (ADHD) in children (strength of recommendation: B, extrapolation from randomized controlled trials [RCTs]). Interventions that have been investigated include removal of sugar and artificial food colorings from the diet and supplementation with fatty acids.
Evidence summary
ADHD affects 7% to 8% of school-age children, and the prevalence is increasing.1 The quality of studies investigating the link between diet and ADHD is limited by small sample sizes, subjective outcome measures, and nonstandardized intervention protocols.
Elimination diets show little or no effect
Studies of elimination diets for ADHD have investigated the effects of withholding sugar and artificial food colorings (AFCs).
Sugar. A 1995 meta-analysis of 16 double-blind, randomized, placebo-controlled trials evaluated the effect of dietary sugar in the form of sucrose, glucose, and fructose on behavior or cognition of children. Outcomes included subjective measurements from teachers, parents, and researchers, as well as objective scoring of activities.
No significant differences in the summary effect size were noted for any measured variable. A weakness of the analysis was that not all of the trials studied children who had been specifically diagnosed with ADHD.2
AFCs. A 2004 meta-analysis of 15 double-blind, placebo-controlled trials (total 219 children) evaluated the effect of AFCs on hyperactivity. Outcomes were measured by behavioral rating scales that ranged from standardized forms such as the Conners Parent-Teacher Questionnaire (12 trials) to nonvalidated author-developed scales (3 trials). Analysis revealed a small summary effect size (0.283; 95% confidence interval, 0.079-0.488), and the authors concluded that AFCs do have a small effect on hyperactivity.3
A secondary analysis of children who previously showed worsening of hyperactivity with AFCs (either by parental report or in an earlier study) found a larger effect size (0.53). This finding implies that a subset of children whose parents notice an increase in hyperactivity with AFCs may benefit from exclusion. However, because the quality of the meta-analysis is limited by the heterogeneity of the studies, publication bias, unvalidated outcome measures, and variety of diagnoses in the participants, no recommendation can be made for AFC exclusion diets.3
Supplementation with fatty acids doesn’t improve symptoms
Because polyunsaturated fatty acids (PUFAs) are essential for brain development and function, a deficiency theoretically may contribute to a range of developmental disorders, including ADHD. An RCT of 63 children 6 to 12 years of age with ADHD randomly assigned the children to supplementation with the most abundant PUFA, docosahexanoic (DHA), or placebo for 4 months. Measured outcomes included objective attention evaluation by computer and written tests and standardized objective measures such as the Conners Rating Scales.4 The study found no significant improvement in any ADHD symptom.4
The findings of this trial were confirmed by another double-blinded RCT of 40 children with ADHD who were randomized to DHA or placebo. The second trial found no significant differences in ADHD symptoms after 2 months.5
Recommendations
The American Academy of Pediatrics states that there is a need for well-designed, rigorous studies of currently promoted but less well-established therapies for ADHD, such as occupational therapy, biofeedback, herbs, vitamins, and food supplements. These interventions aren’t supported by evidence-based studies at present.6
The American Academy of Child and Adolescent Psychiatry’s guidelines on managing ADHD don’t mention dietary interventions.7
Investigators from the Cincinnati Children’s Hospital report that elimination diets and food supplements have little or no quality evidence to support their effectiveness.8
1. Centers for Disease Control and Prevention. Epidemiologic issues in ADHD. Available at: www.cdc.gov/ncbddd/adhd/adhdprevalence.htm. Accessed February 2009.
2. Wolraich ML, Wilson DB, White JW. The effect of sugar on behavior or cognition in children. A meta-analysis. JAMA. 1995;274:1617-1621.
3. Schab DW, Trinh NH. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind, placebo-controlled trials. J Dev Behav Pediatr 2004;25:423-434.
4. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001;139:189-196.
5. Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder—a placebo-controlled double-blind study. Eur J Clin Nutr 2004;58:467-473.
6. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:1033-1044.
7. Pliszka S. AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46:894-921.
8. Cincinnati Children’s Hospital Medical Center. Evidence-Based Clinical Practice Guideline for Outpatient Evaluation and Management of Attention Deficit/Hyperactivity Disorder. Cincinnati: Cincinnati Children’s Hospital Medical Center; 2004. Available at: www.guideline.gov/summary/summary.aspx?doc_id=5334&nbr=003647&string=attention+AND+deficit. Accessed October 18, 2009.
PROBABLY NOT, based on available data. Insufficient evidence exists to suggest that dietary interventions improve the symptoms of attention deficit hyperactivity disorder (ADHD) in children (strength of recommendation: B, extrapolation from randomized controlled trials [RCTs]). Interventions that have been investigated include removal of sugar and artificial food colorings from the diet and supplementation with fatty acids.
Evidence summary
ADHD affects 7% to 8% of school-age children, and the prevalence is increasing.1 The quality of studies investigating the link between diet and ADHD is limited by small sample sizes, subjective outcome measures, and nonstandardized intervention protocols.
Elimination diets show little or no effect
Studies of elimination diets for ADHD have investigated the effects of withholding sugar and artificial food colorings (AFCs).
Sugar. A 1995 meta-analysis of 16 double-blind, randomized, placebo-controlled trials evaluated the effect of dietary sugar in the form of sucrose, glucose, and fructose on behavior or cognition of children. Outcomes included subjective measurements from teachers, parents, and researchers, as well as objective scoring of activities.
No significant differences in the summary effect size were noted for any measured variable. A weakness of the analysis was that not all of the trials studied children who had been specifically diagnosed with ADHD.2
AFCs. A 2004 meta-analysis of 15 double-blind, placebo-controlled trials (total 219 children) evaluated the effect of AFCs on hyperactivity. Outcomes were measured by behavioral rating scales that ranged from standardized forms such as the Conners Parent-Teacher Questionnaire (12 trials) to nonvalidated author-developed scales (3 trials). Analysis revealed a small summary effect size (0.283; 95% confidence interval, 0.079-0.488), and the authors concluded that AFCs do have a small effect on hyperactivity.3
A secondary analysis of children who previously showed worsening of hyperactivity with AFCs (either by parental report or in an earlier study) found a larger effect size (0.53). This finding implies that a subset of children whose parents notice an increase in hyperactivity with AFCs may benefit from exclusion. However, because the quality of the meta-analysis is limited by the heterogeneity of the studies, publication bias, unvalidated outcome measures, and variety of diagnoses in the participants, no recommendation can be made for AFC exclusion diets.3
Supplementation with fatty acids doesn’t improve symptoms
Because polyunsaturated fatty acids (PUFAs) are essential for brain development and function, a deficiency theoretically may contribute to a range of developmental disorders, including ADHD. An RCT of 63 children 6 to 12 years of age with ADHD randomly assigned the children to supplementation with the most abundant PUFA, docosahexanoic (DHA), or placebo for 4 months. Measured outcomes included objective attention evaluation by computer and written tests and standardized objective measures such as the Conners Rating Scales.4 The study found no significant improvement in any ADHD symptom.4
The findings of this trial were confirmed by another double-blinded RCT of 40 children with ADHD who were randomized to DHA or placebo. The second trial found no significant differences in ADHD symptoms after 2 months.5
Recommendations
The American Academy of Pediatrics states that there is a need for well-designed, rigorous studies of currently promoted but less well-established therapies for ADHD, such as occupational therapy, biofeedback, herbs, vitamins, and food supplements. These interventions aren’t supported by evidence-based studies at present.6
The American Academy of Child and Adolescent Psychiatry’s guidelines on managing ADHD don’t mention dietary interventions.7
Investigators from the Cincinnati Children’s Hospital report that elimination diets and food supplements have little or no quality evidence to support their effectiveness.8
PROBABLY NOT, based on available data. Insufficient evidence exists to suggest that dietary interventions improve the symptoms of attention deficit hyperactivity disorder (ADHD) in children (strength of recommendation: B, extrapolation from randomized controlled trials [RCTs]). Interventions that have been investigated include removal of sugar and artificial food colorings from the diet and supplementation with fatty acids.
Evidence summary
ADHD affects 7% to 8% of school-age children, and the prevalence is increasing.1 The quality of studies investigating the link between diet and ADHD is limited by small sample sizes, subjective outcome measures, and nonstandardized intervention protocols.
Elimination diets show little or no effect
Studies of elimination diets for ADHD have investigated the effects of withholding sugar and artificial food colorings (AFCs).
Sugar. A 1995 meta-analysis of 16 double-blind, randomized, placebo-controlled trials evaluated the effect of dietary sugar in the form of sucrose, glucose, and fructose on behavior or cognition of children. Outcomes included subjective measurements from teachers, parents, and researchers, as well as objective scoring of activities.
No significant differences in the summary effect size were noted for any measured variable. A weakness of the analysis was that not all of the trials studied children who had been specifically diagnosed with ADHD.2
AFCs. A 2004 meta-analysis of 15 double-blind, placebo-controlled trials (total 219 children) evaluated the effect of AFCs on hyperactivity. Outcomes were measured by behavioral rating scales that ranged from standardized forms such as the Conners Parent-Teacher Questionnaire (12 trials) to nonvalidated author-developed scales (3 trials). Analysis revealed a small summary effect size (0.283; 95% confidence interval, 0.079-0.488), and the authors concluded that AFCs do have a small effect on hyperactivity.3
A secondary analysis of children who previously showed worsening of hyperactivity with AFCs (either by parental report or in an earlier study) found a larger effect size (0.53). This finding implies that a subset of children whose parents notice an increase in hyperactivity with AFCs may benefit from exclusion. However, because the quality of the meta-analysis is limited by the heterogeneity of the studies, publication bias, unvalidated outcome measures, and variety of diagnoses in the participants, no recommendation can be made for AFC exclusion diets.3
Supplementation with fatty acids doesn’t improve symptoms
Because polyunsaturated fatty acids (PUFAs) are essential for brain development and function, a deficiency theoretically may contribute to a range of developmental disorders, including ADHD. An RCT of 63 children 6 to 12 years of age with ADHD randomly assigned the children to supplementation with the most abundant PUFA, docosahexanoic (DHA), or placebo for 4 months. Measured outcomes included objective attention evaluation by computer and written tests and standardized objective measures such as the Conners Rating Scales.4 The study found no significant improvement in any ADHD symptom.4
The findings of this trial were confirmed by another double-blinded RCT of 40 children with ADHD who were randomized to DHA or placebo. The second trial found no significant differences in ADHD symptoms after 2 months.5
Recommendations
The American Academy of Pediatrics states that there is a need for well-designed, rigorous studies of currently promoted but less well-established therapies for ADHD, such as occupational therapy, biofeedback, herbs, vitamins, and food supplements. These interventions aren’t supported by evidence-based studies at present.6
The American Academy of Child and Adolescent Psychiatry’s guidelines on managing ADHD don’t mention dietary interventions.7
Investigators from the Cincinnati Children’s Hospital report that elimination diets and food supplements have little or no quality evidence to support their effectiveness.8
1. Centers for Disease Control and Prevention. Epidemiologic issues in ADHD. Available at: www.cdc.gov/ncbddd/adhd/adhdprevalence.htm. Accessed February 2009.
2. Wolraich ML, Wilson DB, White JW. The effect of sugar on behavior or cognition in children. A meta-analysis. JAMA. 1995;274:1617-1621.
3. Schab DW, Trinh NH. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind, placebo-controlled trials. J Dev Behav Pediatr 2004;25:423-434.
4. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001;139:189-196.
5. Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder—a placebo-controlled double-blind study. Eur J Clin Nutr 2004;58:467-473.
6. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:1033-1044.
7. Pliszka S. AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46:894-921.
8. Cincinnati Children’s Hospital Medical Center. Evidence-Based Clinical Practice Guideline for Outpatient Evaluation and Management of Attention Deficit/Hyperactivity Disorder. Cincinnati: Cincinnati Children’s Hospital Medical Center; 2004. Available at: www.guideline.gov/summary/summary.aspx?doc_id=5334&nbr=003647&string=attention+AND+deficit. Accessed October 18, 2009.
1. Centers for Disease Control and Prevention. Epidemiologic issues in ADHD. Available at: www.cdc.gov/ncbddd/adhd/adhdprevalence.htm. Accessed February 2009.
2. Wolraich ML, Wilson DB, White JW. The effect of sugar on behavior or cognition in children. A meta-analysis. JAMA. 1995;274:1617-1621.
3. Schab DW, Trinh NH. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind, placebo-controlled trials. J Dev Behav Pediatr 2004;25:423-434.
4. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001;139:189-196.
5. Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder—a placebo-controlled double-blind study. Eur J Clin Nutr 2004;58:467-473.
6. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:1033-1044.
7. Pliszka S. AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46:894-921.
8. Cincinnati Children’s Hospital Medical Center. Evidence-Based Clinical Practice Guideline for Outpatient Evaluation and Management of Attention Deficit/Hyperactivity Disorder. Cincinnati: Cincinnati Children’s Hospital Medical Center; 2004. Available at: www.guideline.gov/summary/summary.aspx?doc_id=5334&nbr=003647&string=attention+AND+deficit. Accessed October 18, 2009.
Evidence-based answers from the Family Physicians Inquiries Network
What is the best way to evaluate secondary infertility?
The work-up for secondary infertility—the inability to conceive after 1 year of regular unprotected intercourse for a couple who have previously had a child1—should include a history and physical exam for both patients, plus evaluation of ovulation, semen analysis, and imaging of the uterus and fallopian tubes (strength of recommendation [SOR]: B, based on cohort studies).
Check the male partner for varicoceles: they are the leading cause of male secondary infertility. For the female partner, a hysterosalpingogram is an effective first test in the initial evaluation of the uterine cavity and tubal patency (SOR: B, based on cohort studies). Laparoscopy is indicated where there is evidence or strong suspicion of endometriosis, adhesions, or significant tubal disease (SOR: B, cohort studies). Routine postcoital testing is unnecessary (SOR: A, randomized controlled trial and cohort studies).
Simple steps may reveal treatable causes
Peter Danis, MD
St. John’s Mercy Medical Center, St. Louis, MO
Many times, family physicians are too quick to refer couples with infertility problems. Conception and early pregnancy require 6 basic elements of good quality: mucus, egg, sperm, timing, anatomy, and hormonal support. Couples that learn how to chart their cycles can provide physicians with valuable information such as bleeding pattern, quality of mucus, and luteal phase length. This can help the couple to focus on their time of maximal fertility.
A good working relationship with an obstetrician and urologist is important for more complicated workups and treatments. A couple with secondary infertility has shown that things were once working right; it’s up to the physician to determine what may have changed since that success.
Evidence summary
The prevalence of infertility in the US is approximately 15% to 17%.2,3 Secondary infertility may comprise 80% of these cases, though reports vary.2 Begin the evaluation of secondary infertility with a thorough history and physical, as outlined in the TABLE), followed by semen analysis and evaluation of ovulation.1,3,4
TABLE
Secondary infertility? Here’s what to cover in the history and exam
| HISTORY | |
| FEMALE | MALE |
| Prior pregnancies and complications; fertility in other relationships | Sexual dysfunction or impotence |
| Menstrual history: Age at menarche, cycle length, regularity, characteristics, dysmenorrhea | Testicular surgery, history of mumps, prior infections |
| Gyn history: Infections, prior surgeries, endometriosis, cervical dysplasia, DES exposure, prior contraceptive use | BOTH |
| Symptoms of thyroid disease, pelvic pain, abdominal pain, galactorrhea, hirsutism, and dyspareunia | Duration of infertility |
| Exercise and dietary history, presence of eating disorder | Previous evaluations and results |
| Current medications | Frequency of intercourse and use of lubricants |
| Occupational history | History of chemotherapy, radiation, and other environmental and occupational exposures like alcohol and drugs |
| Breast exam/secretions | Preconception counseling |
| PHYSICAL | |
| FEMALE | MALE |
| Genitourinary exam: Vaginal/cervical abnormalities or discharge, uterine size and shape, adnexal mass or tenderness | Genitourinary exam: testicular size and consistency, location of urethral meatus, presence of varicocele |
| Weight: body-mass index >29 or <19 | Weight/body habitus |
| Thyroid enlargement, nodules, or tenderness | Hair distribution |
| Presence of hirsutism | Breast development |
| Digital rectal exam | |
Evaluate the male partner for varicoceles
The semen sample can be taken after the patient abstains from ejaculation for 2 to 6 days. Analyze the sample for volume, pH, sperm concentration, motility, and total number. If the sample is abnormal, repeat the analysis within 3 months.1,5
Evaluate the male for varicoceles. A retrospective chart review compared 285 men with secondary infertility with 285 men with primary infertility. Varicoceles were the cause of secondary infertility in 177 (69%) of men with secondary infertility compared with 128 (50%) of men with primary infertility (P<.0001).6
Order tests to evaluate ovulation
To evaluate ovulation, look at menstrual history, serum progesterone, and urine luteinizing hormone (LH).1,3,4 If the woman has signs of androgenic dysfunction, draw tests for LH, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), testosterone, prolactin, and 17-hydroxyprogesterone. A woman with irregular menses should have her LH and FSH checked.1
A hysterosalpingogram is an effective first test in the evaluation of the uterine cavity and tubal patency.1,7,8 If the woman has comorbidities—such as a history of pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis—then laparoscopy should be the initial test.1,3 One study demonstrated increased diagnostic yield with a combined approach of hysteroscopy and laparoscopy, in communities where the risk of pelvic infection was great.9
Routine postcoital testing is unnecessary.10 A randomized controlled trial compared 227 couples who received the postcoital test with 217 couples who did not. Routine use of the postcoital test led to more tests and more treatments but had no significant effect on the pregnancy rate.
Recommendations from others
According to the Royal College of Obstetricians and Gynecologists:1
- The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
- The routine measurement of thyroid function should not be offered.
- Women should not be offered an endometrial biopsy to evaluate the luteal phase because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
- Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis) should be offered hysterosalpingography to screen for tubal occlusion.
- Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.
1. National Collaborating Centre for Women’s and Children’s Health. Fertility: Assessment and Treatment for People with Fertility Problems. London: RCOG Press; 2004:216.
2. Wyshak G. Infertility in American college alumnae. Intl J Gynaecol Obstet 2001;73:237-242.
3. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril 2004;82(Suppl 1):S169-S172.
4. Brigham and Women’s Hospital. Infertility: A Guide to Evaluation, Treatment, and Counseling. Boston, Mass: Brigham and Women’s Hospital; 2003:11.
5. Report on optimal evaluation of the infertile male. Baltimore, Md: American Urological Association; 2001:14.
6. Witt MA, Lipshultz LI. Varicocele: A progressive or static lesion? Urology 1993;42:541-543.
7. Valenzano M, Mistrangelo E, Lijoi D, et al. Transvaginal sonohysterographic evaluation of uterine malformations. Eur J Obstet Gynecol Reprod Biol 2006;124:246-249.
8. Roma Dalfó A, Ubeda B, Ubeda A, et al. Diagnostic value of hysterosalpingography in the detection of intrauterine abnormalities: a comparison with hysteroscopy. AJR Am J Roentgenol 2004;183:1405-1409.
9. Shokeir T, Shalan H, El-Shafei M. Combined diagnostic approach of laparoscopy and hysteroscopy in the evaluation of female infertility: Results of 612 patients. J Obstet Gynaecol Res 2004;30:9-14.
10. Oei SG, Helmerhorst F, Bloemenkamp K, Hollants F, Meerpoel D, Keirse M. Effectiveness of the postcoital test: randomized controlled trial. BMJ 1998;317:502-505.
The work-up for secondary infertility—the inability to conceive after 1 year of regular unprotected intercourse for a couple who have previously had a child1—should include a history and physical exam for both patients, plus evaluation of ovulation, semen analysis, and imaging of the uterus and fallopian tubes (strength of recommendation [SOR]: B, based on cohort studies).
Check the male partner for varicoceles: they are the leading cause of male secondary infertility. For the female partner, a hysterosalpingogram is an effective first test in the initial evaluation of the uterine cavity and tubal patency (SOR: B, based on cohort studies). Laparoscopy is indicated where there is evidence or strong suspicion of endometriosis, adhesions, or significant tubal disease (SOR: B, cohort studies). Routine postcoital testing is unnecessary (SOR: A, randomized controlled trial and cohort studies).
Simple steps may reveal treatable causes
Peter Danis, MD
St. John’s Mercy Medical Center, St. Louis, MO
Many times, family physicians are too quick to refer couples with infertility problems. Conception and early pregnancy require 6 basic elements of good quality: mucus, egg, sperm, timing, anatomy, and hormonal support. Couples that learn how to chart their cycles can provide physicians with valuable information such as bleeding pattern, quality of mucus, and luteal phase length. This can help the couple to focus on their time of maximal fertility.
A good working relationship with an obstetrician and urologist is important for more complicated workups and treatments. A couple with secondary infertility has shown that things were once working right; it’s up to the physician to determine what may have changed since that success.
Evidence summary
The prevalence of infertility in the US is approximately 15% to 17%.2,3 Secondary infertility may comprise 80% of these cases, though reports vary.2 Begin the evaluation of secondary infertility with a thorough history and physical, as outlined in the TABLE), followed by semen analysis and evaluation of ovulation.1,3,4
TABLE
Secondary infertility? Here’s what to cover in the history and exam
| HISTORY | |
| FEMALE | MALE |
| Prior pregnancies and complications; fertility in other relationships | Sexual dysfunction or impotence |
| Menstrual history: Age at menarche, cycle length, regularity, characteristics, dysmenorrhea | Testicular surgery, history of mumps, prior infections |
| Gyn history: Infections, prior surgeries, endometriosis, cervical dysplasia, DES exposure, prior contraceptive use | BOTH |
| Symptoms of thyroid disease, pelvic pain, abdominal pain, galactorrhea, hirsutism, and dyspareunia | Duration of infertility |
| Exercise and dietary history, presence of eating disorder | Previous evaluations and results |
| Current medications | Frequency of intercourse and use of lubricants |
| Occupational history | History of chemotherapy, radiation, and other environmental and occupational exposures like alcohol and drugs |
| Breast exam/secretions | Preconception counseling |
| PHYSICAL | |
| FEMALE | MALE |
| Genitourinary exam: Vaginal/cervical abnormalities or discharge, uterine size and shape, adnexal mass or tenderness | Genitourinary exam: testicular size and consistency, location of urethral meatus, presence of varicocele |
| Weight: body-mass index >29 or <19 | Weight/body habitus |
| Thyroid enlargement, nodules, or tenderness | Hair distribution |
| Presence of hirsutism | Breast development |
| Digital rectal exam | |
Evaluate the male partner for varicoceles
The semen sample can be taken after the patient abstains from ejaculation for 2 to 6 days. Analyze the sample for volume, pH, sperm concentration, motility, and total number. If the sample is abnormal, repeat the analysis within 3 months.1,5
Evaluate the male for varicoceles. A retrospective chart review compared 285 men with secondary infertility with 285 men with primary infertility. Varicoceles were the cause of secondary infertility in 177 (69%) of men with secondary infertility compared with 128 (50%) of men with primary infertility (P<.0001).6
Order tests to evaluate ovulation
To evaluate ovulation, look at menstrual history, serum progesterone, and urine luteinizing hormone (LH).1,3,4 If the woman has signs of androgenic dysfunction, draw tests for LH, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), testosterone, prolactin, and 17-hydroxyprogesterone. A woman with irregular menses should have her LH and FSH checked.1
A hysterosalpingogram is an effective first test in the evaluation of the uterine cavity and tubal patency.1,7,8 If the woman has comorbidities—such as a history of pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis—then laparoscopy should be the initial test.1,3 One study demonstrated increased diagnostic yield with a combined approach of hysteroscopy and laparoscopy, in communities where the risk of pelvic infection was great.9
Routine postcoital testing is unnecessary.10 A randomized controlled trial compared 227 couples who received the postcoital test with 217 couples who did not. Routine use of the postcoital test led to more tests and more treatments but had no significant effect on the pregnancy rate.
Recommendations from others
According to the Royal College of Obstetricians and Gynecologists:1
- The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
- The routine measurement of thyroid function should not be offered.
- Women should not be offered an endometrial biopsy to evaluate the luteal phase because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
- Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis) should be offered hysterosalpingography to screen for tubal occlusion.
- Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.
The work-up for secondary infertility—the inability to conceive after 1 year of regular unprotected intercourse for a couple who have previously had a child1—should include a history and physical exam for both patients, plus evaluation of ovulation, semen analysis, and imaging of the uterus and fallopian tubes (strength of recommendation [SOR]: B, based on cohort studies).
Check the male partner for varicoceles: they are the leading cause of male secondary infertility. For the female partner, a hysterosalpingogram is an effective first test in the initial evaluation of the uterine cavity and tubal patency (SOR: B, based on cohort studies). Laparoscopy is indicated where there is evidence or strong suspicion of endometriosis, adhesions, or significant tubal disease (SOR: B, cohort studies). Routine postcoital testing is unnecessary (SOR: A, randomized controlled trial and cohort studies).
Simple steps may reveal treatable causes
Peter Danis, MD
St. John’s Mercy Medical Center, St. Louis, MO
Many times, family physicians are too quick to refer couples with infertility problems. Conception and early pregnancy require 6 basic elements of good quality: mucus, egg, sperm, timing, anatomy, and hormonal support. Couples that learn how to chart their cycles can provide physicians with valuable information such as bleeding pattern, quality of mucus, and luteal phase length. This can help the couple to focus on their time of maximal fertility.
A good working relationship with an obstetrician and urologist is important for more complicated workups and treatments. A couple with secondary infertility has shown that things were once working right; it’s up to the physician to determine what may have changed since that success.
Evidence summary
The prevalence of infertility in the US is approximately 15% to 17%.2,3 Secondary infertility may comprise 80% of these cases, though reports vary.2 Begin the evaluation of secondary infertility with a thorough history and physical, as outlined in the TABLE), followed by semen analysis and evaluation of ovulation.1,3,4
TABLE
Secondary infertility? Here’s what to cover in the history and exam
| HISTORY | |
| FEMALE | MALE |
| Prior pregnancies and complications; fertility in other relationships | Sexual dysfunction or impotence |
| Menstrual history: Age at menarche, cycle length, regularity, characteristics, dysmenorrhea | Testicular surgery, history of mumps, prior infections |
| Gyn history: Infections, prior surgeries, endometriosis, cervical dysplasia, DES exposure, prior contraceptive use | BOTH |
| Symptoms of thyroid disease, pelvic pain, abdominal pain, galactorrhea, hirsutism, and dyspareunia | Duration of infertility |
| Exercise and dietary history, presence of eating disorder | Previous evaluations and results |
| Current medications | Frequency of intercourse and use of lubricants |
| Occupational history | History of chemotherapy, radiation, and other environmental and occupational exposures like alcohol and drugs |
| Breast exam/secretions | Preconception counseling |
| PHYSICAL | |
| FEMALE | MALE |
| Genitourinary exam: Vaginal/cervical abnormalities or discharge, uterine size and shape, adnexal mass or tenderness | Genitourinary exam: testicular size and consistency, location of urethral meatus, presence of varicocele |
| Weight: body-mass index >29 or <19 | Weight/body habitus |
| Thyroid enlargement, nodules, or tenderness | Hair distribution |
| Presence of hirsutism | Breast development |
| Digital rectal exam | |
Evaluate the male partner for varicoceles
The semen sample can be taken after the patient abstains from ejaculation for 2 to 6 days. Analyze the sample for volume, pH, sperm concentration, motility, and total number. If the sample is abnormal, repeat the analysis within 3 months.1,5
Evaluate the male for varicoceles. A retrospective chart review compared 285 men with secondary infertility with 285 men with primary infertility. Varicoceles were the cause of secondary infertility in 177 (69%) of men with secondary infertility compared with 128 (50%) of men with primary infertility (P<.0001).6
Order tests to evaluate ovulation
To evaluate ovulation, look at menstrual history, serum progesterone, and urine luteinizing hormone (LH).1,3,4 If the woman has signs of androgenic dysfunction, draw tests for LH, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), testosterone, prolactin, and 17-hydroxyprogesterone. A woman with irregular menses should have her LH and FSH checked.1
A hysterosalpingogram is an effective first test in the evaluation of the uterine cavity and tubal patency.1,7,8 If the woman has comorbidities—such as a history of pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis—then laparoscopy should be the initial test.1,3 One study demonstrated increased diagnostic yield with a combined approach of hysteroscopy and laparoscopy, in communities where the risk of pelvic infection was great.9
Routine postcoital testing is unnecessary.10 A randomized controlled trial compared 227 couples who received the postcoital test with 217 couples who did not. Routine use of the postcoital test led to more tests and more treatments but had no significant effect on the pregnancy rate.
Recommendations from others
According to the Royal College of Obstetricians and Gynecologists:1
- The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
- The routine measurement of thyroid function should not be offered.
- Women should not be offered an endometrial biopsy to evaluate the luteal phase because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
- Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis) should be offered hysterosalpingography to screen for tubal occlusion.
- Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.
1. National Collaborating Centre for Women’s and Children’s Health. Fertility: Assessment and Treatment for People with Fertility Problems. London: RCOG Press; 2004:216.
2. Wyshak G. Infertility in American college alumnae. Intl J Gynaecol Obstet 2001;73:237-242.
3. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril 2004;82(Suppl 1):S169-S172.
4. Brigham and Women’s Hospital. Infertility: A Guide to Evaluation, Treatment, and Counseling. Boston, Mass: Brigham and Women’s Hospital; 2003:11.
5. Report on optimal evaluation of the infertile male. Baltimore, Md: American Urological Association; 2001:14.
6. Witt MA, Lipshultz LI. Varicocele: A progressive or static lesion? Urology 1993;42:541-543.
7. Valenzano M, Mistrangelo E, Lijoi D, et al. Transvaginal sonohysterographic evaluation of uterine malformations. Eur J Obstet Gynecol Reprod Biol 2006;124:246-249.
8. Roma Dalfó A, Ubeda B, Ubeda A, et al. Diagnostic value of hysterosalpingography in the detection of intrauterine abnormalities: a comparison with hysteroscopy. AJR Am J Roentgenol 2004;183:1405-1409.
9. Shokeir T, Shalan H, El-Shafei M. Combined diagnostic approach of laparoscopy and hysteroscopy in the evaluation of female infertility: Results of 612 patients. J Obstet Gynaecol Res 2004;30:9-14.
10. Oei SG, Helmerhorst F, Bloemenkamp K, Hollants F, Meerpoel D, Keirse M. Effectiveness of the postcoital test: randomized controlled trial. BMJ 1998;317:502-505.
1. National Collaborating Centre for Women’s and Children’s Health. Fertility: Assessment and Treatment for People with Fertility Problems. London: RCOG Press; 2004:216.
2. Wyshak G. Infertility in American college alumnae. Intl J Gynaecol Obstet 2001;73:237-242.
3. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril 2004;82(Suppl 1):S169-S172.
4. Brigham and Women’s Hospital. Infertility: A Guide to Evaluation, Treatment, and Counseling. Boston, Mass: Brigham and Women’s Hospital; 2003:11.
5. Report on optimal evaluation of the infertile male. Baltimore, Md: American Urological Association; 2001:14.
6. Witt MA, Lipshultz LI. Varicocele: A progressive or static lesion? Urology 1993;42:541-543.
7. Valenzano M, Mistrangelo E, Lijoi D, et al. Transvaginal sonohysterographic evaluation of uterine malformations. Eur J Obstet Gynecol Reprod Biol 2006;124:246-249.
8. Roma Dalfó A, Ubeda B, Ubeda A, et al. Diagnostic value of hysterosalpingography in the detection of intrauterine abnormalities: a comparison with hysteroscopy. AJR Am J Roentgenol 2004;183:1405-1409.
9. Shokeir T, Shalan H, El-Shafei M. Combined diagnostic approach of laparoscopy and hysteroscopy in the evaluation of female infertility: Results of 612 patients. J Obstet Gynaecol Res 2004;30:9-14.
10. Oei SG, Helmerhorst F, Bloemenkamp K, Hollants F, Meerpoel D, Keirse M. Effectiveness of the postcoital test: randomized controlled trial. BMJ 1998;317:502-505.
Evidence-based answers from the Family Physicians Inquiries Network
Which blood tests are most helpful in evaluating pelvic inflammatory disease?
No individual or combination of blood tests can reliably diagnose pelvic inflammatory disease (PID) (strength of recommendation [SOR]: A, meta-analysis). The combination of white blood cell count, Creactive protein (CRP), erythrocyte sedimentation rate (ESR), and vaginal white blood cells can reliably exclude PID if results for all 4 tests are normal (sensitivity=100%) (SOR: B, cohort study, reference standard not uniformly applied).
The combination of CRP and ESR is helpful in excluding PID (sensitivity=91%) and may be especially useful in distinguishing mild from complicated cases (SOR: B, small cohort study). Individual tests do not appear to significantly improve diagnostic accuracy, although the CRP and ESR are somewhat useful to rule out PID (SOR: B, small cohort study).
Evidence summary
Because of the significant inflammatory sequelae of PID, it is the standard of care to treat women with suggestive signs and symptoms. Clinical diagnosis has a positive predictive value of 65% to 90% compared with laparoscopy.1 While no single test is both sensitive and specific, a combination of biochemical tests for inflammation may improve the ability to rule out PID.
A prospective cohort study of 120 women presenting to an ambulatory center with symptoms of PID evaluated the tests commonly used to support the clinical diagnosis of PID.2 The objective criteria used for diagnosis included histologic evidence of acute endometritis via endometrial biopsy, purulent exudates in the pelvis on laparoscopy, or microbiologic evidence of Neisseris gonorrhea or Chlamydia trachomatis from the upper genital tract. The Table shows the sensitivities, specificities, and predictive values for an elevated white blood cells (>10,000/mm), ESR (>15 mm/hr), CRP (>5 mg/dL), and increased vaginal white blood cells (>3 white blood cells/high-power field) for detection of PID. If all 4 test results are negative, PID is reliably ruled out with a sensitivity of 100%. These results may be an overestimate, as the gold standard was not uniformly applied.
The role of CRP and ESR in the diagnosis of acute PID was studied in 41 women with clinically suspected acute PID who presented to a university department of obstetrics and gynecology.3 Women underwent laparoscopy, endometrial sampling, and cultures of the upper genital tract to confirm the diagnosis. When considered together, a positive value in either the ESR (cutoff level of 15 mm/hr) or CRP (cutoff >20 mg/dL) had a sensitivity of 91% and a specificity of 50%.
Another report looked at the ability of ESR and CRP to differentiate between mild, moderate, and severe PID in 72 women undergoing laparoscopy at a university department of gynecology.4 The cutoff levels were ESR >40 mm/hr and CRP >60 mg/dL. If either test was abnormal, the sensitivity and the negative predictive value for severe disease were 97% and 96%, respectively ( Table). All patients with tuboovarian abscess or perihepatitis and 6 of 7 patients who had anaerobic bacteria isolated from the fallopian tubes tested positive with these cutoff levels.
A meta-analysis from 1991 found 12 studies, not including any of the above studies, and assessed the laboratory criteria for the diagnosis of PID. No single or combination diagnostic indicator was found to reliably predict PID. However, the CRP and the ESR were useful in ruling out PID, with good sensitivities for CRP in 4 of 4 studies analyzed (74%–93%) and for the ESR in 4 of 6 studies (64%–81%). Ten of 12 studies used laparoscopy as the gold standard.5
TABLE
Diagnostic performance of blood tests for pelvic inflammatory disease
| Sn (%) | Sp (%) | PPV (%)* | NPV (%)* | |
|---|---|---|---|---|
| WBC (>10,000/mm 3)2 | 57 | 88 | 88 | 58 |
| ESR (>15 mm/hr) 2 | 70 | 52 | 69 | 54 |
| CRP (>5 mg/dL) 2 | 71 | 66 | 76 | 60 |
| Vaginal WBCs 2 | 78 | 39 | 66 | 54 |
| 0 of 4 of the above positive 2 | 100 | 18 | 100 | 65 |
| 4 of 4 of the above positive 2 | 29 | 95 | 90 | 47 |
| CRP >20 or ESR >15 3 | 91 | 50 | N/A | N/A |
| CRP >60 or ESR >40 4 | 97 | 61 | 70 | 96 |
| CRP (metaanalysis)5 | 74%–93% | 50%–90% | ||
| ESR (metaanalysis)5 | 64%–81% | 43%–69% | ||
| *Prevalence=60%. SN, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein. | ||||
Recommendations from others
The Centers for Disease Control and Prevention makes no specific recommendation for the use of specific blood tests in the diagnosis of PID.1 The Association for Genitourinary Medicine states that an elevated ESR or CRP supports the diagnosis of PID.6
When diagnosing PID, a clinician must have a high index of suspicion
Ellen Beck, MD
University of California– San Diego
PID is a difficult diagnosis to make, without clear-cut diagnostic guideposts. The sequelae of PID can be so serious that clinicians must not miss this diagnosis. If results of all 4 tests described above are negative, this can reliably rule out the diagnosis.
Unfortunately, no set of tests can reliably confirm the diagnosis in all cases. The traditional triad of lower abdominal pain, cervical motion tenderness, and adnexal pain are still taught as the classic findings for diagnosing PID. The clinician must also have a high index of suspicion, particularly with teen-agers with abdominal pain, and when the pain is indolent and lingering.
Nonetheless, a recent study concludes there is insufficient evidence to support existing clinical diagnostic criteria and recommends that the clinical criteria for PID be redefined. In a group of patients with laparoscopically confirmed PID, no variable (abnormal vaginal discharge, fever >38°C, vomiting, menstrual irregularity, ongoing bleeding, symptoms of urethritis, rectal temperature >38°C, marked tenderness of pelvic organs on bimanual examination, adnexal mass, and ESR >15 mm) reliably predicted the disease, and found, rather, that most had low specificity and sensitivity. The chance of having PID based on the presence of lower abdominal pain was 79%. Three variables predicted 65% of the cases of PID: elevated ESR, fever, and adnexal tenderness. When evaluating patients for admission, some authors add “the desire to bear children” to the standard admission criteria, which include severity of sickness, pregnancy, possible need for surgical intervention, lack of response to oral medications, or immunosuppression.
1. Sexually transmitted diseases treatment guidelines. MMWR Recomm Rep 2002;51(RR-6):48-52.
2. Peipert JF, Boardman L, Hogan JW, Sung J, Mayer KH. Laboratory evaluation of acute upper genital tract infection. Obstet Gynecol 1996;87:730-736.
3. Lehtinen M, Laine S, Heinonen PK, et al. Serum C-reactive protein determination in acute pelvic inflammatory disease. Am J Obstet Gynecol 1986;154:158-159.
4. Miettinen AK, Heinonen PK, Laippala P, Paavonen J. Test performance of erythrocyte sedimentation rate and C-reactive protein in assessing the severity of acute pelvic inflammatory disease. Am J Obstet Gynecol 1993;169:1143-1149.
5. Kahn JG, Walker CK, Washington AE, Landers DV, Sweet RL. Diagnosing pelvic inflammatory disease. A comprehensive analysis and considerations for developing a new model. JAMA 1991;266:2594-2604.
6. 2002 Guidelines for the management of pelvic infection and perihepatitis. London: Association for Genitourinary Medicine (AGUM); Medical Society for the Study of Venereal Disease (MSSVD); 2002. Available at: www.agum.org.uk/ceg2002/pid0601.htm. Accessed on March 5, 2004.
No individual or combination of blood tests can reliably diagnose pelvic inflammatory disease (PID) (strength of recommendation [SOR]: A, meta-analysis). The combination of white blood cell count, Creactive protein (CRP), erythrocyte sedimentation rate (ESR), and vaginal white blood cells can reliably exclude PID if results for all 4 tests are normal (sensitivity=100%) (SOR: B, cohort study, reference standard not uniformly applied).
The combination of CRP and ESR is helpful in excluding PID (sensitivity=91%) and may be especially useful in distinguishing mild from complicated cases (SOR: B, small cohort study). Individual tests do not appear to significantly improve diagnostic accuracy, although the CRP and ESR are somewhat useful to rule out PID (SOR: B, small cohort study).
Evidence summary
Because of the significant inflammatory sequelae of PID, it is the standard of care to treat women with suggestive signs and symptoms. Clinical diagnosis has a positive predictive value of 65% to 90% compared with laparoscopy.1 While no single test is both sensitive and specific, a combination of biochemical tests for inflammation may improve the ability to rule out PID.
A prospective cohort study of 120 women presenting to an ambulatory center with symptoms of PID evaluated the tests commonly used to support the clinical diagnosis of PID.2 The objective criteria used for diagnosis included histologic evidence of acute endometritis via endometrial biopsy, purulent exudates in the pelvis on laparoscopy, or microbiologic evidence of Neisseris gonorrhea or Chlamydia trachomatis from the upper genital tract. The Table shows the sensitivities, specificities, and predictive values for an elevated white blood cells (>10,000/mm), ESR (>15 mm/hr), CRP (>5 mg/dL), and increased vaginal white blood cells (>3 white blood cells/high-power field) for detection of PID. If all 4 test results are negative, PID is reliably ruled out with a sensitivity of 100%. These results may be an overestimate, as the gold standard was not uniformly applied.
The role of CRP and ESR in the diagnosis of acute PID was studied in 41 women with clinically suspected acute PID who presented to a university department of obstetrics and gynecology.3 Women underwent laparoscopy, endometrial sampling, and cultures of the upper genital tract to confirm the diagnosis. When considered together, a positive value in either the ESR (cutoff level of 15 mm/hr) or CRP (cutoff >20 mg/dL) had a sensitivity of 91% and a specificity of 50%.
Another report looked at the ability of ESR and CRP to differentiate between mild, moderate, and severe PID in 72 women undergoing laparoscopy at a university department of gynecology.4 The cutoff levels were ESR >40 mm/hr and CRP >60 mg/dL. If either test was abnormal, the sensitivity and the negative predictive value for severe disease were 97% and 96%, respectively ( Table). All patients with tuboovarian abscess or perihepatitis and 6 of 7 patients who had anaerobic bacteria isolated from the fallopian tubes tested positive with these cutoff levels.
A meta-analysis from 1991 found 12 studies, not including any of the above studies, and assessed the laboratory criteria for the diagnosis of PID. No single or combination diagnostic indicator was found to reliably predict PID. However, the CRP and the ESR were useful in ruling out PID, with good sensitivities for CRP in 4 of 4 studies analyzed (74%–93%) and for the ESR in 4 of 6 studies (64%–81%). Ten of 12 studies used laparoscopy as the gold standard.5
TABLE
Diagnostic performance of blood tests for pelvic inflammatory disease
| Sn (%) | Sp (%) | PPV (%)* | NPV (%)* | |
|---|---|---|---|---|
| WBC (>10,000/mm 3)2 | 57 | 88 | 88 | 58 |
| ESR (>15 mm/hr) 2 | 70 | 52 | 69 | 54 |
| CRP (>5 mg/dL) 2 | 71 | 66 | 76 | 60 |
| Vaginal WBCs 2 | 78 | 39 | 66 | 54 |
| 0 of 4 of the above positive 2 | 100 | 18 | 100 | 65 |
| 4 of 4 of the above positive 2 | 29 | 95 | 90 | 47 |
| CRP >20 or ESR >15 3 | 91 | 50 | N/A | N/A |
| CRP >60 or ESR >40 4 | 97 | 61 | 70 | 96 |
| CRP (metaanalysis)5 | 74%–93% | 50%–90% | ||
| ESR (metaanalysis)5 | 64%–81% | 43%–69% | ||
| *Prevalence=60%. SN, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein. | ||||
Recommendations from others
The Centers for Disease Control and Prevention makes no specific recommendation for the use of specific blood tests in the diagnosis of PID.1 The Association for Genitourinary Medicine states that an elevated ESR or CRP supports the diagnosis of PID.6
When diagnosing PID, a clinician must have a high index of suspicion
Ellen Beck, MD
University of California– San Diego
PID is a difficult diagnosis to make, without clear-cut diagnostic guideposts. The sequelae of PID can be so serious that clinicians must not miss this diagnosis. If results of all 4 tests described above are negative, this can reliably rule out the diagnosis.
Unfortunately, no set of tests can reliably confirm the diagnosis in all cases. The traditional triad of lower abdominal pain, cervical motion tenderness, and adnexal pain are still taught as the classic findings for diagnosing PID. The clinician must also have a high index of suspicion, particularly with teen-agers with abdominal pain, and when the pain is indolent and lingering.
Nonetheless, a recent study concludes there is insufficient evidence to support existing clinical diagnostic criteria and recommends that the clinical criteria for PID be redefined. In a group of patients with laparoscopically confirmed PID, no variable (abnormal vaginal discharge, fever >38°C, vomiting, menstrual irregularity, ongoing bleeding, symptoms of urethritis, rectal temperature >38°C, marked tenderness of pelvic organs on bimanual examination, adnexal mass, and ESR >15 mm) reliably predicted the disease, and found, rather, that most had low specificity and sensitivity. The chance of having PID based on the presence of lower abdominal pain was 79%. Three variables predicted 65% of the cases of PID: elevated ESR, fever, and adnexal tenderness. When evaluating patients for admission, some authors add “the desire to bear children” to the standard admission criteria, which include severity of sickness, pregnancy, possible need for surgical intervention, lack of response to oral medications, or immunosuppression.
No individual or combination of blood tests can reliably diagnose pelvic inflammatory disease (PID) (strength of recommendation [SOR]: A, meta-analysis). The combination of white blood cell count, Creactive protein (CRP), erythrocyte sedimentation rate (ESR), and vaginal white blood cells can reliably exclude PID if results for all 4 tests are normal (sensitivity=100%) (SOR: B, cohort study, reference standard not uniformly applied).
The combination of CRP and ESR is helpful in excluding PID (sensitivity=91%) and may be especially useful in distinguishing mild from complicated cases (SOR: B, small cohort study). Individual tests do not appear to significantly improve diagnostic accuracy, although the CRP and ESR are somewhat useful to rule out PID (SOR: B, small cohort study).
Evidence summary
Because of the significant inflammatory sequelae of PID, it is the standard of care to treat women with suggestive signs and symptoms. Clinical diagnosis has a positive predictive value of 65% to 90% compared with laparoscopy.1 While no single test is both sensitive and specific, a combination of biochemical tests for inflammation may improve the ability to rule out PID.
A prospective cohort study of 120 women presenting to an ambulatory center with symptoms of PID evaluated the tests commonly used to support the clinical diagnosis of PID.2 The objective criteria used for diagnosis included histologic evidence of acute endometritis via endometrial biopsy, purulent exudates in the pelvis on laparoscopy, or microbiologic evidence of Neisseris gonorrhea or Chlamydia trachomatis from the upper genital tract. The Table shows the sensitivities, specificities, and predictive values for an elevated white blood cells (>10,000/mm), ESR (>15 mm/hr), CRP (>5 mg/dL), and increased vaginal white blood cells (>3 white blood cells/high-power field) for detection of PID. If all 4 test results are negative, PID is reliably ruled out with a sensitivity of 100%. These results may be an overestimate, as the gold standard was not uniformly applied.
The role of CRP and ESR in the diagnosis of acute PID was studied in 41 women with clinically suspected acute PID who presented to a university department of obstetrics and gynecology.3 Women underwent laparoscopy, endometrial sampling, and cultures of the upper genital tract to confirm the diagnosis. When considered together, a positive value in either the ESR (cutoff level of 15 mm/hr) or CRP (cutoff >20 mg/dL) had a sensitivity of 91% and a specificity of 50%.
Another report looked at the ability of ESR and CRP to differentiate between mild, moderate, and severe PID in 72 women undergoing laparoscopy at a university department of gynecology.4 The cutoff levels were ESR >40 mm/hr and CRP >60 mg/dL. If either test was abnormal, the sensitivity and the negative predictive value for severe disease were 97% and 96%, respectively ( Table). All patients with tuboovarian abscess or perihepatitis and 6 of 7 patients who had anaerobic bacteria isolated from the fallopian tubes tested positive with these cutoff levels.
A meta-analysis from 1991 found 12 studies, not including any of the above studies, and assessed the laboratory criteria for the diagnosis of PID. No single or combination diagnostic indicator was found to reliably predict PID. However, the CRP and the ESR were useful in ruling out PID, with good sensitivities for CRP in 4 of 4 studies analyzed (74%–93%) and for the ESR in 4 of 6 studies (64%–81%). Ten of 12 studies used laparoscopy as the gold standard.5
TABLE
Diagnostic performance of blood tests for pelvic inflammatory disease
| Sn (%) | Sp (%) | PPV (%)* | NPV (%)* | |
|---|---|---|---|---|
| WBC (>10,000/mm 3)2 | 57 | 88 | 88 | 58 |
| ESR (>15 mm/hr) 2 | 70 | 52 | 69 | 54 |
| CRP (>5 mg/dL) 2 | 71 | 66 | 76 | 60 |
| Vaginal WBCs 2 | 78 | 39 | 66 | 54 |
| 0 of 4 of the above positive 2 | 100 | 18 | 100 | 65 |
| 4 of 4 of the above positive 2 | 29 | 95 | 90 | 47 |
| CRP >20 or ESR >15 3 | 91 | 50 | N/A | N/A |
| CRP >60 or ESR >40 4 | 97 | 61 | 70 | 96 |
| CRP (metaanalysis)5 | 74%–93% | 50%–90% | ||
| ESR (metaanalysis)5 | 64%–81% | 43%–69% | ||
| *Prevalence=60%. SN, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein. | ||||
Recommendations from others
The Centers for Disease Control and Prevention makes no specific recommendation for the use of specific blood tests in the diagnosis of PID.1 The Association for Genitourinary Medicine states that an elevated ESR or CRP supports the diagnosis of PID.6
When diagnosing PID, a clinician must have a high index of suspicion
Ellen Beck, MD
University of California– San Diego
PID is a difficult diagnosis to make, without clear-cut diagnostic guideposts. The sequelae of PID can be so serious that clinicians must not miss this diagnosis. If results of all 4 tests described above are negative, this can reliably rule out the diagnosis.
Unfortunately, no set of tests can reliably confirm the diagnosis in all cases. The traditional triad of lower abdominal pain, cervical motion tenderness, and adnexal pain are still taught as the classic findings for diagnosing PID. The clinician must also have a high index of suspicion, particularly with teen-agers with abdominal pain, and when the pain is indolent and lingering.
Nonetheless, a recent study concludes there is insufficient evidence to support existing clinical diagnostic criteria and recommends that the clinical criteria for PID be redefined. In a group of patients with laparoscopically confirmed PID, no variable (abnormal vaginal discharge, fever >38°C, vomiting, menstrual irregularity, ongoing bleeding, symptoms of urethritis, rectal temperature >38°C, marked tenderness of pelvic organs on bimanual examination, adnexal mass, and ESR >15 mm) reliably predicted the disease, and found, rather, that most had low specificity and sensitivity. The chance of having PID based on the presence of lower abdominal pain was 79%. Three variables predicted 65% of the cases of PID: elevated ESR, fever, and adnexal tenderness. When evaluating patients for admission, some authors add “the desire to bear children” to the standard admission criteria, which include severity of sickness, pregnancy, possible need for surgical intervention, lack of response to oral medications, or immunosuppression.
1. Sexually transmitted diseases treatment guidelines. MMWR Recomm Rep 2002;51(RR-6):48-52.
2. Peipert JF, Boardman L, Hogan JW, Sung J, Mayer KH. Laboratory evaluation of acute upper genital tract infection. Obstet Gynecol 1996;87:730-736.
3. Lehtinen M, Laine S, Heinonen PK, et al. Serum C-reactive protein determination in acute pelvic inflammatory disease. Am J Obstet Gynecol 1986;154:158-159.
4. Miettinen AK, Heinonen PK, Laippala P, Paavonen J. Test performance of erythrocyte sedimentation rate and C-reactive protein in assessing the severity of acute pelvic inflammatory disease. Am J Obstet Gynecol 1993;169:1143-1149.
5. Kahn JG, Walker CK, Washington AE, Landers DV, Sweet RL. Diagnosing pelvic inflammatory disease. A comprehensive analysis and considerations for developing a new model. JAMA 1991;266:2594-2604.
6. 2002 Guidelines for the management of pelvic infection and perihepatitis. London: Association for Genitourinary Medicine (AGUM); Medical Society for the Study of Venereal Disease (MSSVD); 2002. Available at: www.agum.org.uk/ceg2002/pid0601.htm. Accessed on March 5, 2004.
1. Sexually transmitted diseases treatment guidelines. MMWR Recomm Rep 2002;51(RR-6):48-52.
2. Peipert JF, Boardman L, Hogan JW, Sung J, Mayer KH. Laboratory evaluation of acute upper genital tract infection. Obstet Gynecol 1996;87:730-736.
3. Lehtinen M, Laine S, Heinonen PK, et al. Serum C-reactive protein determination in acute pelvic inflammatory disease. Am J Obstet Gynecol 1986;154:158-159.
4. Miettinen AK, Heinonen PK, Laippala P, Paavonen J. Test performance of erythrocyte sedimentation rate and C-reactive protein in assessing the severity of acute pelvic inflammatory disease. Am J Obstet Gynecol 1993;169:1143-1149.
5. Kahn JG, Walker CK, Washington AE, Landers DV, Sweet RL. Diagnosing pelvic inflammatory disease. A comprehensive analysis and considerations for developing a new model. JAMA 1991;266:2594-2604.
6. 2002 Guidelines for the management of pelvic infection and perihepatitis. London: Association for Genitourinary Medicine (AGUM); Medical Society for the Study of Venereal Disease (MSSVD); 2002. Available at: www.agum.org.uk/ceg2002/pid0601.htm. Accessed on March 5, 2004.
Evidence-based answers from the Family Physicians Inquiries Network