Care of Pregnant Patients

Learning Objectives

Summarize the suggested prenatal screening tests for infectious diseases.
Describe the serum screening tests for Down syndrome and the potential advantages of first- versus second-trimester screening.
Cite the differences between integrated and sequential approaches to prenatal screening.
Summarize the indications and patient-oriented outcomes for prenatal ultrasound.
Discuss the safety concerns associated with exposure to ionizing radiation during pregnancy and the tests with the lowest exposure risks.
Describe the American Diabetes Association screening protocol for gestational diabetes.
Summarize the benefits of optimal glucose level management for women with gestational diabetes.
Cite the roles of insulin and oral drugs in gestational diabetes management.
Analyze the use of fetal fibronectin for assessing and managing preterm labor.
Summarize the strategies for preterm labor prevention in high-risk pregnant women.
Cite the most important intervention for women in preterm labor.
Describe the options and use duration for tocolytic therapy in preterm labor.

Key Practice Recommendations

Ultrasound is the recommended test for determining gestational age in women with uncertain menstrual dates.
Glycemic control using medical nutrition therapy, planned physical activity, and pharmacologic interventions such as insulin in patients with gestational diabetes reduces the rates of adverse perinatal outcomes, including shoulder dystocia and large-for-gestational-age infants.
Women with a history of gestational diabetes have an increased risk of developing type 2 diabetes and should be screened using fasting plasma glucose or 75-g 2-hour oral glucose tolerance test at 6 to 12 weeks’ postpartum. Screening for type 2 diabetes should be repeated every 3 years thereafter.
Tocolytics delay labor 2 to 7 days and allow time for corticosteroid administration. Calcium channel blockers and nonsteroidal anti-inflammatory drugs are the most well tolerated tocolytic agents.

Resources

Strength of evidence: SORT A
Source: Whitworth M, Bricker L, Neilson JP, et al. Ultrasound for fetal assessment in early pregnancy. Cochrane Database Syst Rev. 2010;(4):CD007058; DiGuiseppi C. Screening ultrasonography in pregnancy. In: Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. 2nd ed. Washington, DC: Dept. of Health and Human Services; 1996:407-418. Cochrane & US Preventive Services Task Force

Web Sites: http://www2.cochrane.org/reviews/en/ab007058.html; http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hscps2ed1996&part=A14038
Strength of evidence: SORT A
Source: Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ. 2010;340:c1395; Crowther CA, Hiller JE, Moss JR, et al; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-2486.
Strength of evidence: SORT C
Source: Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 2):S251-S260; Committee on Obstetric Practice. ACOG Committee Opinion No. 435. Postpartum screening for abnormal glucose tolerance in women who had gestational diabetes mellitus. Obstet Gynecol. 2009;113(6):1419-1421; American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33(Suppl1):S11-S61. Cochrane, American Diabetes Association, American College of Obstetricians and Gynecologists

Web Site: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/525/CN-00666525/frame.html
Strength of evidence: SORT A
Source: ACOG Committee on Practice Bulletins. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologist. No. 43. Management of preterm labor. Obstet Gynecol. 2003;101(5 Pt 1):1039-1047; Haas DM, Imperiale TF, Kirkpatrick PR, et al. Tocolytic therapy. A meta-analysis and decision analysis. Obstet Gynecol. 2009;113(3):585-594. Cochrane & American College of Obstetricians and Gynecologists

Web Sites: http://www2.cochrane.org/reviews/en/ab004352.html; http://www2.cochrane.org/reviews/en/ab002255.html

AAFP FP Essentials™ Approved as CME Clinical Content

This activity, FP Essentials™, has been reviewed and is acceptable for up to 60 Prescribed credit(s) by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2010. This activity conforms to the AAFP criteria for evidence-based CME clinical content. Term of approval is for two year(s) from this date with the option of yearly renewal. Each monograph is approved for 5 Prescribed credit(s). Credit may be claimed for 2 years from the date of each monograph.

The evidence-based CME for this activity was based on a current clinical question that identifies gaps in learners’ knowledge, competency and/or performance in medical practice as identified in the current evidence available at the time this activity was approved. Since clinical research is ongoing and new evidence to supporting practice improvement is constant, the AAFP recommends that learners verify sources and review these as well as practice recommendations prior to implementation into practice.

Author Information

S. Lindsey Clarke, MD, is a Medical University of South Carolina (MUSC) Area Health Education Consortium (AHEC) associate professor at the Self Regional Healthcare Family Medicine Residency Program in Greenwood, South Carolina, where he serves as director of medical student education and assistant director of the obstetrics and gynecology curriculum. Dr Clarke completed residency training in family medicine and has clinical experience in obstetrics, adult and pediatric inpatient medicine, and rural practice. He is an advisory faculty member for Advanced Life Support in Obstetrics (ALSO), an editorial board member for the American Academy of Family Physicians’ FP Essentials™, and an associate medical editor for FP Audio™.

Daphne J. Karel, MD, is an MUSC AHEC associate professor and the director of obstetrics and gynecology for the Self Regional Healthcare Family Medicine Residency Program in Greenwood, South Carolina. Dr Karel completed a family medicine residency and served in the US Air Force Medical Corps for 3 years before returning to teaching. She is an advisory faculty member for ALSO.

Martin G. Johns, MD, teaches and practices at the University of Pittsburgh Medical Center McKeesport-Family Medicine Residency Program. He completed a family medicine residency and an executive faculty development program.

Alfred C. Gitu, MD, teaches and practices inpatient medicine at the Self Regional Healthcare Family Medicine Residency Program in Greenwood, South Carolina. He completed a family medicine residency and an executive faculty development program.

Disclosure: According to AAFP policy, authors must disclose all associations with proprietary entities that may have a direct relationship to the subject matter of their manuscript. The authors and staff have returned disclosure forms indicating that they have no such affiliation or financial interest to disclose. The AAFP uses an anonymous peer review process to evaluate the content of this activity. This process ensures a clear resolution of any potential conflicts of interest, and guarantees the fairness and balance of the content.

Foreword

I could tell you that providing prenatal care and performing deliveries will change your practice—it does, by increasing the number of women and children you see. I could also tell you that it will raise your liability insurance rates—it does that, too. But what is truest for me is that my most vivid memories and valuable learning experiences are found in the care of women having babies.

I remember one woman sprawled across the couch in her family room the day after giving birth, infant on one side and a tray of fudge on the other; the incredulous eyes of a new father taking in the sight of his newborn’s smashed nose and pointy head, gasping, “she wasn’t supposed to look like me!” I also recall the sinking feeling of watching the chin folds of an 11-lb infant try to deliver over the perineum—an infant who was delivered vaginally and cemented my procedural skills for shoulder dystocia. Aside from laughter and occasional terror, most of these images and stories are meaningful because of the context of my relationships with the women and their families, relationships solidified during prenatal visits.

This edition of FP Essentials™ helped me sort through the newest routine prenatal screening recommendations, which seem to change every year. I found the section on imaging particularly useful because it provides information to share with patients about the risks of radiation and the diagnostic choices for conditions arising during pregnancy. It was also reassuring to read the body of evidence supporting treatment and use of metformin for gestational diabetes. Finally, the summary of interventions for prevention and treatment of preterm labor make me hopeful that a decrease in rates of preterm delivery may be on the horizon. I hope this FP Essentials™ provides the information to assist you and your patients during prenatal care and delivery, and on the miraculous journey for families that begins with birth.

Mindy A. Smith, MD, MS, Associate Medical Editor
Professor, Department of Family Medicine
Michigan State University College of Human Medicine, East Lansing

Preface

Family physicians who deliver babies often name prenatal care as one of the most rewarding and fulfilling aspects of their medical practices. At the same time, prenatal care can be challenging. Physicians must consider 2 patients at once, complications can arise suddenly and unexpectedly, and medicolegal stakes are high; yet evidence-based practice recommendations can be difficult to find.

Even physicians who do not routinely provide prenatal care need a working knowledge of pregnancy-related health to diagnose and treat nonobstetric medical conditions that arise during pregnancy. For example, what radiologic tests are safe during pregnancy? Are there any special screening recommendations for women with a history of gestational diabetes, and what can be done to prevent the development of type 2 diabetes in these women?

This edition of FP Essentials™ discusses recent advances in 4 clinical areas related to the care of pregnant women: new developments in prenatal diagnosis, new approaches to imaging during pregnancy, gestational diabetes, and preterm labor.

SECTION ONE

Prenatal Diagnosis Developments

Case 1. Alice is a 41-year-old woman who is gravida 3, para 2. She presents to your office at 9 weeks’ gestation for her first prenatal visit and routine laboratory testing. Because of her age, she is concerned about her risk of carrying a child with Down syndrome. She asks about “the new early test for Down syndrome.”

Routine Tests in Prenatal Care

Women undergo a standard battery of diagnostic tests as part of routine prenatal care. Often, these tests are repeated regardless of test results from previous pregnancies or preconception. Routine prenatal tests are listed in Table 1 along with indications and subsequent need to repeat them. Additional tests are obtained for pregnant women at higher risk of specific conditions (Table 2). Important aspects of some of these tests are discussed below.

Table 1

Routine Tests in Pregnancy

Test	Indication	When Obtained	Additional Notes
Blood type and Rh status	Prevention of alloimmunization and hemolytic disease in the newborn	First visit	If known from prior pregnancies, does not need to be repeated Rh-negative women require Rh_o(D) immune globulin at 28 weeks’ gestation and within 24 hours after birth if infant is Rh positive
Antibody screen	Prevention of fetal hydrops	First visit, can repeat in third trimester	Should be performed with each pregnancy, even in Rh-positive women, because other antibodies can develop
Hemoglobin	Anemia	First visit, as-needed based on first result	Low MCV might indicate thalassemia Consider hemoglobin electrophoresis testing for thalassemia
HIV	Prevention of neonatal transmission	First visit, repeat at 36 weeks’ gestation for women at highest risk of infection or in areas of high prevalence	Western blot and ELISA combined test
RPR or VDRL	Prevention of congenital syphilis	First visit	False-positive can occur with pregnancy, infections, or autoimmune disease Women with a positive RPR result should undergo specific treponemal testing (eg, FTA-ABS)
Rubella and varicella	Prevention of congenital rubella or varicella in future pregnancies	First visit	Nonimmune women should be vaccinated after delivery (measles or MMR) and counseled to avoid exposure during pregnancy
Hepatitis B surface antigen	Prevention of neonatal hepatitis B	First visit	Treatment of newborn with hepatitis B immune globulin can prevent peripartum hepatitis B virus transmission
Urine culture	Detection of asymptomatic bacteriuria	12 to 16 weeks’ gestation; if positive, should be repeated after treatment	Pregnant women at increased risk of UTI and pyelonephritis Those with persistent bacteriuria or an episode of pyelonephritis in current pregnancy should receive antibiotic prophylaxis throughout pregnancy
Gonorrhea and chlamydia	Reduction of preterm labor rate (chlamydia) and prevention of neonatal transmission (both)	First visit, repeat at 36 weeks’ gestation for women at high risk of reinfection or in areas of high prevalence	Urine or cervical NAAT has greater sensitivity than cultures

ELISA = enzyme-linked immunosorbent assay; FTA-ABS = fluorescent treponemal antibody absorption; MCV = mean corpuscular volume; MMR = measles-mumps-rubella; NAAT = nucleic acid amplification testing; RPR = rapid plasma reagin; UTI = urinary tract infection; VDRL = Venereal Disease Research Laboratory.

Information from Sheffield JS, Wendel GD Jr. Syphilis in pregnancy. Clin Obstet Gynecol. 1999;42(1):97-106 [Review]; Smaill F, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev. 2007;(2):CD000490.

Table 2

Additional Prenatal Tests for Certain Populations

Test	Population	Notes
Tuberculosis (purified protein derivative)	Women with HIV Women from areas at high risk of endemic tuberculosis
Toxoplasmosis antibody titer	Women with HIV Women in areas of high prevalence
Hemoglobinopathies (hemoglobin electrophoresis)	Women from ethnic populations at higher risk of disease, such as those of African, Southeast Asian, Caribbean, and Mediterranean descent	Solubility tests (Sickledex) only detect hemoglobin S, will miss other abnormalities Increased ethnic diversity has made testing based on race alone unreliable
Tay-Sachs disease genetic testing	Ashkenazi Jewish, Pennsylvania Dutch, Louisiana Cajun descent
Cystic fibrosis genetic testing	Caucasian, European, Ashkenazi Jewish descent	Testing based on race alone is unreliable Consider offering information about testing to all patients Testing is expensive, might not be covered by health insurance

Human Immunodeficiency Virus

The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend universal screening for HIV in pregnancy with an opt-out approach to screening.1 Repeat screening at 36 weeks’ gestation is recommended in high-risk populations or in regions with increased HIV prevalence. In many US states, HIV screening requires a separate consent form and is considered an opt-in only test.

Women who test positive for HIV should undergo further testing for CD4 count, HIV viral load polymerase chain reaction, and antiretroviral drug resistance. HIV transmission can be reduced when women begin highly active antiretroviral therapy during pregnancy.2 Consultation with an infectious disease subspecialist along with an obstetrics or maternal-fetal medicine subspecialist is encouraged. Women with undetectable viral loads at 36 weeks’ gestation may deliver vaginally with appropriate peripartum treatment with zidovudine.3

Papanicolaou Test

A Papanicolaou (Pap) test is often routinely performed in the first trimester. However, there is no particular indication for screening in pregnancy or for changing screening frequency. Colposcopy should be performed during pregnancy when indicated by Pap test results. Biopsy of high-grade lesions by an experienced colposcopist is recommended by the American Society for Colposcopy and Cervical Pathology.4 Endocervical curettage should not be performed during pregnancy.

Gonorrhea and Chlamydia

Screening for gonorrhea and chlamydia is performed on all pregnant women and repeated at 36 weeks’ gestation for women at high risk of infection, including women who test positive initially. The highest sensitivity and specificity for gonorrhea and chlamydia are obtained with nucleic acid amplification testing (NAAT). The sensitivity of NAAT for chlamydia in endocervical swab testing in 1 study was 85.5% versus 74.7% for culture.5 Urine testing for gonorrhea and chlamydia by NAAT has been shown to be nearly as sensitive as endocervical swab testing.5

Urine Glucose and Protein

Urine dipstick testing for glucose and protein traditionally was performed at every prenatal visit to screen for gestational diabetes and preeclampsia. However, several studies have challenged the utility of routine screening for glycosuria.6,7 The screening protocol for gestational diabetes is discussed in Section Three.

Urine dipstick testing for urinary protein at each prenatal visit is also of limited value. Pregnant women whose blood pressure is elevated should undergo urine dipstick testing for protein followed by 24-hour urine protein testing if indicated. One study showed that focused (ie, testing based on specific signs and symptoms, such as elevated blood pressure level) versus routine dipstick testing for protein resulted in no difference in detection rates of preeclampsia and no change in patient management.7

Screening for Birth Defects

Down syndrome is the most common chromosomal abnormality encountered in live birth and the most common etiology of congenital intellectual disability, affecting 1 of every 629 live births in the United States.8 The prevalence of Down syndrome is affected primarily by maternal age. Screening and invasive diagnostic testing for chromosomal abnormalities, such as Down syndrome, have been a major part of prenatal care for several decades.

Second-Trimester Genetic Screening

Serum testing for Down syndrome was introduced in the 1980s when a correlation was recognized between Down syndrome and decreased maternal serum alpha-fetoprotein level. Additional serum markers for Down syndrome were identified when associations with increased intact beta-human chorionic gonadotropin (beta-hCG) levels and decreased unconjugated estriol levels were found. These 3 tests are now combined to form the triple screening test.

To accurately use the triple screen for determining Down syndrome risk, these values are combined with maternal age-related risk and weighted to the pregnancy gestational age. The sensitivity for this screening test is 70% for Down syndrome, and 5% of all pregnant women tested will have a positive result (true positives and false positives).9 The triple screen also is used to detect trisomy 18 (all 3 values are reduced). The quadruple screen adds testing for inhibin A, which is elevated in Down syndrome pregnancies. Adding this test increases sensitivity for Down syndrome to 81% at a 5% false-positive rate.

First-Trimester Screening for Down Syndrome

In the past decade, new genetic screening tests have been developed and approved for detection of Down syndrome in the first trimester.10 First-trimester ultrasound screening for nuchal translucency (NT) was the first to be standardized for aneuploidy screening. Increased NT (a fluid collection seen at the back of the neck) is a predictor of Down syndrome and several other structural anomalies, including congenital cardiac defects, diaphragmatic hernias, and abdominal wall defects.11 NT measurement is 77% sensitive for the detection of Down syndrome at a 5% false-positive rate.12 NT measurements are valid between 10 4/7 and 13 6/7 weeks’ gestation, but optimal measurement is obtained at 12 to 13 weeks’ gestation.10

Guidelines for NT screening have been standardized, and special training is required to perform the procedure; frequent audits of examination quality are recommended.13 Because of this, NT screening is not available in all areas. Also, NT measurements cannot always be made in the first trimester, depending on the position of the fetus.

When NT is expressed as multiples of the median (MoM), it can be combined with 2 first-trimester serum markers, free maternal serum beta-hCG and maternal serum pregnancy-associated plasma protein A (PAPPA).14 Average free beta-hCG levels in Down syndrome pregnancies are increased to 1.98 MoM, and PAPPA levels are reduced to 0.43 MoM. By combining these 3 tests, weighted by maternal age, sensitivity increases to 82% to 87% with a 5% screen positive rate. Free beta-hCG testing is not available in many areas. Intact or total beta-hCG can be substituted, but free beta-hCG is preferred.15

First-trimester screening for Down syndrome using NT and serum-specific markers is an effective screening test when compared with second-trimester serum testing and offers several advantages over traditional second-trimester screening. Women can obtain information sooner regarding their risk of carrying a Down syndrome infant and can request confirmatory diagnostic testing, such as first-trimester chorionic villous sampling (CVS) or second-trimester amniocentesis. Genetic counseling and referral to a geneticist can begin before the second trimester.

First-trimester screening is limited primarily to screening for Down syndrome because there are no known first-trimester serum markers for other conditions. It is recommended that women with normal first trimester screening results undergo second-trimester screening for neural tube defects.10 Those who have abnormal NT levels but negative serum test results for Down syndrome should be considered for level II ultrasound, fetal echocardiography, or both because of increased risk of other congenital conditions.10

Combined First- and Second-Trimester Screening

Combined first- and second-trimester screening can increase sensitivity for Down syndrome, and several strategies have been developed to combine first-trimester and traditional second-trimester quadruple screening. When NT testing is unavailable, serum-only combined screening strategies have been developed, as discussed below. Combined first- and second-trimester screening, with and without NT, can be performed in an integrated or sequential approach.

Integrated Approach.

With integrated testing, first-trimester screening tests (ie, NT, free beta-hCG, and PAPPA) are combined with second-trimester screening tests and maternal age to determine a single risk value for Down syndrome. With this method, the pregnant woman receives the final results in the second trimester, after all test results are obtained. This approach yields 94% to 96% sensitivity at a 5% false-positive rate. Serum-only screening (again waiting until second trimester for results) also can be integrated. Serum-only integrated screening has 85% to 88% sensitivity.

Integrated screening provides the highest sensitivity and the lowest false-positive rate; however, there are potential disadvantages. Women must wait several weeks after initial screening for results. Also, if a woman missed the second portion of the test, she would receive no results. Integrated screening also removes the possibility of earlier diagnostic testing, such as CVS, and eliminates the possibility for first-trimester diagnosis of genetic abnormalities and early termination.

Sequential Approach.

Sequential screening is another method of combining test results from first- and second-trimester screens. In sequential screening, women are given the first-trimester test results, and if the results indicate a high risk of Down syndrome, they may opt for first-trimester invasive testing. If the test results indicate low risk, women can pursue second-trimester screening if desired, and the first- and second-trimester test results are combined to calculate a final risk result. Women whose final test results indicate high risk may then pursue amniocentesis if desired.

Combined screening should not be performed on an independent basis where first-trimester results and second-trimester results are reported as individual scores. Performing first- and second-trimester tests independently and then combining the results increases sensitivity to 98%, but the false-positive rate is additive and increases to an unacceptably high 11% to 17%,9 which would result in many unnecessary invasive procedures.

Several studies have examined the cost-effectiveness of the screening strategies discussed previously.16-18 Each study used different computer models and weighed costs, risks, and benefits differently. Compared with no screening or invasive testing solely for maternal age greater than 35 years, integrated serum screening, integrated screening with NT, first-trimester NT and serum screening only, quadruple screen only, and sequential screening have all been shown to be cost-effective. Which screening strategy is the most cost-effective is unresolved.

Cytogenetic Testing

When test results suggest a high risk of aneuploidy, a cytogenetic sampling of fetal cells through invasive genetic testing is recommended via amniocentesis (second trimester) or CVS (first trimester). Amniocentesis typically is obtained between 15 and 20 weeks’ gestation. Cells isolated from amniotic fluid are grown in a culture medium and DNA results are obtained in approximately 7 days.

Chorionic villous sampling typically is performed at or after 10 weeks’ gestation through the end of the first trimester. There are 2 primary advantages of using CVS over amniocentesis: the test results are available earlier in pregnancy and, because a larger amount of DNA is removed during sampling, results can be obtained within hours to several days. The risk of fetal loss is higher with CVS compared with amniocentesis (1% versus 0.5%) but may be similar when performed at centers with experienced clinicians.19,20 CVS may not be available in some rural settings.

Pretest Counseling and Decision Aids

The American College of Obstetricians and Gynecologists recommends offering screening and invasive testing for aneuploidy to women of all ages.20 Determining the best course of action requires an individualized approach that ultimately places the final decision in the hands of the pregnant woman. Providing pretest counseling about the risks and benefits of invasive testing versus screening, screening sensitivity and false-positive rates, and the limitations of screening for other genetic abnormalities allows pregnant women to make informed decisions. Several decision aids (eg, pamphlets, booklets, computer-based systems) have been developed to assist.21-24 One recent study showed that an interactive, computer-based education system was more effective than booklets in improving knowledge and risk awareness and in reducing decisional conflict for women undergoing prenatal screening and testing.25

Selection of a testing strategy requires informed decision making. There is no one right way to help pregnant women acquire the knowledge they need to match testing options with their preferences and values. Given the time limitations of office visits, physicians should consider using 1 or more of the many available decision aids.

Case 1, cont’d. After a discussion of the risks and benefits of screening or invasive testing and reviewing a written decision aid on prenatal testing, Alice decides to undergo first-trimester screening for Down syndrome with nuchal translucency measurement and serum screening.

SECTION TWO

New Approaches to Imaging During Pregnancy

Case 2. Ellen, a 34-year-old woman, presents to your office at 30 weeks’ gestation for an unscheduled visit with acute onset of severe left-flank pain. The pain is colicky and radiates to the groin. Vital signs are stable with mild tachycardia, and fetal heart tones are normal. Urinalysis reveals microscopic hematuria without evidence of infection.

Prenatal Ultrasonography

Indications

Prenatal ultrasonography has multiple indications, as a screening tool and as an evaluation for specific obstetric and medical conditions. Indications for prenatal ultrasonography include detection and evaluation of anatomical abnormalities, fetal growth restriction, gestational dating, and assessment for multiple gestations.26 Screening ultrasonography typically is performed in the second or third trimester. Structural anomalies of the central nervous system, heart, kidneys, and gastrointestinal tract can be detected using either transabdominal or transvaginal scanning. Eighty percent of central nervous system anomalies can be detected by 13 weeks’ gestation.27

Ultrasound examination is the recommended test for determining gestational age in women with uncertain menstrual dates. Ninety percent of women deliver within 2 weeks of the due date assigned by early second-trimester ultrasound examination, compared with 75% of women whose due date is estimated by menstrual history.28 Improved gestational dating might result in fewer labor inductions for postmaturity.29 Clinical trials show that a single midtrimester ultrasound examination detects multiple gestations and congenital malformations earlier in pregnancy than when screening is not used, but there is no evidence that early detection results in improved outcomes.28

A third-trimester scan can be used to screen for fetal growth restriction and malpresentation, as well as previously undetected multiple gestations and malformations. However, this is not routinely recommended in asymptomatic, low-risk pregnant women.

Risks

Although ultrasound exposure is considered safer than ionizing radiation in pregnancy, it might not be entirely without risk to the fetus, especially if repeated frequently. Several early studies raised concerns about small but measurable risks for adverse effects on birth weight,30 growth, language development,31 and school performance; however, these results have not been reproduced in more recent studies.29,32

As with many screening tests in low-risk populations, the greatest danger of routine prenatal ultrasonography is a false-positive finding leading to more invasive and risky procedures, such as amniocentesis. Markers of uncertain clinical significance, such as echogenic intracardiac foci and choroid plexus cysts, also are reported frequently at midtrimester ultrasound examination. These soft markers can be a source of considerable anxiety for pregnant women, their partners, and prenatal care clinicians, despite recent studies noting the lack of association between these markers and any clinically significant conditions.33 Therefore, in clinical practice, ultrasound examination is recommended only when the benefit outweighs the potential risk and after the limitations of ultrasonography have been discussed with the patient.

Advanced Imaging Modalities

Three-Dimensional Ultrasonography

As with computed tomography (CT) scan and magnetic resonance imaging (MRI) study, 3-dimensional (3-D) ultrasound examination involves the acquisition of a series of volumes that can be displayed and reconstructed in any plane after examination completion. Four-dimensional (4-D), or real-time 3-D, ultrasonography displays fetal movements in addition to 3-D images.

Benefits.

Postulated benefits of 3-D and 4-D ultrasound examination include:

Reformatting: 3-D ultrasonography produces images that can be reformatted in multiple planes; in 2-dimensional (2-D) ultrasonography, images are limited to those obtained by the sonographer.
Faster image acquisition: In 1 study, it took one-third the time to acquire the 3-D volumes and for a physician to interpret them compared with the entire examination time for 2-D ultrasonography. All fetuses with congenital anomalies requiring further evaluation were correctly identified. Total table time for patients was 2 minutes, compared with 19 minutes for 2-D ultrasonography.34
Reduced operator dependence: 3-D ultrasound image acquisition is much less operator-dependent than 2-D ultrasonography.

It should be noted that these benefits do not necessarily correlate with improved outcomes in low-risk women. Most health insurance companies will not pay for these tests without a specific indication.

Clinical Applications.

Clinical applications of 3-D and 4-D ultrasonography include:

Anatomical survey: This is especially true for patients at high risk of anatomical anomalies, such as those with abnormal serum aneuploidy screening results, or for further characterization of abnormalities noted on 2-D scans.
Remote interpretation: Images can be sent to an offsite radiology subspecialist after acquisition by a sonographer with minimal training (unlike training needed for 2-D ultrasound). This is especially useful for physicians practicing in remote areas, or in the indigent or international humanitarian setting.

Umbilical Artery Doppler Velocimetry

In pregnancies with suspected fetal growth restriction based on fetal biometry, subsequent fetal surveillance using umbilical artery Doppler velocimetry helps predict adverse outcomes, such as premature birth, low birth weight, and need for cesarean delivery and admission of the newborn to a neonatal intensive care unit.35 Doppler examination of the uterine artery is comparable to examination of the umbilical arteries. Inclusion of uterine artery Doppler examination in the surveillance of growth-restricted fetuses might detect a group of pregnancies at high risk despite normal umbilical artery Doppler test results.36

Doppler velocimetry of the uterine and/or umbilical arteries during the second trimester has been shown to be a reliable screening tool in women with risk factors for preeclampsia and intrauterine growth restriction.37 Such risk factors include gestational diabetes, hypertensive conditions during pregnancy, and history of severe intrauterine growth restriction or preeclampsia. Although screening may be used to identify women who require closer surveillance, there currently is no evidence that this leads to improved outcomes. A Cochrane review of routine fetal and umbilical Doppler ultrasound examination in 5 controlled trials, including 14,338 low-risk/unselected pregnant women, showed no differences in short-term clinical outcomes, including cesarean delivery, birth weight, and perinatal morbidity and mortality; the procedure also did not lead to increased interventions.38

Diagnostic Imaging for Nonobstetric Conditions in Pregnant Women

Unlike x-ray and CT scan, MRI study and ultrasonography do not involve ionizing radiation and are safer for the fetus. However, situations arise in which CT scan and intravenous contrast media become necessary. The risk to the fetus from ionizing radiation in diagnostic studies historically has been exaggerated, and recent guidelines from the American College of Obstetricians and Gynecologists39 and American College of Radiology40 have sought to clarify this issue.

Safety of Ionizing Radiation

Ionizing radiation is potentially teratogenic; the fetus is most susceptible to this effect between 2 and 20 weeks’ gestation. However, the estimated radiation to the fetus from various imaging modalities often falls below the threshold for teratogenicity. For example, a CT scan of the pelvis exposes the fetus to approximately 1 to 4.5 rad. This single test is below the 5- to 10-rad dose associated with potential but unproven fetal effects and well below the greater than 10-rad dose associated with spontaneous fetal loss at 15 to 28 days’ gestation, possible fetal malformations at 5 to 10 weeks’ gestation, and IQ deficits at 11 to 17 weeks’ gestation.40 However, multiple tests potentially exceed the safe limit.

Radiation exposures from common diagnostic radiologic procedures can be found on the Health Physics Society Web site (http://www.hps.org/documents/meddiagimaging.pdf).

There exists a small but real increase in the risk of childhood malignancies in fetuses exposed to ionizing radiation, particularly if exposure occurs during the first trimester. For a CT scan of the pelvis, this risk increases from 1 in 1,000 in nonexposed children to 2 in 1,000 for exposed children. Termination of pregnancy should not be recommended to women who are exposed inadvertently during diagnostic procedures, and they should be counseled that the absolute risk is very small.

Ionizing radiation can be used for select maternal indications during pregnancy without significant risk of deleterious effects on the fetus. Furthermore, the potential harm to the mother and by extension to the fetus of not performing a medically indicated diagnostic study should be considered.

Some radiologic examinations render exposures to a pregnant uterus that are so low that pregnancy status need not be considered with an indicated examination, as long as the beam is properly collimated, and the woman is positioned to avoid direct irradiation of the pelvis. Such studies include chest x-ray during the first and second trimester; extremity x-ray (with the possible exception of the hip); and any diagnostic examination of the head, including dental imaging. Mammography also can be performed safely at any time during pregnancy because radiation exposure from a properly performed screening mammogram is inconsequential. However, increased breast density reduces the sensitivity of mammography during pregnancy. Providing lead shielding to wrap the pelvis of the pregnant woman during nonpelvic CT scan does not substantially alter exposure due to internal scatter radiation.40

Magnetic Resonance Imaging

Few adverse effects are associated with MRI study during pregnancy, although animal studies have raised concern about teratogenicity in early pregnancy.39 Use of MRI study should be avoided during the first trimester, especially because the baseline rate of spontaneous abortion in early pregnancy is high, and an incidental miscarriage could be blamed on the study. Thermal and fetal ear damage caused by MRI scanners probably is more theoretical than real. Intravenous gadolinium crosses the placenta, and its administration should be avoided during pregnancy unless absolutely necessary.

Specific Medical Conditions

Specific recommendations have been made regarding diagnostic imaging for certain medical conditions occurring during pregnancy.

Appendicitis, Cholelithiasis, and Nephrolithiasis.

Ultrasonography is the initial imaging modality of choice for these suspected conditions in pregnant women. However, if clinical suspicion remains high despite negative findings on ultrasound examination, MRI study or CT scan is reasonable. Ultrasound examination has been shown to be 100% sensitive, 96% specific, and 98% accurate in diagnosing appendicitis in pregnancy.39 In advanced pregnancy (greater than 35 weeks’ gestation) and in obese women, CT scan or MRI study may be more appropriate because ultrasound examination might be technically difficult. Noncontrast CT scan (more accurate) or intravenous pyelogram (less radiation) may be obtained if clinical suspicion of nephrolithiasis is high despite a negative ultrasound examination result.

Pulmonary Embolism.

CT pulmonary angiography should be the initial diagnostic imaging modality for suspected pulmonary embolism. It is more accurate than ventilation-perfusion scintigraphy and exposes the fetus to substantially less radiation.

Trauma.

Ultrasonography may be the initial imaging evaluation for trauma, unless injuries are life threatening, in which case CT scan should be obtained promptly.39

Pneumonia.

Chest x-ray for suspected pneumonia is safe in pregnancy.

Case 2, cont’d. Ellen undergoes a renal and pelvic ultrasound examination, which reveals bilateral hydronephrosis, more prominent on the left, as well as an obstructing calculus at the left ureteropelvic junction. Because she does not have signs of infection, she is treated conservatively with drugs to control pain. She passes the stone within the next 48 hours, with subsequent resolution in symptoms.

SECTION THREE

Gestational Diabetes

Case 3. Jessica is a 26-year-old woman who is gravida 2, para 1. She presents to your office for prenatal care at 12 weeks’ gestation. She delivered a healthy, 4,082-g (9-lb 0-oz) girl under your care 2 years ago; the birth was complicated by shoulder dystocia. Jessica has a body mass index of 31 kg/m², and she reports a 3-kg (6.6-lb) weight gain over the past 2 months. Medical and family history are negative for gestational and type 2 diabetes.

Overview

Gestational diabetes affects 5% of pregnancies in the United States41-43 and causes significant maternal and fetal morbidity. Women with gestational diabetes experience higher rates of gestational hypertension and preeclampsia, operative delivery, and future development of type 2 diabetes. Their newborns have a higher risk of fetal macrosomia, shoulder dystocia, birth-related trauma (eg, fractures, nerve palsies), neonatal hypoglycemia, hyperbilirubinemia, and perinatal mortality.44 A growing body of evidence suggests that early recognition and management of gestational diabetes improve perinatal outcomes.45-49

Risk Factors

The risk of gestational diabetes increases with maternal weight and age. Gestational diabetes occurs more commonly in women with prior impaired glucose tolerance, diabetes in a previous pregnancy, or delivery of an infant with macrosomia. Other risk factors associated with gestational diabetes are listed in Table 3.

Table 3

Risk Factors for Gestational Diabetes

Maternal obesity (BMI >30 kg/m² or prepregnancy weight >110% ideal body weight)

Significant weight gain during the 5 years before pregnancy

Maternal age >25 years

Nonwhite race

History of impaired glucose tolerance

History of gestational diabetes in a previous pregnancy

Previous delivery of an infant weighing >4,082 g (>9 lb 0 oz)

Polycystic ovary syndrome

Glycosuria at the first prenatal visit

Maternal birth weight >4,082 g (>9 lb 0 oz) or <2,722 g (<6 lb)

Family history of diabetes in a first-degree relative (especially a sibling)

BMI = body mass index.

Screening and Diagnosis

Risk of diabetes should be assessed at the first prenatal visit, and every pregnant woman should be stratified as at high, average, or low risk of gestational diabetes.48,50 A screening protocol endorsed by the American Diabetes Association (ADA) and the Fifth International Workshop-Conference on Gestational Diabetes Mellitus is shown in Table 4.

Table 4

Suggested Screening Protocol for Gestational Diabetes

Perform diabetes risk assessment at the first prenatal visit and stratify every patient as high-, average-, or low-risk
High risk	Average risk (most patients)
Perform diabetes testing at or soon after the first prenatal visit in women who have any of the following criteria: Severe obesity (BMI >30 kg/m²) History of gestational diabetes or delivery of a large-for-gestational-age infant Presence of glycosuria Diagnosis of polycystic ovary syndrome Strong family history of type 2 diabetes Results of HbA1c, FPG, or 2-hour postprandial glucose using standard diagnostic criteria for adult type 2 diabetes: HbA1c ≥6.5%^a FPG ≥126 mg/dL 2-hour postprandial glucose level ≥200 mg/dL after a 75-g oral glucose load^a Random plasma glucose level ≥200 mg/dL in a patient with classic symptoms or hyperglycemia If abnormal and if confirmed by repeat testing, diagnose with overt diabetes rather than gestational diabetes If initial testing results are negative, screen for gestational diabetes at 24 to 28 weeks’ gestation using methods described here for women at average risk	Perform glucose testing at 24 to 28 weeks’ gestation using either: Two-step procedure Screening nonfasting 50-g, 1-hour glucose challenge test for all patients Diagnostic fasting 100-g, 3-hour OGTT for patients with abnormally high glucose challenge test results May use either ≥140 mg/dL or ≥130 mg/dL as threshold for abnormal glucose challenge test results One-step, diagnostic, fasting 3-hour OGTT (see Table 5) Low risk Glucose testing not required if all of the following criteria are met^b: Age <25 years Weight normal before pregnancy (BMI <25 kg/m²) Weight normal at birth No first-degree relative with diabetes No history of abnormal glucose tolerance No history of poor obstetric outcome Not member of a group with a high prevalence of gestational diabetes (eg, Asian, black, Hispanic American, American Indian, Pacific Islander)

^aMust be confirmed by repeat testing to diagnose type 2 diabetes.

^bMaternity care clinicians who advocate universal screening for gestational diabetes typically do not stratify any patient as low risk but screen women at 24 to 28 weeks’ gestation.

BMI = body mass index; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; OGTT = oral glucose tolerance test.

Information from Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 2):S251-260. Erratum in Diabetes Care. 2007;30(12):3154; American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33 (Suppl 1):S11-61. Erratum in Diabetes Care. 2010;33(3):692; American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 (Suppl 1):S62-69. Erratum in Diabetes Care. 2010;33(4):e57.

Women at high risk (Table 4) should be screened for diabetes as early in pregnancy as possible using standard criteria for diagnosing type 2 diabetes in adults. According to the ADA, high-risk women who meet criteria for type 2 diabetes early in pregnancy should be diagnosed with overt, rather than gestational, diabetes. High-risk women whose test results are negative before 24 weeks’ gestation should be rescreened at 24 to 28 weeks’ gestation using protocols for women at average risk.48,50

Women at average risk of gestational diabetes should be screened at 24 to 28 weeks’ gestation. The most common approach in the United States is a 1-hour screening glucose challenge test followed by diagnostic testing for women with abnormal test results. However, it is reasonable to replace the glucose challenge test with single-step diagnostic testing in populations with a high prevalence of gestational diabetes.48

The glucose challenge test measures plasma glucose 1 hour after a 50-g oral glucose load (50 g of glucose polymer in a 150-mL solution [Glucola]). The American College of Obstetricians and Gynecologists (The College) and ADA endorse the use of either 130 mg/dL or higher or 140 mg/dL or higher as the threshold for an abnormal glucose challenge test result.44,48 Using a cutoff of 140 mg/dL or higher identifies approximately 80% of patients with gestational diabetes; at this level, 15% of patients will have positive screening tests. Lowering the threshold to 130 mg/dL or higher improves sensitivity to 90%, but nearly 25% of patients will have abnormal test results, producing a much higher false-positive rate.51 Fasting does not affect the accuracy of glucose challenge test results.44

Women with abnormal glucose challenge test results should undergo a diagnostic 3-hour oral glucose tolerance test (OGTT) using a 100-g oral glucose load after an overnight fast (Table 5). More than 1 abnormal measurement on OGTT is diagnostic of gestational diabetes.48

Table 5

Diagnosis of Gestational Diabetes by Oral Glucose Tolerance Test

3-hour, 100-g OGTT (recognized by The College and ADA^a)—2 or more measurements that exceed the following thresholds are diagnostic of gestational diabetes:
	Carpenter and Coustan	NDDG^a
Fasting	≥95 mg/dL	≥105 mg/dL
1-hour	≥180 mg/dL	≥190 mg/dL
2-hour	≥155 mg/dL	≥165 mg/dL
3-hour	≥140 mg/dL	≥145 mg/dL
2-hour, 75-g OGTT (recognized by the ADA, IADPSG^b, and WHO)—2 or more measurements that exceed the following thresholds are diagnostic of gestational diabetes^c:
	ADA^d	IADPSG	WHO
Fasting	≥95 mg/dL	≥92 mg/dL	≥125 mg/dL
1-hour	≥180 mg/dL	≥180 mg/dL	—
2-hour	≥155 mg/dL	≥153 mg/dL	≥140 mg/dL

^aThe ADA no longer recognizes the NDDG criteria; the Carpenter and Coustan criteria are used by most US maternity care providers.

^bThe 2008-2009 IADPSG included ADA representation.

^cThe ADA considers 2 or more abnormal values diagnostic of gestational diabetes, but IADPSG and WHO consider any 1 abnormal value to be sufficient for gestational diabetes diagnosis.

^dADA values from: American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl 1):S64.

ADA = American Diabetes Association; IADPSG = International Association of Diabetes and Pregnancy Study Groups; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test; The College = American College of Obstetricians and Gynecologists; WHO = World Health Organization.

The International Association of Diabetes and Pregnancy Study Groups and the World Health Organization recommend 1-step, 75-g 2-hour OGTT for diagnosis of gestational diabetes in all pregnant women not already diagnosed with diabetes. This approach leads to a greater number of diagnoses of gestational diabetes and is more cost-effective than universal 2-step screening but has not gained wide acceptance in the United States.41,52,53

The ADA and The College suggest that screening might be omitted in low-risk patients, as defined in Table 4.50 However, the vast majority of US prenatal care clinicians practice universal screening.44

Though widely used, routine urine dipstick testing for glycosuria in asymptomatic pregnant women is ineffective as a screening tool for gestational diabetes and should not be repeated after the initial prenatal visit. Sensitivity (7% to 36%) and positive predictive value (7% to 27%) are unacceptably low.54 Urine dipstick testing after glucose challenge testing is unlikely to change management regardless of whether patients have gestational diabetes.6,7

Case 3, cont’d. Based on her average risk of diabetes, Jessica undergoes testing at 26 weeks’ gestation. The blood glucose level after glucose challenge testing is 168 mg/dL, and 3 of 4 oral glucose tolerance test measurements are high, indicating gestational diabetes.

Management

Evidence for Treatment

Management of gestational diabetes includes medical nutrition therapy, planned physical activity, regular blood glucose monitoring, and when necessary, pharmacologic interventions to maintain glycemic control. Recent studies show strong evidence of improved perinatal outcomes with gestational diabetes management.

A study of 1,000 pregnant women with gestational diabetes between 24 and 34 weeks’ gestation showed that dietary advice, glucose monitoring, and insulin therapy as needed reduced serious perinatal complications (eg, mortality, shoulder dystocia, bone fracture, nerve palsy) by 75% (number needed to treat = 34) compared with no treatment. Rates of preeclampsia also were reduced significantly. Induction of labor was more common in the treatment group; rates of cesarean delivery were similar in both groups.45 Another study of 958 patients with mild gestational diabetes (abnormal blood glucose challenge test results but fasting glucose levels of less than 95 mg/dL) showed significant reductions in mean birth weight, macrosomia, shoulder dystocia, cesarean delivery, preeclampsia, and gestational hypertension with treatment compared with usual care.47

Medical Nutrition Therapy and Planned Physical Activity

All women with gestational diabetes should be counseled regarding the benefits of dietary modifications and exercise. A dietitian or a diabetes nurse educator can provide valuable assistance. In general, women with gestational diabetes should restrict carbohydrate intake to 35% to 40% of total daily calories. If body mass index is greater than 30 kg/m², women should reduce total caloric intake by 30% or to 25 kcal/kg per day. Planned physical activity of 30 min/day also improves glycemic control.44,50

Pharmacotherapy

When women with gestational diabetes are not able to achieve glycemic control with nutrition therapy, pharmacologic interventions become necessary. To minimize the risk of fetal macrosomia and perinatal morbidity, glycemic goals are stricter during pregnancy than for nonpregnant women with diabetes. Glycemic thresholds and other indications for pharmacotherapy in women with gestational diabetes are shown in Table 6.

Table 6

Indications for Pharmacotherapy in Gestational Diabetes

Elevated fasting blood glucose (diet has little effect on fasting blood glucose levels)
Inadequate control demonstrated by HbA1c >7.0% or any of the following abnormally high glucose levels on 2 or more occasions during a 2-week interval despite medical nutrition therapy:
Fasting blood glucose	≥95 mg/dL
1-hour postprandial	>130 to 140 mg/dL
2-hour postprandial	≥120 to 127 mg/dL
Lack of expected weight gain as result of calorie restriction
Patient consistently hungry while adhering to diet

HbA1c = glycated hemoglobin.

Information from American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol. 2001;98(3):531; Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 2):S251-260. Erratum in Diabetes Care. 2007;30(12):3154; Serlin DC, Lash RW. Diagnosis and management of gestational diabetes mellitus. Am Fam Physician. 2009;80(1):57-62. Available at http://www.aafp.org/afp/2009/0701/p57.html.

Insulin.

Most US obstetricians consider insulin the drug of choice for women with gestational diabetes not adequately controlled with medical nutrition therapy.44 NPH plus regular or rapid-acting insulin are the most commonly used regimens. Other acceptable choices are 70/30 mixed insulin or basal plus bolus regimens (eg, insulin glargine plus insulin lispro). Data on insulin analogues in pregnancy are sparse, but no significant differences in maternal or fetal outcomes have been reported between analogues and conventional insulin.55-57

Insulin typically is started at a total daily dose of 0.7 units/kg per day. One-half to two-thirds of this dose is administered as intermediate or long-acting insulin and the rest as short- or rapid-acting insulin. If 70/30 premixed insulin is used, two-thirds of the total daily dose is administered in the morning and one-third is administered in the evening. Pregnant women should measure fasting and 1- or 2-hour postprandial blood glucose levels, and insulin is titrated to keep levels below the thresholds noted in Table 6.

Oral Drugs.

A growing body of evidence supports the safety and effectiveness of select oral drugs in gestational diabetes management; the 2 most studied are glyburide and metformin. A systematic review of more than 2,000 women in 9 studies showed no substantial difference in maternal or neonatal outcomes with the use of either oral drug compared with insulin in women with gestational diabetes.58 A study of 751 women with gestational diabetes showed no increase in adverse perinatal outcomes with metformin compared with insulin therapy; patients preferred metformin to insulin therapy by a margin of 3 to 1.59

A recent head-to-head comparison showed the failure rate of metformin to be twice that of glyburide in achieving adequate glycemic control in women with gestational diabetes.60 However, the mean birth weight of infants was lower in the metformin group. Other neonatal outcomes, including rates of macrosomia, did not differ between the 2 groups.

Antepartum Fetal Monitoring

Strategies for fetal surveillance in women with gestational diabetes vary according to glycemic control and local standards of care. High-quality evidence regarding antepartum testing in women with gestational diabetes is lacking. Many experts recommend nonstress testing and amniotic fluid volume measurement twice weekly beginning at approximately 32 weeks’ gestation for women with poorly controlled or insulin-requiring gestational diabetes; there is little consensus regarding fetal surveillance in women with diet-controlled gestational diabetes.41,44,61-63

Delivery

Data on the optimal timing of delivery for women with gestational diabetes are inconclusive.64 The risks of macrosomia and stillbirth must be balanced with the risks of prematurity and neonatal respiratory distress. Women with diet-controlled gestational diabetes probably should deliver by 41 weeks’ gestation. Most obstetricians induce women with pharmacologically managed gestational diabetes at 39 weeks’ gestation or sooner if antepartum testing raises concern about fetal well-being.44,50 However, a recent best-evidence review and a Cochrane review showed insufficient evidence to support induction of labor in women with insulin-requiring gestational diabetes.65,66

If macrosomia is not suspected, then women with gestational diabetes may attempt vaginal delivery. The College suggests elective cesarean delivery if estimated fetal weight exceeds 4,500 g in the presence of gestational diabetes.44 In practice, many obstetricians have even lower thresholds for recommending cesarean delivery. Gestational diabetes is a risk factor for shoulder dystocia even in the absence of macrosomia.

Excessive hyperglycemia should be avoided during labor because it can produce reactive hypoglycemia in the newborn. Insulin infusions can be used for women who remain hyperglycemic during labor. However, most women with gestational diabetes are euglycemic and do not require active management of glucose levels during labor or in the immediate postpartum period.41

Future Risk of Type 2 Diabetes

Between 35% and 60% of women with gestational diabetes develop type 2 diabetes within the next 10 years (relative risk = 7.43).50,67 Factors most strongly associated with subsequent development of type 2 diabetes among women with gestational diabetes include obesity, diagnosis of gestational diabetes before 24 weeks, and insulin use during pregnancy.68

Although often overlooked,69-71 screening should begin with a fasting plasma glucose or a 75-g 2-hour OGTT at 6 to 12 weeks’ postpartum, and screening for type 2 diabetes should be repeated every 3 years.50,72 Prenatal care clinicians should encourage breastfeeding and intensive lifestyle interventions directed at decreasing weight and lowering cardiovascular risk. Intensive lifestyle interventions and metformin are effective in preventing or delaying diabetes in women with a history of gestational diabetes for at least 10 years.73,74

Case 3, cont’d. Jessica successfully uses medical nutrition therapy and a daily walking plan to maintain fasting blood glucose levels of less than 95 mg/dL and 2-hour postprandial glucose levels of less than 120 mg/dL through the remainder of her pregnancy. She goes on to have a spontaneous vaginal delivery of a healthy, 3,800-g (8-lb 6-oz) boy at 39 weeks’ gestation.

SECTION FOUR

Preterm Labor

Case 4. Maria is a 17-year-old girl who is primigravida. She presents to your office at 32 weeks’ gestation (by 8-week ultrasound) with 6 hours of regular contractions. She denies bleeding or loss of fluid. Fetal heart tracing is reassuring and tocometry reveals contractions every 4 minutes. Vaginal examination confirms the infant is vertex, and the cervix is 1-cm dilated and 20% effaced.

Overview

An estimated 12.9 million infants are born prematurely, accounting for 9.6% of births and 41% of child mortalities worldwide.75,76 The majority (60% to 70%) of preterm infants are delivered at 34 to 36 weeks’ gestation, 15% at 28 to 31 weeks’, and 5% at less than 24 weeks’ gestation.77 In the United States, the preterm birth rate is 12.3%, a rate that decreased for 2 consecutive years (2006 to 2008) for the first time since 1990 (11.7% to 11.1% for white infants and 18.5% to 17.5% for black infants).78

The high rate of premature births in the United States might be due in part to fertility treatments and multiple gestations, medical conditions (eg, preeclampsia, diabetes) resulting in early induced delivery, and pregnancies later in life. Efforts to prolong pregnancy show limited effectiveness, but improved neonatal care has increased preterm infant survival rates.

Risk Factors

Pregnancy risk screening predicts 24% to 43% of adverse outcomes, allowing enhanced surveillance, risk management, and arrangement for neonatal tertiary care services.79 Most preterm births occur in lower-risk mothers and are not anticipated. Risk factors for preterm delivery are listed in Table 7.

Table 7

Preterm Delivery Risk Factors

Family and social history

Pregnancy specific (maternal-fetal factors)

Preterm birth in biological female relatives (RR = 1.4 if sister with preterm birth, RR = 1.4 to 1.6 if mother with preterm birth)
Low socioeconomic status
Low educational status
Maternal age (<20 years or >35 years)
Hard physical labor or long work hours
Black race (17.5% compared with 11.1% for whites)
Smoking (RR = 2), cocaine, heroin, heavy alcohol use
Psychologic or social stress (RR = 2)
Medical history
Prior preterm birth (RR = 5.6)
Conception within 6 months of prior delivery
Malnutrition; prepregnancy body mass index <19 kg/m²; or folate, iron, or zinc deficiency
Diabetes
Hypertension
Obesity
Thyroid disease
Asthma
History of cervical cone biopsy (but probably not with LEEP)
Depression
Nongenital tract infection during pregnancy (eg, urinary tract infection, pneumonia, appendicitis, periodontal disease)

Neural tube defects
Preeclampsia
Gestational diabetes
Intrauterine infection (Ureaplasma urealyticum on amniocentesis)
Bacterial vaginosis (RR = 1.5 to 3.0)
Vaginal infections (eg, Trichomonas, chlamydia, syphilis, gonorrhea; RR = 1.3 to 2.0)
Multiple gestations (60% of twins, almost all higher number gestation; 2% to 3% of pregnancies with multiple gestations cause 15% to 20% of preterm births)
Oligohydramnios or polyhydramnios
Vaginal bleeding in any trimester (eg, abruption, placenta previa, idiopathic)
Abdominal surgery late in pregnancy
Cervical shortening (cervical length <25 mm)
Elevated fetal fibronectin level between 24 and 34 weeks’ gestation

LEEP = loop electrosurgical excision procedure; RR = relative risk.

Information from Goldenberg RL, Culhane JF, Iams JD, et al. Epidemiology and causes of preterm birth. Lancet. 20085;371(9606):75-84 [Review]; Werner CL, Lo JY, Heffernan T, et al. Loop electrosurgical excision procedure and risk of preterm birth. Obstet Gynecol. 2010;115(3):605-608; Martin JA, Osterman MJ, Sutton PD. Are preterm births on the decline in the United States? Recent data from the National Vital Statistics System. NCHS Data Brief. 2010;(39):1-8. Available at http://www.cdc.gov/nchs/data/databriefs/db39.htm.

Quantitative fetal fibronectin (fFN) screening has some value in predicting preterm labor (PTL) in high-risk pregnancies without preterm contractions. A negative fFN level measured between 23 and 24 6/7 weeks’ gestation predicts a 5% chance of delivery before 34 weeks’ gestation (baseline risk is 6.7%) and a value of greater than 200 ng/mL predicts a 50% chance of preterm delivery.80

Diagnosis

Traditionally, prenatal care clinicians have diagnosed labor by monitoring women with preterm contractions and assessing cervical changes. However, by the time cervical dilation is identified, intervention may be unsuccessful; most diagnostic tools proposed for PTL simply stratify risk factors.

Cervical-Length Measurement

Cervical-length measurement is a predictor of delivery before 34 weeks’ gestation; risk is high in asymptomatic women with a very short cervix (15 mm or less). Serial measurements do not add prognostic value to a single cervical-length measurement.81

Fetal Fibronectin

Fetal fibronectin testing is used to differentiate between early and false labor. A meta-analysis of 32 trials (5,355 symptomatic women at less than 37 weeks’ gestation) showed a 7.7% pretest probability of delivering within 7 days of testing. Posttest probability of delivering within 7 days was 2.4% with a negative test result and 25.9% with a positive test result.82 The sensitivity and specificity of fFN testing are 76.1% and 81.9%, respectively.83 Despite the poor predictive value of fFN testing, knowledge of fFN test results is associated with a reduced preterm birth rate (15.6% versus 28.6% without this knowledge).83 With an fFN test specificity of 81.9% and preterm birth prevalence of 12.3%, the negative predictive value is approximately 96%. Future research may better define the role of fFN testing in the management of preterm contractions.

Prevention

Prenatal care includes primary prevention of PTL by addressing modifiable risk factors (Table 7). Strategies for secondary prevention of PTL include cervical cerclage, routine screening and treatment of bacterial vaginosis, progesterone therapy, and dietary supplementation.

Cervical Length and Cerclage

Vaginal ultrasound measurement of cervical length in women with prior PTL helps identify higher risk of preterm delivery; risk increases as cervical length decreases. In a study of women with a history of preterm birth and a short cervix (less than 25 mm), preterm birth occurred in up to 42%.84

This knowledge alone has not reduced the preterm birth rate.85 In a Cochrane review of women with low or moderate risk of preterm delivery and any cervical length, cervical cerclage did not reduce preterm birth rates.86 However, in a multicenter randomized controlled trial (RCT) of more than 1,000 women, cerclage significantly reduced preterm delivery in women with a cervical length of less than 15 mm but not in women with a cervical length of 16 to 24 mm.84 In another RCT of women with cervical length less than 20 mm, investigators compared history-indicated cerclage (physician decision, blinded to the ultrasound results) to ultrasound-indicated cerclage. Women in the ultrasound group were more likely to receive cerclage (32% versus 19%), but preterm delivery incidence was the same in both groups (15%), suggesting that clinical judgment is as effective as ultrasound evaluation in determining need for cerclage.87

Screening for Vaginal Infection

Abnormal vaginal flora (ie, Ureaplasma, Gardnerella vaginalis, Atopobium vaginae) have been associated with an increased risk of preterm delivery.88-90 One large, high-quality study featured in a Cochrane review compared screening and treatment for chlamydia, gonorrhea, bacterial vaginosis, and candidiasis before 20 weeks’ gestation with no treatment. The intervention group had a significantly lower risk of preterm birth and low birth weight (relative risk = 0.55).91 Despite this association, treatment of women with asymptomatic bacterial vaginosis and a low to moderate risk of preterm delivery was not beneficial in decreasing rates of preterm delivery, preterm rupture of membranes, or low birth weight.91 Data on high-risk pregnancies are conflicting and inconclusive.90,92 A Cochrane review of antibiotics used to treat women with Ureaplasma infection showed insufficient evidence for a reduction in preterm birth rates.93

Progesterone

Progesterone administered to pregnant women with a history of preterm birth decreases the rates of recurrent preterm birth (at less than 34 weeks and less than 37 weeks) and low birth weight (less than 2,500 g). Preterm birth (less than 34 weeks) rates also are reduced when progesterone is administered to women with cervical length of less than 15 mm.94 The American College of Obstetricians and Gynecologists recommends that progesterone be offered to all women with a history of preterm birth at less than 37 weeks’ gestation.95 Optimal timing, dose, route, and duration of therapy are unknown. The role of progesterone in multiple gestations and threatened preterm labor, as well as potential fetal effects, is not well defined.

Folic Acid

A large population-based study found that continuing folic acid supplementation throughout pregnancy has a protective effect against PTL.96 Folic acid supplementation continued in the third trimester prolonged mean gestational age by 0.3 weeks, with a mean birth-weight gain of 32 g (number needed to treat = 29). Adding a multivitamin to folic acid gave an additional 0.3 weeks’ gestation and a 47-g gain in birth weight (number needed to treat = 15). Although RCTs are needed to prove benefit, folic acid is safe and inexpensive.

Other Interventions

Omega-3 fatty acid supplementation has no proven benefit, and there is insufficient evidence to support probiotics in PTL prevention.97,98 Periodontal infection has been associated with preterm delivery, but a study of 1,806 women with periodontal disease failed to show benefit with periodontal therapy.99

One RCT of 1,047 women showed a significant reduction in preterm birth rates for women receiving group prenatal care (from 13.8% in the standard care group to 9.8%). Women receiving group care participated in a 2-hour session that included physical assessment, education and skills training, and group discussion. The results in black women showed reductions from 15.8% to 10.0%.100

Treatment

Antenatal Corticosteroids

The single most effective intervention for preterm labor is antenatal corticosteroid administration. Corticosteroids reduce neonatal mortality; promote fetal lung development; and decrease the risk of respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis.101 Betamethasone (12 mg intramuscularly every 12 hours for 2 doses) and dexamethasone (6 mg intramuscularly every 12 hours for 4 doses) have similar effectiveness. However, a lower rate of intraventricular hemorrhage and a slightly higher rate of intensive care unit admission is reported for dexamethasone.102 Sepsis rates are higher with oral dexamethasone compared with intramuscular injection.102

A Cochrane review showed that a repeat dose of corticosteroids administered to women who remained at risk of preterm delivery more than 7 days after the initial dose reduced respiratory risk and serious neonatal health problems.103 However, lower birth weights and smaller head circumferences were seen among infants receiving a repeat steroid dose. A subsequent RCT of 1,858 women using repeat corticosteroid doses every 14 days showed decreased infant weight, height, and head circumference without significant benefit.104 Further research is needed to support the dosage and timing of repeat steroids if they are to be used routinely.

Tocolytics

Tocolytics administered early in labor can delay delivery for 48 hours in most women (75% to 93%) and up to 1 week in some women (61% to 78%).105 Tocolytics alone do not significantly improve other neonatal outcomes; their primary benefit is to delay delivery long enough to allow steroid administration. All tocolytics (Table 8) are superior to placebo at delaying delivery, and there is no significant difference in respiratory distress syndrome or neonatal mortality rates. There is no consensus on the most effective tocolytic option, but 1 meta-analysis showed that calcium channel blockers were superior at delaying delivery until 37 weeks and prostaglandin inhibitors were most effective at delaying labor for 48 hours.105 Prostaglandin inhibitors and calcium channel blockers were better tolerated.105,106

Table 8

Tocolytics for Preterm Labor Management

Class	Drug	Dosage	Complications/Precautions	Contraindications
Beta₂-agonist	Terbutaline^a	0.25 subcutaneously every 20 minutes to 6 hours	Maternal: hypokalemia, hyperglycemia, hypotension, pulmonary edema, tachycardia, arrhythmias, cardiac insufficiency, myocardial infarction Fetal: tachycardia, hyperglycemia, hypoglycemia, myocardial hypertrophy, ischemia	Maternal arrhythmias; uncontrolled diabetes, hypertension, or thyrotoxicosis Hold for maternal heart rate greater than 120 beats/min
Calcium channel blocker	Nifedipine^a	30 mg orally or sublingual load, followed by 10 to 20 mg orally every 4 to 6 hours	Maternal: typically well tolerated, but headache, nausea, hypotension, flushing, palpitations, weakness, dry mouth reported; avoid using with magnesium sulfate (pulmonary edema) Fetal: sudden fetal death/distress	Maternal liver disease, hypotension; use with caution in patients with cardiac and renal disease
Prostaglandin inhibitors	Indomethacin	50 to 100 mg rectally initially; or 25 to 50 mg orally every 6 hours for 48 hours	Maternal: typically well tolerated; side effects include GI distress and renal or cardiac perfusion issues Fetal: constriction of ductus arteriosus, pulmonary hypertension, oligohydramnios, hyperbilirubinemia, necrotizing enterocolitis, intraventricular hemorrhage	NSAID- or aspirin-sensitive asthma, CAD, GI bleed, renal failure, oligohydramnios, fetal cardiac or renal anomalies
	Sulindac	200 mg orally every 12 hours for 48 hours
	Ketorolac	60 mg IM, then 30 mg every 6 hours for 48 hours
Nitric oxide donors	Glyceryl trinitrate, nitroglycerin	10-mg patch every 12 hours up to 24 hours	Maternal: headache, hypotension Fetal: neonatal hypotension	Headache
Oxytocin receptor antagonist	Atosiban (not approved for use in United States)	6.75 mg IV over 1 minute, then 18 mg/hour infusion for 3 hours and 6 mg/hour for up to 45 hours	Maternal: nausea, allergic reaction, headache Fetal: none known	None
Adipose protein hormone	Leptin	Theoretical benefit; not yet studied	Unknown	Unknown

^aDosages from Clinical Pharmacology Web site. Available by subscription at https://clinicalpharmacology.com/.

CAD = coronary artery disease; GI = gastrointestinal; IM = intramuscular; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug.

Information from ACOG Committee on Practice Bulletins. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologist. Number 43, May 2003. Management of preterm labor. Obstet Gynecol. 2003;101(5 Pt 1):1039-1047 [Review]; Di Renzo GC, Roura LC; European Association of Perinatal Medicine-Study Group on Preterm Birth. Guidelines for the management of spontaneous preterm labor. J Perinat Med. 2006;34(5):359-366; Wuntakal R, Hollingworth T. Leptin—a tocolytic agent for the future? Med Hypotheses. 2010;74(1):81-82.

Magnesium sulfate is no longer recommended for tocolysis. A Cochrane review showed that it is ineffective for preventing preterm birth and increases infant mortality rates.107-109

Antibiotics

Antibiotics administered to women with preterm rupture of membranes prolong pregnancy and reduce chorioamnionitis, neonatal infection, neonatal oxygen requirements, and ultrasound-diagnosed neonatal cerebral abnormalities.110 Antibiotics have no benefit in PTL without rupture of membranes unless there is a specific indication, such as group B streptococcus prophylaxis or urinary tract infection treatment.111

Other Interventions

Tocolytics administered as maintenance therapy, bed rest, thyrotropin-releasing hormone, vitamin K administered to the mother, and phenobarbital have no proven benefit in PTL.112-121

Case 4, cont’d. Maria is treated with oral nifedipine and a course of intramuscular dexamethasone. The neonatal resuscitation team is on standby when she delivers 72 hours later. The infant requires initial oxygen and feeding support but has no other complications.

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119 Crowther CA, Crosby DD, Henderson-Smart DJ. Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev. 2010;(1):CD000229.

120 Sosa C, Althabe F, Belizán JM, et al. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev. 2004;(1):CD003581.

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Care of Pregnant Patients

Learning Objectives

Key Practice Recommendations

Author Information

Prenatal Diagnosis Developments

Routine Tests in Prenatal Care

Screening for Birth Defects

Pretest Counseling and Decision Aids

New Approaches to Imaging During Pregnancy

Prenatal Ultrasonography

Advanced Imaging Modalities

Diagnostic Imaging for Nonobstetric Conditions in Pregnant Women

Gestational Diabetes

Overview

Risk Factors

Screening and Diagnosis

Management

Future Risk of Type 2 Diabetes

Preterm Labor

Overview

Risk Factors

Diagnosis

Prevention

Treatment

References

Suggested Reading