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Is guaifenesin safe during pregnancy?
It’s not clear; little evidence supports or refutes the safety of guaifenesin, a common expectorant, in pregnancy. A small number of observational and case-control studies suggest a weak association between guaifenesin use and inguinal hernias and neural tube defects in newborns. However, substantial methodological flaws, the absence of statistical significance, and low rates of prevalence cast a shadow of a doubt over the data (strength of recommendation [SOR]: B, based on observational and case-control studies).
Always take a conservative approach to obstetrics
Christopher P. Paulson, MD, FAAFP
Eglin Family Medicine residency, Eglin Air Force Base, Fla
In my practice as a family physician, a conservative approach to obstetrical care has been the rule. It seems prudent to avoid guaifenesin during the first trimester. Although the evidence is inconclusive on potential harm to the fetus, the marginal benefit gained seems insufficient to justify treatment early in pregnancy when the fetus is most vulnerable to teratogenic effects in general.
As with most other Category C medications (except those with clear clinical benefit and no safer alternative), I typically avoid guaifenesin throughout pregnancy. However, it may be reasonable to prescribe it in the latter half of pregnancy when the potential risk is lower; particularly in light of the lack of any clear evidence demonstrating harmful effects.
Evidence summary
Guaifenesin, available in numerous preparations (eg, Mucinex, Robitussin), is one of the most commonly used over-the-counter medications in pregnancy. The National Birth Defects Prevention Study surveyed 2970 pregnant women from 1997 to 2001; 6.2% reported taking guaifenesin during pregnancy.1 A second survey evaluated 7563 mothers from 1998 to 2004; 9.2% of the mothers reported that they took it during pregnancy.1
A weak link to inguinal hernias
Guaifenesin use in pregnancy has been associated with inguinal hernias in newborns. From 1958 to 1965, the Collaborative Perinatal Project recruited 132,500 women to participate in a multicenter study; however, selection and exclusion criteria were not consistent. From this initial group, only 50,282 mother-child pairs were studied. Trained examiners interviewed the women at the child’s 4, 8, 12, and 24-month visits, and then annually thereafter to 8 years of age.
The examiners identified 7 children with inguinal hernias among 197 mothers who had used guaifenesin during their first trimester (standardized relative risk [RR] of 2.6; no CI or P value reported). Twenty children had inguinal hernias among the 1337 mothers who had used guaifenesin during any trimester of their pregnancy (RR=1.1; no confidence interval [CI] or P value reported).2 The authors acknowledged that reporting bias among the participating centers prevented them from drawing any conclusions from the data.
A possible trend toward neural tube defects?
Guaifenesin use in pregnancy may also be associated with neural tube defects. In a case-control study, researchers identified 538 fetuses and live-born infants with neural tube defects between 1989 and 1991.3 Twelve patients with neural tube defects were exposed to guaifenesin during gestation; 6 in the control group reported exposure.
The authors reported a trend towards increased risk of neural tube defects in offspring of guaifenesin-exposed mothers (odds ratio=2.04; 95% CI, 0.79–5.28).3 However, since the results were not statistically significant, the authors concluded that guaifenesin had not contributed to the occurrence of neural tube defects.
In a study evaluating 6509 women whose pregnancies resulted in live births, 241 women reported first-trimester exposure to guaifenesin.4 Five of the guaifenesin-exposed infants (2.1%) had 1 of the birth defects studied (types of disorders not reported). The calculated RR of birth defect after in utero guaifenesin exposure was 1.3 (no CIs or P values reported); the authors concluded that there was no strong association between guaifenesin and the malformations studied.4
Interpret results with caution
Because of the significant potential for recall bias, interpret the findings of these case-control studies with caution.5 The mother of a child with a birth defect may search her memory more aggressively for potential causes than a mother of a healthy infant, leading to different rates of recalled, rather than actual, exposures. In the absence of confirmatory prospective data, such as medication diaries or pharmacy databases, recall bias accounts for many spurious positive findings in case control studies.
Recommendations from others
Food and Drug Administration. The FDA assigned guaifenesin to category C—that is, its risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking. Guaifenesin is recommended if the benefit to the pregnant woman warrants the risk to the fetus.6
ACOG. The American College of Obstetricians and Gynecologists (ACOG) makes no recommendation.7 The textbook Drugs in Pregnancy and Lactation reports that guaifenesin use during pregnancy exhibits very low risk to the fetus.6 The National Collaborating Centre for Women’s and Children’s Health suggests that guaifenesin be used sparingly during pregnancy.8
1. Werler MM, Mitchel AA, Hernandez-Diaz S, Honein MA. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193:771-777.
2. Heinonen OP, Sione D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, Mass: Publishing Sciences Group, 1977.
3. Shaw GM, Todoroff K, Velie EM, Lammer EJ. Maternal Illness, including fever, and medication use as risk factors for neural tube defects. Teratology 1998;57:1-7.
4. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451-455.
5. Chouinard E, Walter S. Title recall bias in case-control studies: an empirical analysis and theoretical framework. J Clin Epidemiology 1995;48:245-254.
6. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 7th ed. Baltimore, Md: Lippincott Williams & Wilkins;2005.
7. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475-480.
8. National Collaborating Centre for Women’s and Children’s Health. Antenatal Care: Routine Care for the Healthy Pregnant Woman London: RCOG Press; 2003.
It’s not clear; little evidence supports or refutes the safety of guaifenesin, a common expectorant, in pregnancy. A small number of observational and case-control studies suggest a weak association between guaifenesin use and inguinal hernias and neural tube defects in newborns. However, substantial methodological flaws, the absence of statistical significance, and low rates of prevalence cast a shadow of a doubt over the data (strength of recommendation [SOR]: B, based on observational and case-control studies).
Always take a conservative approach to obstetrics
Christopher P. Paulson, MD, FAAFP
Eglin Family Medicine residency, Eglin Air Force Base, Fla
In my practice as a family physician, a conservative approach to obstetrical care has been the rule. It seems prudent to avoid guaifenesin during the first trimester. Although the evidence is inconclusive on potential harm to the fetus, the marginal benefit gained seems insufficient to justify treatment early in pregnancy when the fetus is most vulnerable to teratogenic effects in general.
As with most other Category C medications (except those with clear clinical benefit and no safer alternative), I typically avoid guaifenesin throughout pregnancy. However, it may be reasonable to prescribe it in the latter half of pregnancy when the potential risk is lower; particularly in light of the lack of any clear evidence demonstrating harmful effects.
Evidence summary
Guaifenesin, available in numerous preparations (eg, Mucinex, Robitussin), is one of the most commonly used over-the-counter medications in pregnancy. The National Birth Defects Prevention Study surveyed 2970 pregnant women from 1997 to 2001; 6.2% reported taking guaifenesin during pregnancy.1 A second survey evaluated 7563 mothers from 1998 to 2004; 9.2% of the mothers reported that they took it during pregnancy.1
A weak link to inguinal hernias
Guaifenesin use in pregnancy has been associated with inguinal hernias in newborns. From 1958 to 1965, the Collaborative Perinatal Project recruited 132,500 women to participate in a multicenter study; however, selection and exclusion criteria were not consistent. From this initial group, only 50,282 mother-child pairs were studied. Trained examiners interviewed the women at the child’s 4, 8, 12, and 24-month visits, and then annually thereafter to 8 years of age.
The examiners identified 7 children with inguinal hernias among 197 mothers who had used guaifenesin during their first trimester (standardized relative risk [RR] of 2.6; no CI or P value reported). Twenty children had inguinal hernias among the 1337 mothers who had used guaifenesin during any trimester of their pregnancy (RR=1.1; no confidence interval [CI] or P value reported).2 The authors acknowledged that reporting bias among the participating centers prevented them from drawing any conclusions from the data.
A possible trend toward neural tube defects?
Guaifenesin use in pregnancy may also be associated with neural tube defects. In a case-control study, researchers identified 538 fetuses and live-born infants with neural tube defects between 1989 and 1991.3 Twelve patients with neural tube defects were exposed to guaifenesin during gestation; 6 in the control group reported exposure.
The authors reported a trend towards increased risk of neural tube defects in offspring of guaifenesin-exposed mothers (odds ratio=2.04; 95% CI, 0.79–5.28).3 However, since the results were not statistically significant, the authors concluded that guaifenesin had not contributed to the occurrence of neural tube defects.
In a study evaluating 6509 women whose pregnancies resulted in live births, 241 women reported first-trimester exposure to guaifenesin.4 Five of the guaifenesin-exposed infants (2.1%) had 1 of the birth defects studied (types of disorders not reported). The calculated RR of birth defect after in utero guaifenesin exposure was 1.3 (no CIs or P values reported); the authors concluded that there was no strong association between guaifenesin and the malformations studied.4
Interpret results with caution
Because of the significant potential for recall bias, interpret the findings of these case-control studies with caution.5 The mother of a child with a birth defect may search her memory more aggressively for potential causes than a mother of a healthy infant, leading to different rates of recalled, rather than actual, exposures. In the absence of confirmatory prospective data, such as medication diaries or pharmacy databases, recall bias accounts for many spurious positive findings in case control studies.
Recommendations from others
Food and Drug Administration. The FDA assigned guaifenesin to category C—that is, its risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking. Guaifenesin is recommended if the benefit to the pregnant woman warrants the risk to the fetus.6
ACOG. The American College of Obstetricians and Gynecologists (ACOG) makes no recommendation.7 The textbook Drugs in Pregnancy and Lactation reports that guaifenesin use during pregnancy exhibits very low risk to the fetus.6 The National Collaborating Centre for Women’s and Children’s Health suggests that guaifenesin be used sparingly during pregnancy.8
It’s not clear; little evidence supports or refutes the safety of guaifenesin, a common expectorant, in pregnancy. A small number of observational and case-control studies suggest a weak association between guaifenesin use and inguinal hernias and neural tube defects in newborns. However, substantial methodological flaws, the absence of statistical significance, and low rates of prevalence cast a shadow of a doubt over the data (strength of recommendation [SOR]: B, based on observational and case-control studies).
Always take a conservative approach to obstetrics
Christopher P. Paulson, MD, FAAFP
Eglin Family Medicine residency, Eglin Air Force Base, Fla
In my practice as a family physician, a conservative approach to obstetrical care has been the rule. It seems prudent to avoid guaifenesin during the first trimester. Although the evidence is inconclusive on potential harm to the fetus, the marginal benefit gained seems insufficient to justify treatment early in pregnancy when the fetus is most vulnerable to teratogenic effects in general.
As with most other Category C medications (except those with clear clinical benefit and no safer alternative), I typically avoid guaifenesin throughout pregnancy. However, it may be reasonable to prescribe it in the latter half of pregnancy when the potential risk is lower; particularly in light of the lack of any clear evidence demonstrating harmful effects.
Evidence summary
Guaifenesin, available in numerous preparations (eg, Mucinex, Robitussin), is one of the most commonly used over-the-counter medications in pregnancy. The National Birth Defects Prevention Study surveyed 2970 pregnant women from 1997 to 2001; 6.2% reported taking guaifenesin during pregnancy.1 A second survey evaluated 7563 mothers from 1998 to 2004; 9.2% of the mothers reported that they took it during pregnancy.1
A weak link to inguinal hernias
Guaifenesin use in pregnancy has been associated with inguinal hernias in newborns. From 1958 to 1965, the Collaborative Perinatal Project recruited 132,500 women to participate in a multicenter study; however, selection and exclusion criteria were not consistent. From this initial group, only 50,282 mother-child pairs were studied. Trained examiners interviewed the women at the child’s 4, 8, 12, and 24-month visits, and then annually thereafter to 8 years of age.
The examiners identified 7 children with inguinal hernias among 197 mothers who had used guaifenesin during their first trimester (standardized relative risk [RR] of 2.6; no CI or P value reported). Twenty children had inguinal hernias among the 1337 mothers who had used guaifenesin during any trimester of their pregnancy (RR=1.1; no confidence interval [CI] or P value reported).2 The authors acknowledged that reporting bias among the participating centers prevented them from drawing any conclusions from the data.
A possible trend toward neural tube defects?
Guaifenesin use in pregnancy may also be associated with neural tube defects. In a case-control study, researchers identified 538 fetuses and live-born infants with neural tube defects between 1989 and 1991.3 Twelve patients with neural tube defects were exposed to guaifenesin during gestation; 6 in the control group reported exposure.
The authors reported a trend towards increased risk of neural tube defects in offspring of guaifenesin-exposed mothers (odds ratio=2.04; 95% CI, 0.79–5.28).3 However, since the results were not statistically significant, the authors concluded that guaifenesin had not contributed to the occurrence of neural tube defects.
In a study evaluating 6509 women whose pregnancies resulted in live births, 241 women reported first-trimester exposure to guaifenesin.4 Five of the guaifenesin-exposed infants (2.1%) had 1 of the birth defects studied (types of disorders not reported). The calculated RR of birth defect after in utero guaifenesin exposure was 1.3 (no CIs or P values reported); the authors concluded that there was no strong association between guaifenesin and the malformations studied.4
Interpret results with caution
Because of the significant potential for recall bias, interpret the findings of these case-control studies with caution.5 The mother of a child with a birth defect may search her memory more aggressively for potential causes than a mother of a healthy infant, leading to different rates of recalled, rather than actual, exposures. In the absence of confirmatory prospective data, such as medication diaries or pharmacy databases, recall bias accounts for many spurious positive findings in case control studies.
Recommendations from others
Food and Drug Administration. The FDA assigned guaifenesin to category C—that is, its risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking. Guaifenesin is recommended if the benefit to the pregnant woman warrants the risk to the fetus.6
ACOG. The American College of Obstetricians and Gynecologists (ACOG) makes no recommendation.7 The textbook Drugs in Pregnancy and Lactation reports that guaifenesin use during pregnancy exhibits very low risk to the fetus.6 The National Collaborating Centre for Women’s and Children’s Health suggests that guaifenesin be used sparingly during pregnancy.8
1. Werler MM, Mitchel AA, Hernandez-Diaz S, Honein MA. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193:771-777.
2. Heinonen OP, Sione D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, Mass: Publishing Sciences Group, 1977.
3. Shaw GM, Todoroff K, Velie EM, Lammer EJ. Maternal Illness, including fever, and medication use as risk factors for neural tube defects. Teratology 1998;57:1-7.
4. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451-455.
5. Chouinard E, Walter S. Title recall bias in case-control studies: an empirical analysis and theoretical framework. J Clin Epidemiology 1995;48:245-254.
6. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 7th ed. Baltimore, Md: Lippincott Williams & Wilkins;2005.
7. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475-480.
8. National Collaborating Centre for Women’s and Children’s Health. Antenatal Care: Routine Care for the Healthy Pregnant Woman London: RCOG Press; 2003.
1. Werler MM, Mitchel AA, Hernandez-Diaz S, Honein MA. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193:771-777.
2. Heinonen OP, Sione D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, Mass: Publishing Sciences Group, 1977.
3. Shaw GM, Todoroff K, Velie EM, Lammer EJ. Maternal Illness, including fever, and medication use as risk factors for neural tube defects. Teratology 1998;57:1-7.
4. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451-455.
5. Chouinard E, Walter S. Title recall bias in case-control studies: an empirical analysis and theoretical framework. J Clin Epidemiology 1995;48:245-254.
6. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 7th ed. Baltimore, Md: Lippincott Williams & Wilkins;2005.
7. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475-480.
8. National Collaborating Centre for Women’s and Children’s Health. Antenatal Care: Routine Care for the Healthy Pregnant Woman London: RCOG Press; 2003.
Evidence-based answers from the Family Physicians Inquiries Network
What is the best way to manage GERD symptoms in the elderly?
No evidence supports one method over another in managing uncomplicated gastroesophageal reflux disease (GERD) for patients aged >65 years. For those with endoscopically documented esophagitis, proton pump inhibitors (PPIs) relieve symptoms faster than histamine H2 receptor antagonists (H2RAs) (strength of recommendation [SOR]: B, extrapolation from randomized controlled trials [RCTs]). Treating elderly patients with pantoprazole (Protonix) after resolution of acute esophagitis results in fewer relapses than with placebo (SOR: B, double-blind RCT). Limited evidence suggests that such maintenance therapy for prior esophagitis with either H2RAs or PPIs, at half- and full-dose strength,1 decreases the frequency of relapse (SOR: B, extrapolation from uncontrolled clinical trial).
Laparoscopic antireflux surgery for treating symptomatic GERD among elderly patients without paraesophageal hernia reduces esophageal acidity, with no apparent increase in postoperative morbidity or mortality compared with younger patients (SOR: C, nonequivalent before-after study). Upper endoscopy is recommended for elderly patients with alarm symptoms, new-onset GERD, or longstanding disease (SOR: C, expert consensus; see TABLE).
Elderly patients are at risk for more severe complications from GERD, and their relative discomfort from the disease process is often less than from comparable pathology for younger patients (SOR: C, expert consensus). Based on safety profiles and success in the general patient population, PPIs as a class are considered first-line treatment for GERD and esophagitis for the elderly (SOR: C, expert consensus).
Teasing out serious disease from routine GERD is a challenge in the elderly
Peter Danis, MD
St. John’s Mercy Medical Center, St. Louis, Mo
Who really needs the invasive workup and expensive medicine, and who needs the simple approach? Elderly patients can attribute symptoms to “just indigestion” when there are other more serious diseases present (ie, angina, severe esophagitis, stricture, cancer). The physician may need a more detailed and patient approach to get the “real” story. Lifestyle changes and over-the-counter medications will resolve the majority of GERD symptoms. If the simple things don’t work or there are warning signs/symptoms, then a further workup is needed. The older patient may then be willing to pay the cost of the long term PPI when they know that there is significant pathology and the potential for long term symptom relief.
Evidence summary
Aggregated data from 2 randomized reflux esophagitis trials conducted in the United Kingdom were analyzed with respect to patient age. Comparison of symptom relief and esophageal lesion healing showed that elderly patients treated with omeprazole (Prilosec) fared better than those treated with either cimetidine (Tagamet) or ranitidine (Zantac).2 The pooled data involved 555 patients with endoscopically proven reflux esophagitis, 154 of whom were over the age of 65. After 8 weeks, rates of esophageal healing among the elderly were 70% for those receiving omeprazole and 29% for those receiving H2RAs (41% difference; 95% confidence interval [CI], 26–55), while the rate of asymptomatic elderly patients was 79% for the omeprazole group and 51% for the H2RA group (28% difference; 95% CI, 12–44).3 Patients treated with omeprazole healed faster than those taking H2RAs, as shown by endoscopy, and more of them experienced symptom relief.
A multicenter, randomized, double-blind trial of GERD maintenance therapy started with an initial open phase in which elderly patients with GERD and documented esophagitis were treated and then had documented resolution of esophagitis by endoscopy after 6 months. The researchers then randomized 105 of these elderly patients to receive treatment with either low-dose (20 mg/d) pantoprazole or placebo for 6 months. Endoscopy was performed after 12 months for all patients, unless indicated sooner. Intention-to-treat analysis showed a disease-free rate of 79.6% (95% CI, 68.3–90.9) in the treatment group, compared with 30.4% (95% CI, 18.3–42.4) in the placebo group (number needed to treat [NNT]=2). Symptom reports concerning the same patients also suggest a marked drop in symptoms that correlated with healing.4
A prospective, nonequivalence, before-after study compared efficacy of, and complications from, laparoscopic surgery for symptomatic GERD between younger and older (≥65 years) patients. The investigators examined postoperative morbidity and mortality for 359 patients referred for laparoscopic surgery, either a partial or Nissen (full) fundoplication. They excluded those requiring more extensive surgery or repair of paraesophageal hernia. The 42 elderly patients had a higher mean American Society of Anesthesiologists score compared with the younger patients, reflecting higher preoperative comorbidity, but were similar with regard to weight and gender.
Before surgery, investigators performed 24-hour ambulatory pH monitoring. Preoperative exposure times to a pH below 4 (TpH <4) were similar for the younger and older patients (median 14.2% and 13.9%, respectively). Postoperative complication rates were similar for both groups. No deaths occurred. Minor postoperative complications involved 7% of the elderly patients and 6% of the younger group. The 24-hour pH monitoring scores showed improvement at 6 weeks after surgery for both groups, with the median TpH <4 at 1.1% (95% CL, 0.5) in the elderly vs a median of 1.8% (95% CL, 1.9) in the younger patients. At 1 year postoperatively, the values were also similar between the two groups; the median TpH <4 (95% CL) were 1.4% (1.5) in the elderly group and 1.2% (0.6) in the younger patient group.
The results of this study should be interpreted with caution, however. The study design is prone to bias, the patients had relatively low symptom scores at baseline, and sicker patients may have been excluded during the referral process.5
TABLE
Warning signs and symptoms of dyspepsia and GERD that suggest complicated disease or more serious underlying process1
| Dysphagia |
| Unexplained weight loss |
| History of gastrointestinal bleeding |
| Early satiety |
| Iron deficiency anemia |
| Vomiting |
| Odynophagia (sharp substernal pain on swallowing) |
| Initial onset of heartburn-like symptoms after the age of 50 years |
| History of immunocompromised state |
| Anorexia |
Recommendations from others
The Veterans Health Affairs/Department of Defense clinical practice guidelines recommend differentiating GERD (feelings of substernal burning associated with acid regurgitation) from dyspepsia (chronic or recurrent discomfort centered in the upper abdomen), of which GERD is a subset.6 The guidelines recommend gastroenterology consultation or upper endoscopy to rule out neoplastic or pre-neoplastic lesions if alarm symptoms (TABLE) suggesting complicated GERD are present.7
The Institute for Clinical Systems Improvement guidelines on dyspepsia and GERD recommend that all patients aged ≥50 years with symptoms of uncomplicated dyspepsia undergo upper endoscopy non-urgently because of the increased incidence of peptic ulcer disease, pre-neoplastic lesions, malignancy, and increased morbidity out of proportion to symptoms that are more common in an older patient population. The guidelines also recommend endoscopy for patients aged ≥50 years with uncomplicated GERD and the presence of symptoms for greater than 10 years because of the increased risk of pre-neoplastic and neoplastic lesions, including Barrett’s esophagus.8
1. Pilotto A, Franceschi M, Leandro G, et al. Long-term clinical outcome of elderly patients with reflux esophagitis: a six-month to three-year follow-up study. Am J Ther 2002;9:295-300.
2. James OF, Parry-Billings K. Comparison of omeprazole and histamine H2–receptor antagonists in the treatment of elderly and young patients with reflux oesophagitis. Age Aging 1994;23:121-126.
3. Omeprazole was better than H2-antagonists in reflux esophagitis. ACP Journal Club 1994;121:65.-
4. Pilotto A, Leandro G, Franceschi M. Short and long term therapy for reflux oesophagitis in the elderly: a multicentre, placebo-controlled study with pantoprazole. Aliment Pharmacol Ther 2003;17:1399-1406.
5. Trus TL, Laycock WS, Wo JM, et al. Laparoscopic antireflux surgery in the elderly. Am J Gastroenterol 1998;93:351-353.
6. Bazaldua OV, Schneider FD. Evaluation and management of dyspepsia. Am Fam Physician 1999;60:1773-1784.
7. VHA/DoD Clinical Practice Guideline for the Management of Adults with Gastroesophageal Reflux Disease in Primary Care Practice. Washington, DC: Veterans Health Administration, Department of Defense; 2003 March 12. Available at: www.guideline.gov/summary/summary.aspx?ss=15&doc_id=5188&nbr=3570#s25. Accessed on February 9, 2006.
8. Institute for Clinical Systems Improvement (ICSI). Dyspepsia and GERD. Bloomington, Minn: ICSI Guidelines; July 2004. Available at: www.guideline.gov/summary/summary.aspx?doc_id=5624. Accessed on February 9, 2006.
No evidence supports one method over another in managing uncomplicated gastroesophageal reflux disease (GERD) for patients aged >65 years. For those with endoscopically documented esophagitis, proton pump inhibitors (PPIs) relieve symptoms faster than histamine H2 receptor antagonists (H2RAs) (strength of recommendation [SOR]: B, extrapolation from randomized controlled trials [RCTs]). Treating elderly patients with pantoprazole (Protonix) after resolution of acute esophagitis results in fewer relapses than with placebo (SOR: B, double-blind RCT). Limited evidence suggests that such maintenance therapy for prior esophagitis with either H2RAs or PPIs, at half- and full-dose strength,1 decreases the frequency of relapse (SOR: B, extrapolation from uncontrolled clinical trial).
Laparoscopic antireflux surgery for treating symptomatic GERD among elderly patients without paraesophageal hernia reduces esophageal acidity, with no apparent increase in postoperative morbidity or mortality compared with younger patients (SOR: C, nonequivalent before-after study). Upper endoscopy is recommended for elderly patients with alarm symptoms, new-onset GERD, or longstanding disease (SOR: C, expert consensus; see TABLE).
Elderly patients are at risk for more severe complications from GERD, and their relative discomfort from the disease process is often less than from comparable pathology for younger patients (SOR: C, expert consensus). Based on safety profiles and success in the general patient population, PPIs as a class are considered first-line treatment for GERD and esophagitis for the elderly (SOR: C, expert consensus).
Teasing out serious disease from routine GERD is a challenge in the elderly
Peter Danis, MD
St. John’s Mercy Medical Center, St. Louis, Mo
Who really needs the invasive workup and expensive medicine, and who needs the simple approach? Elderly patients can attribute symptoms to “just indigestion” when there are other more serious diseases present (ie, angina, severe esophagitis, stricture, cancer). The physician may need a more detailed and patient approach to get the “real” story. Lifestyle changes and over-the-counter medications will resolve the majority of GERD symptoms. If the simple things don’t work or there are warning signs/symptoms, then a further workup is needed. The older patient may then be willing to pay the cost of the long term PPI when they know that there is significant pathology and the potential for long term symptom relief.
Evidence summary
Aggregated data from 2 randomized reflux esophagitis trials conducted in the United Kingdom were analyzed with respect to patient age. Comparison of symptom relief and esophageal lesion healing showed that elderly patients treated with omeprazole (Prilosec) fared better than those treated with either cimetidine (Tagamet) or ranitidine (Zantac).2 The pooled data involved 555 patients with endoscopically proven reflux esophagitis, 154 of whom were over the age of 65. After 8 weeks, rates of esophageal healing among the elderly were 70% for those receiving omeprazole and 29% for those receiving H2RAs (41% difference; 95% confidence interval [CI], 26–55), while the rate of asymptomatic elderly patients was 79% for the omeprazole group and 51% for the H2RA group (28% difference; 95% CI, 12–44).3 Patients treated with omeprazole healed faster than those taking H2RAs, as shown by endoscopy, and more of them experienced symptom relief.
A multicenter, randomized, double-blind trial of GERD maintenance therapy started with an initial open phase in which elderly patients with GERD and documented esophagitis were treated and then had documented resolution of esophagitis by endoscopy after 6 months. The researchers then randomized 105 of these elderly patients to receive treatment with either low-dose (20 mg/d) pantoprazole or placebo for 6 months. Endoscopy was performed after 12 months for all patients, unless indicated sooner. Intention-to-treat analysis showed a disease-free rate of 79.6% (95% CI, 68.3–90.9) in the treatment group, compared with 30.4% (95% CI, 18.3–42.4) in the placebo group (number needed to treat [NNT]=2). Symptom reports concerning the same patients also suggest a marked drop in symptoms that correlated with healing.4
A prospective, nonequivalence, before-after study compared efficacy of, and complications from, laparoscopic surgery for symptomatic GERD between younger and older (≥65 years) patients. The investigators examined postoperative morbidity and mortality for 359 patients referred for laparoscopic surgery, either a partial or Nissen (full) fundoplication. They excluded those requiring more extensive surgery or repair of paraesophageal hernia. The 42 elderly patients had a higher mean American Society of Anesthesiologists score compared with the younger patients, reflecting higher preoperative comorbidity, but were similar with regard to weight and gender.
Before surgery, investigators performed 24-hour ambulatory pH monitoring. Preoperative exposure times to a pH below 4 (TpH <4) were similar for the younger and older patients (median 14.2% and 13.9%, respectively). Postoperative complication rates were similar for both groups. No deaths occurred. Minor postoperative complications involved 7% of the elderly patients and 6% of the younger group. The 24-hour pH monitoring scores showed improvement at 6 weeks after surgery for both groups, with the median TpH <4 at 1.1% (95% CL, 0.5) in the elderly vs a median of 1.8% (95% CL, 1.9) in the younger patients. At 1 year postoperatively, the values were also similar between the two groups; the median TpH <4 (95% CL) were 1.4% (1.5) in the elderly group and 1.2% (0.6) in the younger patient group.
The results of this study should be interpreted with caution, however. The study design is prone to bias, the patients had relatively low symptom scores at baseline, and sicker patients may have been excluded during the referral process.5
TABLE
Warning signs and symptoms of dyspepsia and GERD that suggest complicated disease or more serious underlying process1
| Dysphagia |
| Unexplained weight loss |
| History of gastrointestinal bleeding |
| Early satiety |
| Iron deficiency anemia |
| Vomiting |
| Odynophagia (sharp substernal pain on swallowing) |
| Initial onset of heartburn-like symptoms after the age of 50 years |
| History of immunocompromised state |
| Anorexia |
Recommendations from others
The Veterans Health Affairs/Department of Defense clinical practice guidelines recommend differentiating GERD (feelings of substernal burning associated with acid regurgitation) from dyspepsia (chronic or recurrent discomfort centered in the upper abdomen), of which GERD is a subset.6 The guidelines recommend gastroenterology consultation or upper endoscopy to rule out neoplastic or pre-neoplastic lesions if alarm symptoms (TABLE) suggesting complicated GERD are present.7
The Institute for Clinical Systems Improvement guidelines on dyspepsia and GERD recommend that all patients aged ≥50 years with symptoms of uncomplicated dyspepsia undergo upper endoscopy non-urgently because of the increased incidence of peptic ulcer disease, pre-neoplastic lesions, malignancy, and increased morbidity out of proportion to symptoms that are more common in an older patient population. The guidelines also recommend endoscopy for patients aged ≥50 years with uncomplicated GERD and the presence of symptoms for greater than 10 years because of the increased risk of pre-neoplastic and neoplastic lesions, including Barrett’s esophagus.8
No evidence supports one method over another in managing uncomplicated gastroesophageal reflux disease (GERD) for patients aged >65 years. For those with endoscopically documented esophagitis, proton pump inhibitors (PPIs) relieve symptoms faster than histamine H2 receptor antagonists (H2RAs) (strength of recommendation [SOR]: B, extrapolation from randomized controlled trials [RCTs]). Treating elderly patients with pantoprazole (Protonix) after resolution of acute esophagitis results in fewer relapses than with placebo (SOR: B, double-blind RCT). Limited evidence suggests that such maintenance therapy for prior esophagitis with either H2RAs or PPIs, at half- and full-dose strength,1 decreases the frequency of relapse (SOR: B, extrapolation from uncontrolled clinical trial).
Laparoscopic antireflux surgery for treating symptomatic GERD among elderly patients without paraesophageal hernia reduces esophageal acidity, with no apparent increase in postoperative morbidity or mortality compared with younger patients (SOR: C, nonequivalent before-after study). Upper endoscopy is recommended for elderly patients with alarm symptoms, new-onset GERD, or longstanding disease (SOR: C, expert consensus; see TABLE).
Elderly patients are at risk for more severe complications from GERD, and their relative discomfort from the disease process is often less than from comparable pathology for younger patients (SOR: C, expert consensus). Based on safety profiles and success in the general patient population, PPIs as a class are considered first-line treatment for GERD and esophagitis for the elderly (SOR: C, expert consensus).
Teasing out serious disease from routine GERD is a challenge in the elderly
Peter Danis, MD
St. John’s Mercy Medical Center, St. Louis, Mo
Who really needs the invasive workup and expensive medicine, and who needs the simple approach? Elderly patients can attribute symptoms to “just indigestion” when there are other more serious diseases present (ie, angina, severe esophagitis, stricture, cancer). The physician may need a more detailed and patient approach to get the “real” story. Lifestyle changes and over-the-counter medications will resolve the majority of GERD symptoms. If the simple things don’t work or there are warning signs/symptoms, then a further workup is needed. The older patient may then be willing to pay the cost of the long term PPI when they know that there is significant pathology and the potential for long term symptom relief.
Evidence summary
Aggregated data from 2 randomized reflux esophagitis trials conducted in the United Kingdom were analyzed with respect to patient age. Comparison of symptom relief and esophageal lesion healing showed that elderly patients treated with omeprazole (Prilosec) fared better than those treated with either cimetidine (Tagamet) or ranitidine (Zantac).2 The pooled data involved 555 patients with endoscopically proven reflux esophagitis, 154 of whom were over the age of 65. After 8 weeks, rates of esophageal healing among the elderly were 70% for those receiving omeprazole and 29% for those receiving H2RAs (41% difference; 95% confidence interval [CI], 26–55), while the rate of asymptomatic elderly patients was 79% for the omeprazole group and 51% for the H2RA group (28% difference; 95% CI, 12–44).3 Patients treated with omeprazole healed faster than those taking H2RAs, as shown by endoscopy, and more of them experienced symptom relief.
A multicenter, randomized, double-blind trial of GERD maintenance therapy started with an initial open phase in which elderly patients with GERD and documented esophagitis were treated and then had documented resolution of esophagitis by endoscopy after 6 months. The researchers then randomized 105 of these elderly patients to receive treatment with either low-dose (20 mg/d) pantoprazole or placebo for 6 months. Endoscopy was performed after 12 months for all patients, unless indicated sooner. Intention-to-treat analysis showed a disease-free rate of 79.6% (95% CI, 68.3–90.9) in the treatment group, compared with 30.4% (95% CI, 18.3–42.4) in the placebo group (number needed to treat [NNT]=2). Symptom reports concerning the same patients also suggest a marked drop in symptoms that correlated with healing.4
A prospective, nonequivalence, before-after study compared efficacy of, and complications from, laparoscopic surgery for symptomatic GERD between younger and older (≥65 years) patients. The investigators examined postoperative morbidity and mortality for 359 patients referred for laparoscopic surgery, either a partial or Nissen (full) fundoplication. They excluded those requiring more extensive surgery or repair of paraesophageal hernia. The 42 elderly patients had a higher mean American Society of Anesthesiologists score compared with the younger patients, reflecting higher preoperative comorbidity, but were similar with regard to weight and gender.
Before surgery, investigators performed 24-hour ambulatory pH monitoring. Preoperative exposure times to a pH below 4 (TpH <4) were similar for the younger and older patients (median 14.2% and 13.9%, respectively). Postoperative complication rates were similar for both groups. No deaths occurred. Minor postoperative complications involved 7% of the elderly patients and 6% of the younger group. The 24-hour pH monitoring scores showed improvement at 6 weeks after surgery for both groups, with the median TpH <4 at 1.1% (95% CL, 0.5) in the elderly vs a median of 1.8% (95% CL, 1.9) in the younger patients. At 1 year postoperatively, the values were also similar between the two groups; the median TpH <4 (95% CL) were 1.4% (1.5) in the elderly group and 1.2% (0.6) in the younger patient group.
The results of this study should be interpreted with caution, however. The study design is prone to bias, the patients had relatively low symptom scores at baseline, and sicker patients may have been excluded during the referral process.5
TABLE
Warning signs and symptoms of dyspepsia and GERD that suggest complicated disease or more serious underlying process1
| Dysphagia |
| Unexplained weight loss |
| History of gastrointestinal bleeding |
| Early satiety |
| Iron deficiency anemia |
| Vomiting |
| Odynophagia (sharp substernal pain on swallowing) |
| Initial onset of heartburn-like symptoms after the age of 50 years |
| History of immunocompromised state |
| Anorexia |
Recommendations from others
The Veterans Health Affairs/Department of Defense clinical practice guidelines recommend differentiating GERD (feelings of substernal burning associated with acid regurgitation) from dyspepsia (chronic or recurrent discomfort centered in the upper abdomen), of which GERD is a subset.6 The guidelines recommend gastroenterology consultation or upper endoscopy to rule out neoplastic or pre-neoplastic lesions if alarm symptoms (TABLE) suggesting complicated GERD are present.7
The Institute for Clinical Systems Improvement guidelines on dyspepsia and GERD recommend that all patients aged ≥50 years with symptoms of uncomplicated dyspepsia undergo upper endoscopy non-urgently because of the increased incidence of peptic ulcer disease, pre-neoplastic lesions, malignancy, and increased morbidity out of proportion to symptoms that are more common in an older patient population. The guidelines also recommend endoscopy for patients aged ≥50 years with uncomplicated GERD and the presence of symptoms for greater than 10 years because of the increased risk of pre-neoplastic and neoplastic lesions, including Barrett’s esophagus.8
1. Pilotto A, Franceschi M, Leandro G, et al. Long-term clinical outcome of elderly patients with reflux esophagitis: a six-month to three-year follow-up study. Am J Ther 2002;9:295-300.
2. James OF, Parry-Billings K. Comparison of omeprazole and histamine H2–receptor antagonists in the treatment of elderly and young patients with reflux oesophagitis. Age Aging 1994;23:121-126.
3. Omeprazole was better than H2-antagonists in reflux esophagitis. ACP Journal Club 1994;121:65.-
4. Pilotto A, Leandro G, Franceschi M. Short and long term therapy for reflux oesophagitis in the elderly: a multicentre, placebo-controlled study with pantoprazole. Aliment Pharmacol Ther 2003;17:1399-1406.
5. Trus TL, Laycock WS, Wo JM, et al. Laparoscopic antireflux surgery in the elderly. Am J Gastroenterol 1998;93:351-353.
6. Bazaldua OV, Schneider FD. Evaluation and management of dyspepsia. Am Fam Physician 1999;60:1773-1784.
7. VHA/DoD Clinical Practice Guideline for the Management of Adults with Gastroesophageal Reflux Disease in Primary Care Practice. Washington, DC: Veterans Health Administration, Department of Defense; 2003 March 12. Available at: www.guideline.gov/summary/summary.aspx?ss=15&doc_id=5188&nbr=3570#s25. Accessed on February 9, 2006.
8. Institute for Clinical Systems Improvement (ICSI). Dyspepsia and GERD. Bloomington, Minn: ICSI Guidelines; July 2004. Available at: www.guideline.gov/summary/summary.aspx?doc_id=5624. Accessed on February 9, 2006.
1. Pilotto A, Franceschi M, Leandro G, et al. Long-term clinical outcome of elderly patients with reflux esophagitis: a six-month to three-year follow-up study. Am J Ther 2002;9:295-300.
2. James OF, Parry-Billings K. Comparison of omeprazole and histamine H2–receptor antagonists in the treatment of elderly and young patients with reflux oesophagitis. Age Aging 1994;23:121-126.
3. Omeprazole was better than H2-antagonists in reflux esophagitis. ACP Journal Club 1994;121:65.-
4. Pilotto A, Leandro G, Franceschi M. Short and long term therapy for reflux oesophagitis in the elderly: a multicentre, placebo-controlled study with pantoprazole. Aliment Pharmacol Ther 2003;17:1399-1406.
5. Trus TL, Laycock WS, Wo JM, et al. Laparoscopic antireflux surgery in the elderly. Am J Gastroenterol 1998;93:351-353.
6. Bazaldua OV, Schneider FD. Evaluation and management of dyspepsia. Am Fam Physician 1999;60:1773-1784.
7. VHA/DoD Clinical Practice Guideline for the Management of Adults with Gastroesophageal Reflux Disease in Primary Care Practice. Washington, DC: Veterans Health Administration, Department of Defense; 2003 March 12. Available at: www.guideline.gov/summary/summary.aspx?ss=15&doc_id=5188&nbr=3570#s25. Accessed on February 9, 2006.
8. Institute for Clinical Systems Improvement (ICSI). Dyspepsia and GERD. Bloomington, Minn: ICSI Guidelines; July 2004. Available at: www.guideline.gov/summary/summary.aspx?doc_id=5624. Accessed on February 9, 2006.
Evidence-based answers from the Family Physicians Inquiries Network
What is appropriate fetal surveillance for women with diet-controlled gestational diabetes?
No evidence clearly supports the practice of increased fetal surveillance in the pregnancies of women with well-controlled (ie, fasting blood sugar <105 mg/dL) class A1 gestational diabetes (strength of recommendation [SOR]: B, consistent retrospective cohort studies). However, a number of guidelines recommend beginning surveillance of some kind between 32 and 40 weeks based on cumulative risk factors, including gestational diabetes (SOR: C, expert opinion).
Follow local standards of care and continue fetal surveillance
Julia Fashner, MD
Piqua, OH
Because malpractice issues weigh heavy in many states, a Family Physician who practices obstetrics may be liable even when a patient is at low risk. We know diabetes has devastating effects on patients. Why would there not be risk with gestational diabetes? The findings in this Clinical Inquiry provide practicing doctors little evidence for or against antenatal testing for women with gestational diabetes. I agree more research is needed to reassure physicians that increased fetal surveillance does not make a difference in fetal or maternal outcomes. Until that time, it would seem prudent to find out what your local standards of care would be—possibly non-stress testing or biophysical profiles during 32 to 40 weeks—and continue your fetal surveillance.
Evidence summary
Gestational diabetes mellitus is diagnosed when at least 2 of 4 values measured in a 3-hour glucose tolerance test are elevated; 2 different definitions of “elevated” are accepted (TABLE 1). White’s classification stratifies the risk of various types of diabetes during pregnancy (TABLE 2): Class A includes patients without a diagnosis of diabetes before pregnancy; classes B, C, and D include patients with pre-existing diabetes of increasing duration; and classes F, H, R, and T include patients with diabetes with various vascular complications.
Infants of mothers with pre-existing diabetes are at increased risk of pre- and neonatal complications (including stillbirth); it has been commonly assumed that type A1 gestational diabetes confers similar risks. However, 2 observational studies call this assumption into question. One study evaluated antepartum predictors of fetal distress requiring a cesarean delivery among 2134 pregnant women with gestational diabetes.4 Antepartum surveillance consisted of biweekly nonstress testing with amniotic fluid index determination starting at 34 weeks gestation. Of the 1501 eligible participants, the study included 810 and 580 class A1 and A2 patients, respectively; the remaining 111 were classes B–T. They considered women with A1 gestational diabetes with fasting plasma glucose levels <105 mg/dL to be well-controlled. Results of antepartum surveillance did not significantly differ among the different diabetic classes.
In univariate and multivariate analyses, the greatest indicator for cesarean section due to fetal distress was a nonreactive non-stress test with decelerations (odds ratio [OR]=5.63; 95% confidence interval [CI], 2.67–11.9). Routine amniotic fluid measurement was not significantly related to either the classification of diabetes or to cesarean delivery for fetal distress. No patients with normal surveillance testing within 4 days of delivery had a stillbirth. However, all 5 stillbirths in the study population occurred among those with A2 diabetes whose last non-stress test was >4 days prior.
An earlier retrospective study followed 97 pregnant patients with gestational diabetes, 69 of whom were diet-controlled (class A1, fasting glucose <105 mg/dL).5 Antepartum surveillance consisted of maternal monitoring and non-stress testing. At 28 weeks, pregnant patients assessed daily fetal activity; reassuring fetal well-being was defined as 10 fetal movements in a 12-hour period. At 40 weeks, a non-stress test was performed weekly. Contraction stress testing was performed for those with nonreactive non-stress tests. To observe for macrosomia, serial ultrasonography was performed every 4 to 6 weeks, starting at 28 weeks. Forty-four patients (64%) had spontaneous labors without intervention, while the rest required induction of labor or cesarean section (primary or failed induction). Five patients had primary cesarean section for suspected macrosomia, 3 patients had intervention for suspected intrauterine growth restriction, and only 4 (5.7%) patients were delivered due to fetal indications, defined as decreased fetal movement or a nonreactive nonstress test. No stillbirths or neonatal deaths occurred. Perinatal complications included hypoglycemia (n=13; 19%), hyperbilirubinemia (n=12; 17%), and macrosomia (n=11; 16%). The study did not compare complication rates between diet-controlled and insulin-requiring patients (SOR: B, retrospective study).
A Cochrane review found no evidence for or against increased surveillance in A1 gestational diabetes: “A lack of conclusive evidence has lead clinicians to equate the risk of adverse perinatal outcome with pre-existing diabetes. Consequently women are often managed with increased obstetrical monitoring, dietary regulation, and [pharmacological] treatment. However, no sound evidence base supports such intensive treatment.”6
TABLE
At least 2 of 4 measurements over 3 hours must be higher than these values to diagnose gestational diabetes mellitus
| STATUS | PLASMA OR SERUM GLUCOSE LEVEL (CARPENTER/COUSTAN CONVERSION AMERICAN DIABETES ASSOCIATION)1 | PLASMA LEVEL DATA (NATIONAL DIABETES GROUP CONVERSION AMERICAN COLLEGE OF OB/GYN)2 | ||
|---|---|---|---|---|
| MG/DL | MMOL/L | MG/DL | MMOL/L | |
| Fasting | 95 | 5.3 | 105 | 5.8 |
| 1 hour | 180 | 10.0 | 190 | 10.6 |
| 2 hours | 155 | 8.6 | 165 | 9.2 |
| 3 hours | 140 | 7.8 | 145 | 8.0 |
TABLE
White’s classification for gestational diabetes mellitus
| CLASS | DEFINITION |
|---|---|
| A1 | Diabetes diagnosed during pregnancy; non-insulin-dependent |
| A2 | Diabetes diagnosed during pregnancy; insulin-dependent |
| B | Diabetes diagnosed after age 20 years or duration less than 10 years; no vascular complications |
| C | Diabetes diagnosed between age 10 to 19 years or duration of 10 to 19 years; no vascular complications |
| D | Diabetes diagnosed before age of 10 years or duration greater than 20 years; vascular complications present |
| F | Diabetes with nephropathy |
| H | Diabetes with coronary artery or other heart disease |
| R | Diabetes with retinopathy |
| T | Diabetes status post–renal transplant |
Recommendations from others
The American College of Obstetricians and Gynecologists’ practice bulletin on gestational diabetes states that there is no consensus regarding fetal surveillance for women with diet-controlled gestational diabetes. However, local practice may include non-stress and contraction stress testing, amniotic fluid determination, and biophysical profile; this may start as early as 32 weeks to or as late as 40 weeks, based upon the total cumulative risk to the fetus from all potential complications.2 The American Diabetes Association states that increased fetal surveillance is appropriate but is not any more specific with this recommendation.1
1. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(suppl 1):S88-S90.
2. American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Gestational diabetes. Obstet Gynecol 2001;98:525-538.
3. White P. Classification of obstetric diabetes. Am J Obstet Gynecol 1978;130:228-230.
4. Kjos SL, Leung A, Henry OA, Victor MR, Paul RH, Medearis AL. Antepartum surveillance in diabetic pregnancies: Predictors of fetal distress in labor. Am J Obstet Gynecol 1995;173:1532-1539.
5. Landon MB, Gabbe SG. Antepartum fetal surveillance in gestational diabetes mellitus. Diabetes 1985;34(Suppl 2):50-54.
6. Tuffnell DJ, West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy. Cochrane Database Syst Rev 2003;(3):CD003395.-
No evidence clearly supports the practice of increased fetal surveillance in the pregnancies of women with well-controlled (ie, fasting blood sugar <105 mg/dL) class A1 gestational diabetes (strength of recommendation [SOR]: B, consistent retrospective cohort studies). However, a number of guidelines recommend beginning surveillance of some kind between 32 and 40 weeks based on cumulative risk factors, including gestational diabetes (SOR: C, expert opinion).
Follow local standards of care and continue fetal surveillance
Julia Fashner, MD
Piqua, OH
Because malpractice issues weigh heavy in many states, a Family Physician who practices obstetrics may be liable even when a patient is at low risk. We know diabetes has devastating effects on patients. Why would there not be risk with gestational diabetes? The findings in this Clinical Inquiry provide practicing doctors little evidence for or against antenatal testing for women with gestational diabetes. I agree more research is needed to reassure physicians that increased fetal surveillance does not make a difference in fetal or maternal outcomes. Until that time, it would seem prudent to find out what your local standards of care would be—possibly non-stress testing or biophysical profiles during 32 to 40 weeks—and continue your fetal surveillance.
Evidence summary
Gestational diabetes mellitus is diagnosed when at least 2 of 4 values measured in a 3-hour glucose tolerance test are elevated; 2 different definitions of “elevated” are accepted (TABLE 1). White’s classification stratifies the risk of various types of diabetes during pregnancy (TABLE 2): Class A includes patients without a diagnosis of diabetes before pregnancy; classes B, C, and D include patients with pre-existing diabetes of increasing duration; and classes F, H, R, and T include patients with diabetes with various vascular complications.
Infants of mothers with pre-existing diabetes are at increased risk of pre- and neonatal complications (including stillbirth); it has been commonly assumed that type A1 gestational diabetes confers similar risks. However, 2 observational studies call this assumption into question. One study evaluated antepartum predictors of fetal distress requiring a cesarean delivery among 2134 pregnant women with gestational diabetes.4 Antepartum surveillance consisted of biweekly nonstress testing with amniotic fluid index determination starting at 34 weeks gestation. Of the 1501 eligible participants, the study included 810 and 580 class A1 and A2 patients, respectively; the remaining 111 were classes B–T. They considered women with A1 gestational diabetes with fasting plasma glucose levels <105 mg/dL to be well-controlled. Results of antepartum surveillance did not significantly differ among the different diabetic classes.
In univariate and multivariate analyses, the greatest indicator for cesarean section due to fetal distress was a nonreactive non-stress test with decelerations (odds ratio [OR]=5.63; 95% confidence interval [CI], 2.67–11.9). Routine amniotic fluid measurement was not significantly related to either the classification of diabetes or to cesarean delivery for fetal distress. No patients with normal surveillance testing within 4 days of delivery had a stillbirth. However, all 5 stillbirths in the study population occurred among those with A2 diabetes whose last non-stress test was >4 days prior.
An earlier retrospective study followed 97 pregnant patients with gestational diabetes, 69 of whom were diet-controlled (class A1, fasting glucose <105 mg/dL).5 Antepartum surveillance consisted of maternal monitoring and non-stress testing. At 28 weeks, pregnant patients assessed daily fetal activity; reassuring fetal well-being was defined as 10 fetal movements in a 12-hour period. At 40 weeks, a non-stress test was performed weekly. Contraction stress testing was performed for those with nonreactive non-stress tests. To observe for macrosomia, serial ultrasonography was performed every 4 to 6 weeks, starting at 28 weeks. Forty-four patients (64%) had spontaneous labors without intervention, while the rest required induction of labor or cesarean section (primary or failed induction). Five patients had primary cesarean section for suspected macrosomia, 3 patients had intervention for suspected intrauterine growth restriction, and only 4 (5.7%) patients were delivered due to fetal indications, defined as decreased fetal movement or a nonreactive nonstress test. No stillbirths or neonatal deaths occurred. Perinatal complications included hypoglycemia (n=13; 19%), hyperbilirubinemia (n=12; 17%), and macrosomia (n=11; 16%). The study did not compare complication rates between diet-controlled and insulin-requiring patients (SOR: B, retrospective study).
A Cochrane review found no evidence for or against increased surveillance in A1 gestational diabetes: “A lack of conclusive evidence has lead clinicians to equate the risk of adverse perinatal outcome with pre-existing diabetes. Consequently women are often managed with increased obstetrical monitoring, dietary regulation, and [pharmacological] treatment. However, no sound evidence base supports such intensive treatment.”6
TABLE
At least 2 of 4 measurements over 3 hours must be higher than these values to diagnose gestational diabetes mellitus
| STATUS | PLASMA OR SERUM GLUCOSE LEVEL (CARPENTER/COUSTAN CONVERSION AMERICAN DIABETES ASSOCIATION)1 | PLASMA LEVEL DATA (NATIONAL DIABETES GROUP CONVERSION AMERICAN COLLEGE OF OB/GYN)2 | ||
|---|---|---|---|---|
| MG/DL | MMOL/L | MG/DL | MMOL/L | |
| Fasting | 95 | 5.3 | 105 | 5.8 |
| 1 hour | 180 | 10.0 | 190 | 10.6 |
| 2 hours | 155 | 8.6 | 165 | 9.2 |
| 3 hours | 140 | 7.8 | 145 | 8.0 |
TABLE
White’s classification for gestational diabetes mellitus
| CLASS | DEFINITION |
|---|---|
| A1 | Diabetes diagnosed during pregnancy; non-insulin-dependent |
| A2 | Diabetes diagnosed during pregnancy; insulin-dependent |
| B | Diabetes diagnosed after age 20 years or duration less than 10 years; no vascular complications |
| C | Diabetes diagnosed between age 10 to 19 years or duration of 10 to 19 years; no vascular complications |
| D | Diabetes diagnosed before age of 10 years or duration greater than 20 years; vascular complications present |
| F | Diabetes with nephropathy |
| H | Diabetes with coronary artery or other heart disease |
| R | Diabetes with retinopathy |
| T | Diabetes status post–renal transplant |
Recommendations from others
The American College of Obstetricians and Gynecologists’ practice bulletin on gestational diabetes states that there is no consensus regarding fetal surveillance for women with diet-controlled gestational diabetes. However, local practice may include non-stress and contraction stress testing, amniotic fluid determination, and biophysical profile; this may start as early as 32 weeks to or as late as 40 weeks, based upon the total cumulative risk to the fetus from all potential complications.2 The American Diabetes Association states that increased fetal surveillance is appropriate but is not any more specific with this recommendation.1
No evidence clearly supports the practice of increased fetal surveillance in the pregnancies of women with well-controlled (ie, fasting blood sugar <105 mg/dL) class A1 gestational diabetes (strength of recommendation [SOR]: B, consistent retrospective cohort studies). However, a number of guidelines recommend beginning surveillance of some kind between 32 and 40 weeks based on cumulative risk factors, including gestational diabetes (SOR: C, expert opinion).
Follow local standards of care and continue fetal surveillance
Julia Fashner, MD
Piqua, OH
Because malpractice issues weigh heavy in many states, a Family Physician who practices obstetrics may be liable even when a patient is at low risk. We know diabetes has devastating effects on patients. Why would there not be risk with gestational diabetes? The findings in this Clinical Inquiry provide practicing doctors little evidence for or against antenatal testing for women with gestational diabetes. I agree more research is needed to reassure physicians that increased fetal surveillance does not make a difference in fetal or maternal outcomes. Until that time, it would seem prudent to find out what your local standards of care would be—possibly non-stress testing or biophysical profiles during 32 to 40 weeks—and continue your fetal surveillance.
Evidence summary
Gestational diabetes mellitus is diagnosed when at least 2 of 4 values measured in a 3-hour glucose tolerance test are elevated; 2 different definitions of “elevated” are accepted (TABLE 1). White’s classification stratifies the risk of various types of diabetes during pregnancy (TABLE 2): Class A includes patients without a diagnosis of diabetes before pregnancy; classes B, C, and D include patients with pre-existing diabetes of increasing duration; and classes F, H, R, and T include patients with diabetes with various vascular complications.
Infants of mothers with pre-existing diabetes are at increased risk of pre- and neonatal complications (including stillbirth); it has been commonly assumed that type A1 gestational diabetes confers similar risks. However, 2 observational studies call this assumption into question. One study evaluated antepartum predictors of fetal distress requiring a cesarean delivery among 2134 pregnant women with gestational diabetes.4 Antepartum surveillance consisted of biweekly nonstress testing with amniotic fluid index determination starting at 34 weeks gestation. Of the 1501 eligible participants, the study included 810 and 580 class A1 and A2 patients, respectively; the remaining 111 were classes B–T. They considered women with A1 gestational diabetes with fasting plasma glucose levels <105 mg/dL to be well-controlled. Results of antepartum surveillance did not significantly differ among the different diabetic classes.
In univariate and multivariate analyses, the greatest indicator for cesarean section due to fetal distress was a nonreactive non-stress test with decelerations (odds ratio [OR]=5.63; 95% confidence interval [CI], 2.67–11.9). Routine amniotic fluid measurement was not significantly related to either the classification of diabetes or to cesarean delivery for fetal distress. No patients with normal surveillance testing within 4 days of delivery had a stillbirth. However, all 5 stillbirths in the study population occurred among those with A2 diabetes whose last non-stress test was >4 days prior.
An earlier retrospective study followed 97 pregnant patients with gestational diabetes, 69 of whom were diet-controlled (class A1, fasting glucose <105 mg/dL).5 Antepartum surveillance consisted of maternal monitoring and non-stress testing. At 28 weeks, pregnant patients assessed daily fetal activity; reassuring fetal well-being was defined as 10 fetal movements in a 12-hour period. At 40 weeks, a non-stress test was performed weekly. Contraction stress testing was performed for those with nonreactive non-stress tests. To observe for macrosomia, serial ultrasonography was performed every 4 to 6 weeks, starting at 28 weeks. Forty-four patients (64%) had spontaneous labors without intervention, while the rest required induction of labor or cesarean section (primary or failed induction). Five patients had primary cesarean section for suspected macrosomia, 3 patients had intervention for suspected intrauterine growth restriction, and only 4 (5.7%) patients were delivered due to fetal indications, defined as decreased fetal movement or a nonreactive nonstress test. No stillbirths or neonatal deaths occurred. Perinatal complications included hypoglycemia (n=13; 19%), hyperbilirubinemia (n=12; 17%), and macrosomia (n=11; 16%). The study did not compare complication rates between diet-controlled and insulin-requiring patients (SOR: B, retrospective study).
A Cochrane review found no evidence for or against increased surveillance in A1 gestational diabetes: “A lack of conclusive evidence has lead clinicians to equate the risk of adverse perinatal outcome with pre-existing diabetes. Consequently women are often managed with increased obstetrical monitoring, dietary regulation, and [pharmacological] treatment. However, no sound evidence base supports such intensive treatment.”6
TABLE
At least 2 of 4 measurements over 3 hours must be higher than these values to diagnose gestational diabetes mellitus
| STATUS | PLASMA OR SERUM GLUCOSE LEVEL (CARPENTER/COUSTAN CONVERSION AMERICAN DIABETES ASSOCIATION)1 | PLASMA LEVEL DATA (NATIONAL DIABETES GROUP CONVERSION AMERICAN COLLEGE OF OB/GYN)2 | ||
|---|---|---|---|---|
| MG/DL | MMOL/L | MG/DL | MMOL/L | |
| Fasting | 95 | 5.3 | 105 | 5.8 |
| 1 hour | 180 | 10.0 | 190 | 10.6 |
| 2 hours | 155 | 8.6 | 165 | 9.2 |
| 3 hours | 140 | 7.8 | 145 | 8.0 |
TABLE
White’s classification for gestational diabetes mellitus
| CLASS | DEFINITION |
|---|---|
| A1 | Diabetes diagnosed during pregnancy; non-insulin-dependent |
| A2 | Diabetes diagnosed during pregnancy; insulin-dependent |
| B | Diabetes diagnosed after age 20 years or duration less than 10 years; no vascular complications |
| C | Diabetes diagnosed between age 10 to 19 years or duration of 10 to 19 years; no vascular complications |
| D | Diabetes diagnosed before age of 10 years or duration greater than 20 years; vascular complications present |
| F | Diabetes with nephropathy |
| H | Diabetes with coronary artery or other heart disease |
| R | Diabetes with retinopathy |
| T | Diabetes status post–renal transplant |
Recommendations from others
The American College of Obstetricians and Gynecologists’ practice bulletin on gestational diabetes states that there is no consensus regarding fetal surveillance for women with diet-controlled gestational diabetes. However, local practice may include non-stress and contraction stress testing, amniotic fluid determination, and biophysical profile; this may start as early as 32 weeks to or as late as 40 weeks, based upon the total cumulative risk to the fetus from all potential complications.2 The American Diabetes Association states that increased fetal surveillance is appropriate but is not any more specific with this recommendation.1
1. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(suppl 1):S88-S90.
2. American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Gestational diabetes. Obstet Gynecol 2001;98:525-538.
3. White P. Classification of obstetric diabetes. Am J Obstet Gynecol 1978;130:228-230.
4. Kjos SL, Leung A, Henry OA, Victor MR, Paul RH, Medearis AL. Antepartum surveillance in diabetic pregnancies: Predictors of fetal distress in labor. Am J Obstet Gynecol 1995;173:1532-1539.
5. Landon MB, Gabbe SG. Antepartum fetal surveillance in gestational diabetes mellitus. Diabetes 1985;34(Suppl 2):50-54.
6. Tuffnell DJ, West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy. Cochrane Database Syst Rev 2003;(3):CD003395.-
1. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(suppl 1):S88-S90.
2. American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Gestational diabetes. Obstet Gynecol 2001;98:525-538.
3. White P. Classification of obstetric diabetes. Am J Obstet Gynecol 1978;130:228-230.
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Evidence-based answers from the Family Physicians Inquiries Network