Joseph Biggio, MD, MS

Soft markers are minor ultrasound findings identified in the midtrimester that commonly do not represent a structural abnormality. These may be normal variants but are noteworthy because of their association with an increased aneuploidy risk. Commonly identified soft markers include echogenic intracardiac focus; echogenic bowel; choroid plexus cyst(s); single umbilical artery; urinary tract dilation; shortened humerus, femur, or both; thickened nuchal fold; and absent or hypoplastic nasal bone

Isolated Soft Markers: Background and Recommended Management

Contemporaneously with the advancement in aneuploidy detection with soft markers was the development of improved serum screening methods to predict aneuploidy risk.

 The introduction of cell-free DNA (cfDNA) techniques greatly improved the ability to screen for common aneuploidies. Given the high sensitivity and specificity of cfDNA for trisomies 21, 18, and 13 across all age groups, in 2020, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine endorsed the option of cfDNA screening for all patients.

What is the initial approach when an isolated soft marker is identified?

“Isolated” is a soft marker that has been identified in the absence of any fetal structural anomaly, growth restriction, or additional soft marker, following a detailed obstetrical ultrasound examination. Identification of a soft marker is an indication for a detailed obstetrical ultrasound examination (Current Procedural Terminology code 76811) to ensure the finding is isolated. 

The decision to perform a detailed examination should be made through a shared decision-making framework. In the case of multiple soft markers or structural abnormalities, the approach to evaluation should be individualized.

If an isolated soft marker is confirmed, subsequent evaluation and counseling depend on prior aneuploidy screening results, additional risk factors for aneuploidy, and associations with nonaneuploid conditions.

Traditionally, the presence or absence of specific soft markers was used to modify the probability of trisomy 21 and 18 for high-risk patients.

However, the relative importance of this approach has evolved rapidly with improved prenatal screening techniques. 

The detection rates for aneuploidy with commonly employed serum screening strategies (ie, first-trimester screen, integrated screen, sequential screen, contingent screen, or quad screen) are high. 

cfDNA is the single best screening test for the common trisomies (trisomies 21, 18, and 13), and the posttest probability of a common aneuploidy after negative cfDNA screening is very low.

 Although a range of positive likelihood ratios (LRs) for a particular aneuploidy exists for each soft marker, even when the highest positive LRs are applied to a population that has previously had a negative cfDNA result, the risk of trisomy 21 is negligibly affected.

Only diagnostic testing removes residual risk for aneuploidy detection. 

Thus, a patient may elect diagnostic testing for any indication. However, we do not recommend diagnostic testing for aneuploidy solely for the evaluation of an isolated soft marker following a negative serum or cfDNA screening result (grade 1B). 

Similarly, if a pregnant person has undergone diagnostic testing and the results indicate a normal karyotype, identification of a soft marker is insignificant with regard to aneuploidy and should be reported as such.

Some pregnant people may decline any aneuploidy screening following a shared decision-making process that incorporates accurate information, accessible health care resources, and the patient’s clinical context, values, beliefs, and potential anxiety created by the identification and discussion of a soft marker.

Each practice should establish a standardized protocol for how the identification of an isolated soft marker will be documented and managed for patients who have previously declined aneuploidy screening. 

These protocols should ensure patients are informed prior to the ultrasound examination of how findings will be handled to enhance shared decision-making and patient autonomy.

What is the counseling and management regarding soft ultrasound markers?

Table 1 summarizes the definition, prevalence, range of LRs, evaluation, and follow-up for commonly identified soft markers. 

 summarizes recommendations for the evaluation and management of isolated soft ultrasound markers for aneuploidy in the
second trimester. 

Benacerraf BR, Frigoletto FD Jr, Cramer DW. Down syndrome: sonographic sign for diagnosis in the second-trimester fetus. 

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Benacerraf BR, Gelman R, Frigoletto FD Jr. Sonographic identification of second-trimester fetuses with Down’s syndrome. 

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Benacerraf BR, Mandell J, Estroff JA, Harlow BL, Frigoletto FD Jr. Fetal pyelectasis: a possible association with Down syndrome. 

Lockwood C, Benacerraf B, Krinsky A, et al. A sonographic screening method for Down syndrome. 

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Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. 

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American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics; Committee on Genetics; Society for Maternal-Fetal Medicine. Screening for fetal chromosomal abnormalities: ACOG practice bulletin, number 226. 

. 2020;136(4):e48-e69. doi:10.1097/AOG.0000000000004084

Nyberg DA, Luthy DA, Resta RG, Nyberg BC, Williams MA. Age-adjusted ultrasound risk assessment for fetal Down’s syndrome during the second trimester: description of the method and analysis of 142 cases. 

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Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. 

. 2017;50(3):302-314. doi:10.1002/uog.17484

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Articles

In this consult series, experts from SMFM discuss the evaluation and management of soft ultrasound markers for aneuploidy.

SMFM Consult Series #57: Evaluation and management of soft ultrasound markers for aneuploidy

Created in partnership with the Society for Maternal-Fetal Medicine. SMFM was established in 1977 to “give Maternal-Fetal Medicine (MFM) physicians and scientists a place to share knowledge, research and clinical best practices in order to improve care for moms and babies.”

Fetal growth restriction (FGR) can result from a variety of maternal, fetal, and placental conditions. It occurs in up to 10% of pregnancies and is second to premature birth as the most common cause of infant morbidity and mortality.

FGR is commonly defined as an ultrasonographic estimated fetal weight (EFW) below the 10th percentile for gestational age. Small for gestational age (SGA) describes a newborn whose birth weight is less than the 10th percentile for gestational age. A challenge in the prenatal management of FGR is differentiating the constitutionally small fetus with a normal neonatal outcome from one who is pathologically growth restricted and at risk for postnatal complications.

There is significant variation in the diagnostic criteria used for FGR 

. However, evidence supports the use of abdominal circumference (AC) as a diagnostic criterion for FGR.

We recommend that FGR be defined as an ultrasonographic EFW or AC below the 10th percentile for gestational age. (GRADE 1B)

Ultrasonographic estimation of fetal weight

The most widely used method for estimating fetal weight and calculating weight percentile in the United States is based on the Hadlock formula.

 Use of new standards, such as INTERGROWTH-21, National Institute of Child Health and Human Development (NICHD), and World Health Organization (WHO) standards, has not been shown to improve the detection and outcome of FGR.

We recommend the use of population-based fetal growth references (such as Hadlock) in determining fetal weight percentiles. (GRADE 1B)

Fetal growth restriction has been categorized as early- or late-onset based on gestational age at prenatal ultrasound diagnosis. Early-onset FGR is diagnosed before 32 weeks of gestation, is typically more severe, tends to follow an established Doppler pattern of fetal deterioration, shows more significant placental dysfunction than late-onset FGR, and is more commonly associated with maternal hypertensive disorders of pregnancy. 

Fetuses with genetic abnormalities can also present with early-onset FGR, commonly in association with fetal and amniotic fluid abnormalities. Late-onset FGR is diagnosed at or after 32 weeks of gestation. Late-onset FGR represents approximately 70% to 80% of FGR cases and is typically milder in presentation.

The presence of abnormal umbilical artery Doppler indices has been found to predict adverse perinatal outcomes.

An EFW below the 3rd percentile has also been associated with an increased risk of adverse perinatal outcome irrespective of umbilical and middle cerebral artery Doppler indices,

 and has therefore been found to represent a more severe form of FGR.

FGR has been classified as symmetric or asymmetric based on the ratio between the head circumference and the abdominal circumference (HC/AC). Growth and developmental delay from birth to 4 years of age are similar in symmetric and asymmetric growth-restricted preterm newborns.

 Furthermore, HC/AC is not an independent predictor of adverse pregnancy outcomes.

No preventive strategies or treatments, including nutritional and dietary supplements or bed rest, have been proven to be effective in preventing FGR or reducing the incidence of SGA births.

 The American College of Obstetricians and Gynecologists recommends against low-dose aspirin for the sole indication of FGR prevention.

We recommend against the use of low-molecular-weight heparin for the sole indication of prevention of recurrent FGR. (GRADE 1B) We also recommend against sildenafil or activity restriction for in-utero treatment of FGR. (GRADE 1B)

Management of FGR is based on early diagnosis, optimal fetal surveillance, and timely delivery. In pregnancies with FGR, delivery decisions require balancing the risk of prematurity against that of stillbirth. Accumulating evidence suggests a benefit to the use of umbilical artery Doppler in the surveillance of FGR. The presence of a standardized protocol for diagnosis and management appears to be associated with more favorable outcomes.

 The single most important prognostic factor in preterm fetuses with growth restriction is the gestational age at delivery.

With the initial diagnosis of FGR and if not previously performed, 

we recommend that a detailed obstetrical ultrasound examination (CPT code 76811) be performed with early-onset FGR since up to 20% of cases are associated with fetal or chromosomal abnormalities. (GRADE 1B)

We recommend that women be offered fetal diagnostic testing, including chromosomal microarray analysis (CMA), when FGR is detected and a fetal malformation, polyhydramnios, or both are also present, regardless of gestational age. (GRADE 1B)

 Recent studies evaluating the role of CMA in fetuses with early-onset growth restriction and no structural malformations have identified a 4% to 10% incremental yield of CMA over karyotype.

we recommend that pregnant women be offered prenatal diagnostic testing with CMA when unexplained isolated FGR is diagnosed at less than 32 weeks of gestation. (GRADE 1C)

Regarding the association of maternal infections with FGR, a study that included 319 pregnancies found no cases of maternal or congenital infection with toxoplasma, rubella, or herpes. Six (1.8%) fetuses were diagnosed with congenital CMV; 2 (0.6%) of these fetuses had no ultrasonographic findings other than FGR.29 

We recommend against screening for toxoplasmosis, rubella, or herpes in pregnancies with FGR in the absence of other risk factors and recommend PCR for CMV in women with unexplained FGR who elect diagnostic testing with amniocentesis. (GRADE 1C)

An abnormal umbilical artery Doppler waveform reflects the presence of placental insufficiency and can help differentiate the growth-restricted fetus from the fetus that is constitutionally small. Incorporation of umbilical artery Doppler evaluation in the management of high-risk pregnancies has been shown to significantly reduce the risk of perinatal death, induction of labor, and cesarean delivery. However, it does not reliably predict adverse pregnancy outcome in late-onset FGR.

An abnormal umbilical artery Doppler is defined as a pulsatility index (PI), resistance index (RI), or systolic/diastolic (S/D) ratio S/D ratio greater than the 95th percentile for gestational age or an absent or reversed end-diastolic velocity (AEDV or REDV).

Because no randomized trials with adequate sample size have been done regarding the optimal frequency of umbilical artery Doppler for FGR surveillance, protocols vary from weekly umbilical artery Doppler to a 2- to 4-week interval. 

We recommend that once FGR is diagnosed, serial umbilical artery Doppler assessment should be performed to assess for deterioration. (GRADE 1C) 

This assessment should initially occur every 1 to 2 weeks. If the umbilical artery Doppler remains normal after this initial assessment, a less frequent interval of umbilical artery Doppler testing (eg, every 2 to 4 weeks) may be considered.

With decreased end-diastolic velocity, ie, flow ratios greater than the 95th percentile, or in pregnancies with severe FGR (EFW less than the 3rd percentile), we suggest weekly umbilical artery Doppler evaluation. (GRADE 2C) We recommend Doppler assessment up to 2 to 3 times per week when umbilical artery AEDV is detected due to the potential for deterioration and development of REDV. (GRADE 1C) In the setting of REDV, we suggest hospitalization, administration of antenatal corticosteroids, heightened surveillance with cardiotocography (CTG) at least 1 to 2 times per day, and consideration of delivery depending on the entire clinical picture and results of additional evaluation of fetal well-being. (GRADE 2C)

 Hospital admission should be considered if fetal surveillance of more often than 3 times per week is deemed necessary.

Once FGR is diagnosed, assessment of fetal growth and weight should be performed at least every 3 to 4 weeks. Consideration can be given for a 2-week interval in cases of severe FGR or with abnormal umbilical artery Doppler.

Doppler assessment of other blood vessels

Clinical trials are needed to evaluate the use of ductus venosus Doppler and middle cerebral artery Doppler in guiding clinical management of early- to late-onset FGR. In addition, uterine artery Doppler has limited diagnostic accuracy and clinical utility in predicting FGR, SGA birth, and perinatal mortality. 

We suggest that Doppler assessment of the ductus venosus, middle cerebral artery, or uterine artery not be used for routine clinical management of early- or late-onset FGR. (GRADE 2B)

Despite the absence of large prospective studies on the role of CTG in the management of FGR, a normal CTG in pregnancies with FGR is more likely to be associated with a normal perinatal outcome, and the presence of spontaneous repetitive late decelerations is accepted as an indication for delivery in viable pregnancies with FGR, irrespective of Doppler findings. 

We suggest weekly CTG testing after viability for FGR without A/REDV and that the frequency be increased when FGR is complicated by A/REDV or other comorbidities or risk factors. (GRADE 2C)

Recent studies have questioned the value of BPP in fetal surveillance of high-risk pregnancies, including early-onset severe FGR, due to a high prevalence of false-positive and false-negative results. While fetal deterioration has been reported to be independently reflected by Doppler and BPP testing, further studies are required to prove the usefulness of BPP or of combining these testing modalities.

Amniotic fluid volume abnormalities do not independently increase the risk for adverse outcomes in FGR.

 There is currently a paucity of data on the role of amniotic fluid volume measurement in FGR management and delivery. However, current guidelines on medically indicated late-preterm and early-term deliveries suggest delivery between 34 weeks 0 days and 37 weeks 6 days of gestation for FGR associated with oligohydramnios.

The decision for delivery in FGR is driven by fetal and maternal factors. Fetal factors include EFW, gestational age, and findings on fetal surveillance. Maternal factors include the presence of comorbidities, such as hypertension.

The evidence supporting the timing of delivery in pregnancies with FGR and abnormal umbilical artery Doppler but without AEDV/REDV is limited. 

We recommend delivery at 37 weeks of gestation in pregnancies with FGR and an umbilical artery Doppler waveform with decreased diastolic flow (S/D, RI, or PI greater than the 95th percentile) but without AEDV/REDV or with severe FGR with EFW less than the 3rd percentile. (GRADE 1B)

Neonatal morbidity and mortality rates associated with AEDV are higher than rates of complications of prematurity at 33 to 34 weeks of gestation.

we recommend delivery at 33 to 34 weeks of gestation for pregnancies with FGR and AEDV. (GRADE 1B) 

In the presence of REDV, neonatal morbidity and mortality rates are higher than complications of prematurity at 30 to 32 weeks of gestation.

we recommend delivery at 30 to 32 weeks of gestation for pregnancies with FGR and REDV. (GRADE 1B) We suggest delivery at 38 to 39 weeks of gestation with FGR when the EFW is between the 3rd and 10th percentile and the umbilical artery Doppler is normal. (GRADE 2C)

Growth-restricted fetuses, particularly those with AEDV/REDV, are at an increased risk for decelerations in labor, emergency cesarean delivery, and metabolic acidemia at delivery. 

We suggest that for pregnancies with FGR complicated by AEDV/REDV, cesarean delivery should be considered based on the entire clinical scenario. (GRADE 2C)

We recommend antenatal corticosteroids if delivery is anticipated before 33 weeks 6 days of gestation or for pregnancies between 34 weeks 1 days and 36 weeks 6 days of gestation in women without contraindications who are at risk of preterm delivery within 7 days and who have not received a prior course of antenatal corticosteroids. (GRADE 1A) We also recommend magnesium sulfate for fetal and neonatal neuroprotection for women with pregnancies that are less than 32 weeks of gestation. (GRADE 1A)

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8.Blue NR, Yordan JMP, Holbrook BD, Nirgudkar PA, Mozurkewich EL. Abdominal Circumference Alone versus Estimated Fetal Weight after 24 Weeks to Predict Small or Large for Gestational Age at Birth: A Meta-Analysis. Am J Perinatol 2017;34:1115-24.

9.Caradeux J, Martinez-Portilla RJ, Peguero A, Sotiriadis A, Figueras F. Diagnostic performance of third-trimester ultrasound for the prediction of late-onset fetal growth restriction: a systematic review and meta-analysis. Am J Obstet Gynecol 2019;220:449-59.e19.

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11.Blue NR, Beddow ME, Savabi M, Katukuri VR, Chao CR. Comparing the Hadlock fetal growth standard to the Eunice Kennedy Shriver National Institute of Child Health and Human Development racial/ethnic standard for the prediction of neonatal morbidity and small for gestational age. Am J Obstet Gynecol 2018;219:474.e1-.e12.

12.Blue NR, Savabi M, Beddow ME, et al. The Hadlock Method Is Superior to Newer Methods for the Prediction of the Birth Weight Percentile. J Ultrasound Med 2019;38:587-96.

13.Monier I, Ego A, Benachi A, Ancel PY, Goffinet F, Zeitlin J. Comparison of the Hadlock and INTERGROWTH formulas for calculating estimated fetal weight in a preterm population in France. Am J Obstet Gynecol 2018;219:476.e1-.e12.

14.Figueras F, Caradeux J, Crispi F, Eixarch E, Peguero A, Gratacos E. Diagnosis and surveillance of late-onset fetal growth restriction. Am J Obstet Gynecol 2018;218:S790-S802.e1.

15.Dall'Asta A, Brunelli V, Prefumo F, Frusca T, Lees CC. Early onset fetal growth restriction. Matern Health Neonatol Perinatol 2017;3:2.

16.Unterscheider J, Daly S, Geary MP, et al. Predictable progressive Doppler deterioration in IUGR: does it really exist? Am J Obstet Gynecol 2013;209:539.e1-7.

17.Savchev S, Figueras F, Cruz-Martinez R, Illa M, Botet F, Gratacos E. Estimated weight centile as a predictor of perinatal outcome in small-for-gestational-age pregnancies with normal fetal and maternal Doppler indices. Ultrasound Obstet Gynecol 2012;39:299-303.

18.Bocca-Tjeertes I, Bos A, Kerstjens J, de Winter A, Reijneveld S. Symmetrical and asymmetrical growth restriction in preterm-born children. Pediatrics 2014;133:e650-6.

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20.Gülmezoglu AM, Hofmeyr GJ. Bed rest in hospital for suspected impaired fetal growth. Cochrane Database Syst Rev 2000;1996:Cd000034.

21.Khoury J, Henriksen T, Christophersen B, Tonstad S. Effect of a cholesterol-lowering diet on maternal, cord, and neonatal lipids, and pregnancy outcome: a randomized clinical trial. Am J Obstet Gynecol 2005;193:1292-301.

22.Mori R, Ota E, Middleton P, Tobe-Gai R, Mahomed K, Bhutta ZA. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev 2012:Cd000230.

23.Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev 2015:Cd004736.

24.American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol 2018;132:e44-e52.

25.Lees C, Marlow N, Arabin B, et al. Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Ultrasound Obstet Gynecol 2013;42:400-8.

26.An G, Lin Y, Xu LP, et al. Application of chromosomal microarray to investigate genetic causes of isolated fetal growth restriction. Mol Cytogenet 2018;11:33.

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 A challenge in the prenatal management of FGR is differentiating the constitutionally small fetus with a normal neonatal outcome from one who is pathologically growth restricted and at risk for postnatal complications.

Summary of Society for Maternal-Fetal Medicine (SMFM) Consult Series #52: Diagnosis and management of fetal growth restriction

Since the 1900s, based on the belief that activity restriction results in uterine quiescence and increased blood flow to the uterus, obstetrical care providers have recommended activity restriction to prevent preterm birth (PTB), and it remains a common intervention for PTB prevention in multiple clinical settings (Table 1). 

Restriction of activity is also used in management of pregnancy complications such as preterm premature rupture of membranes (PPROM), gestational hypertension, preeclampsia, fetal growth restriction (FGR), placenta previa, threatened miscarriage, and complications of multiple gestations. Activity restriction has been prescribed in nearly 20% of all pregnancies at risk for PTB.

Survey data from 2009 demonstrated that over 80% of maternal-fetal medicine subspecialists recommended activity restriction in women with cervical dilation, threatened preterm labor, and PPROM.

A growing body of literature suggests that activity restriction fails to provide benefit, and in fact, confers significant physical and psychosocial risks for pregnant women, including deconditioning, inadequate maternal weight gain and lower infant birth weight, bone loss, increased risk of thromboembolic events, and significant financial costs and maternal stress. 

The American College of Obstetricians and Gynecologists (ACOG) and other obstetric experts do not recommend the prescription of activity restriction and specifically "bed rest" for the prevention or treatment of preterm labor.

Nevertheless, activity restriction continues to be commonly recommended by obstetricians and maternal-fetal medicine subspecialists.

What is the definition of activity restriction in pregnancy?

One of the difficulties in determining the benefits and harms associated with activity restriction is that no standard definition exists for this term. The terms "bed rest" and "activity restriction" are often used synonymously but may denote significantly different levels and intensity of activity. "Activity restriction" is typically used as a general term to describe some form of reduction in normal activity, while "bed rest" is usually considered the most restricted form of activity restriction. 

Bed rest has been variously defined in research studies as limited ambulation of not more than 1 to 2 hours per day with bathroom use and bathing permitted

; confinement to bed with bathroom use permitted

; or resting three times a day for 1 hour.

Additional restrictions of activity may include pelvic rest and cessation from exercise, heavy lifting, and employment. Pelvic rest has been variously defined as refraining from placement of anything in the vagina, with or without cessation of sexual intercourse and other sexual activities (such as orgasm).

In addition to the lack of a standard definition, there are no universally accepted objective measurements for activity restriction. Measures of activity restriction used in most studies are based on patient report in which subjects may be asked to keep a diary of their activity to quantify data. 

The lack of objective measurements, such as heart rate or electronic activity monitoring, complicates the interpretation of research data and further limits the quality of available evidence.

What is the evidence regarding the benefits of activity restriction to prevent PTB in women with singleton pregnancies?

Two randomized clinical trials (RCTs) conducted by Elliott et al7 and Hobel et al8 found no differences in the rates of PTB in women who were prescribed activity restriction during pregnancy and those who were not prescribed this intervention. In addition to the lack of defined objective measurement of activity restriction, these two trials are limited by additional factors, including insufficient detail about methodology, absence of baseline characteristics of some of the study participants, and inclusion of both singleton and multiple gestations.

Some evidence suggests harm resulting from activity restriction. A secondary analysis of the Maternal-Fetal Medicine Unit (MFMU) Preterm Prediction Study9 found that women who were assessed as being at increased of PTB at 23 to 24 weeks of gestation and who were prescribed activity restriction were twice as likely to have a preterm delivery than those who were not prescribed activity restriction. 

Study limitations included a lack of a consistent definition of activity restriction, absence of information regarding patient compliance with activity restriction, and the possibility that it was primarily the women at the highest risk for PTB who were prescribed activity restriction.

In a secondary analysis of a trial of nulliparous women with singleton gestations and cervical length less than 30 mm who were randomized to treatment with 17-α hydroxyprogesterone caproate or placebo, Grobman and colleagues 20 found that PTB at less than 37 and less than 34 weeks of gestation was more common when women were placed on any type of activity restriction, whether inpatient or outpatient. 

After controlling for potential confounders, they found an increase in the risk of delivery at less than 37 weeks of gestation and at less than 34 weeks of gestation (aOR 2.28, 95% CI 1.36–3.80) in women placed on activity restriction.

A small pilot study used quantitative methods to study the effect of maternal activity on the rate of PTB.

 In this study, 49 pregnant women assessed as high risk for PTB wore a smart band activity tracker continuously for a week between 24 and 32 weeks of gestation. 

The primary outcome was the rate of PTB at less than 37 weeks of gestation, and a secondary outcome was the rate of PTB at less than 34 weeks of gestation. 

In all, 37 of the participants delivered preterm, and 12 delivered at 37 weeks of gestation or later. The median number of steps per day was significantly lower in participants who delivered preterm. In addition, regression analyses found an inverse association between the number of median steps per day and PTB.

In summary, although the evidence is limited and the quality generally low, available data do not demonstrate a benefit of activity restriction in women at risk for PTB, and some data suggest that this approach increases the risk of PTB. 

We recommend against the routine use of activity restriction in pregnant women at risk for PTB based on preterm labor symptoms, arrested preterm labor, or shortened cervix. (GRADE 1B)

What is the evidence regarding the benefits of activity restriction in women with hypertension, PPROM, multiple gestations, and FGR?

In addition to prevention of PTB, management of hypertensive disorders of pregnancy, PPROM, multiple gestation, and FGR are common reasons for antepartum hospital admission and frequently lead to a recommendation for activity restriction. 

With regard to hypertensive disorders, it has been hypothesized that activity restriction might result in a decrease in systolic blood pressure and an improvement in placental perfusion. 

At present, the evidence regarding use of activity restriction for the prevention or management of hypertensive disorders in pregnancy is too limited to inform recommendations.

Women with PPROM are typically managed with inpatient admission and are also placed on activity restriction or bed rest in an attempt to prolong gestation and prevent umbilical cord prolapse. However, we identified no studies examining the effects of this practice on pregnancy outcomes.

Inpatient bed rest in mid- to late gestation was once recommended routinely for women with multiple gestations. A 2010 Cochrane review12 identified 7 RCTs that included 713 women assigned to routine inpatient bed rest versus hospitalization only if complications developed. 

These trials did not demonstrate any difference in the rates of PTB or perinatal mortality. The only detectable benefit of hospital bed rest was a decrease in the number of neonates born weighing less than 2500 g. 

A later Cochrane review in 201713 investigated the effect of strict bed rest (defined as resting in bed as much as possible with minimal physical activity) or partial bed rest (defined as rest for a few hours during the day with no other physical activity restrictions) in the hospital versus routine care on perinatal outcomes in women with a multiple gestation and found no differences in the risk of very PTB, perinatal mortality, low birth weight, small-for-gestational-age (SGA) infants, or PPROM. 

Similar findings were noted for partial bed rest. While strict bed rest was associated with a higher mean birth weight, it was not associated with a decrease in SGA infants.

A few studies have examined maternal outcomes in women with multiple gestations on activity restriction, such as weight gain and indicators of mental health status. Maloni and colleagues found that maternal stressors, symptomatic side effects, and depressive symptoms were all increased, and maternal weight gain was suboptimal in patients placed on hospital bed rest.

We recommend against the use of routine inpatient hospitalization and activity restriction for the prevention of PTB in women with multiple gestations. (GRADE 1A)

FGR is often attributed to placental insufficiency, and activity restriction or bed rest is often prescribed to improve placental perfusion. 

However, a Cochrane review15 found only a single RCT that allocated women with growth-restricted fetuses to either bed rest in the hospital or work restriction at home (no subjects were allocated to normal activity). No differences were found in infant birth weight, Apgar scores, cord pH, or operative delivery rate. 

Given the lack of data definitively demonstrating that activity restriction improves perinatal outcome in pregnancies complicated by FGR, PPROM, or hypertensive disease of pregnancy, coupled with evidence of adverse effects of activity restriction, we suggest that activity restriction not be prescribed for treatment of pregnancies complicated by FGR, PPROM, or hypertensive disease. (GRADE 2B)

What are the potential maternal risks of activity restriction?

Obstetric care providers frequently recommend activity restriction due to a perception that activity restriction has little associated harm. Studies in nonpregnant adults have revealed that clinically significant physiologic changes affecting multiple organ systems occur after only a few days of immobility (Table 2).

In nonpregnant adults, lying supine during strict activity restriction shifts the position of the internal organs. 

The abdominal viscera are displaced upwards against the diaphragm, which increases the effort required by the inspiratory muscles, decreases oxygen inspiration, and ultimately impairs gas exchange. 

Furthermore, cardiovascular and physical deconditioning occur in addition to muscle atrophy and a prolonged decrease in cardiac output. 

Resumption of physical activity is often difficult and impaired. Following several weeks of bed rest, there is a decrease in metabolism and appetite, as well as skin breakdown, nerve compression, and shifts in hormone levels, including cortisol, thyroid hormone, and aldosterone. 

Alterations in hormonal levels can affect sleep cycles and lead to insomnia and can also impair the function of the immune system.

Several studies in the pregnant population have reported similar adverse effects of prolonged inactivity. Pregnant women are also affected by physical deconditioning and loss of muscle mass. 

One study examined muscle metabolism in the gastrocnemius muscle after prolonged antepartum inactivity and identified impairment of oxygenation indicative of deconditioning.

Postpartum, women had protracted symptoms of deconditioning, including muscle soreness and impaired mobility. Similarly, inactivity in pregnancy has been shown to impair maternal weight gain. In one study, inadequate weight gain was correlated with low fetal birth weight across all gestational ages.

RCTs are needed to compare women with high-risk pregnancies who are ambulatory with those on bed rest to analyze the extent to which bed rest, underlying maternal-fetal disease, or both contribute to inadequate maternal weight gain and poor intrauterine growth.

As in nonpregnant adults, prolonged inactivity in pregnant women is associated with negative effects on bone health. Studies of pregnant women treated with strict bed rest found an increased rate of trabecular bone loss19 and an increase in bone resorption markers, one of which continued to increase gradually over time and persisted into the postpartum period.

Evidence suggests that inpatient activity restriction is associated with higher rates of gestational diabetes mellitus (GDM) among women admitted to the hospital for antepartum management of pregnancy-related complications.

One retrospective study found that the risk of GDM increased by 4% for every day a pregnant woman remained on the inpatient unit. While data in pregnancy are limited, elevated blood glucose levels have been well documented in nonpregnant patients placed on activity restriction.

Another serious concern with prolonged bed rest is the potential increased risk of thromboembolic events. 

In general, inactivity increases the risk for venous thromboembolism (VTE), which is compounded by the hypercoagulable state of pregnancy. In one study, Kovacevich et al found a significant increase in the risk of thromboembolic events in pregnant women treated with bed rest lasting 3 days or more compared with those not on bed rest (15.6 cases per 1000 women vs 0.8 cases per 1000 women; 

What are the psychosocial effects of activity restriction?

Activity restriction in pregnancy can also cause significant emotional and psychological distress. 

Compared with women with uncomplicated pregnancies, high-risk women on bed rest have more anxiety and depression. The negative psychosocial effects of bed rest are apparent with both inpatient and outpatient management, although hospitalized patients are known to have more sources of stress.

In particular, the extended time in bed can result in negative feelings, perseveration, and excessive worrying that can manifest as somatic symptoms. Women reported anxiety about the threat of losing their unborn child, guilt about separation from other children and loved ones, and concern for loss of employment or financial stability. The loss of wages can lead to significant financial concerns and is often a major source of stress for women.

Many women who are placed on hospitalized bed rest express frustration and anger resulting from a lack of control or the perception that hospitalization confers minimal clinical benefit. Bed rest can also be associated with family disruption, leading to emotional stress for the spouse and other children. Separation from one's family has been shown to be the most significant stressor for some women.

Social support from family, friends, and professionals is an important mediator of stress and depressive symptoms. Strain on these relationships compromises an important coping mechanism.

Little evidence supports the routine use of activity restriction for preterm birth and other obstetric conditions, and some data indicate adverse impact on obstetric outcomes. In addition, prolonged inactivity is associated with a variety of negative physiological and psychological effects (Table 3). 

Given the lack of data definitively demonstrating that activity restriction improves perinatal outcome, coupled with evidence of adverse effects, we suggest that activity restriction should not routinely be prescribed.

For more on activity restriction, read Dr. Spong's editorial from the September issue of 

1. Kovacevich GJ, Gaich SA, Lavin JP, Hopkins MP, Crane SS, Stewart J, et al. The prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment for premature labor or preterm premature rupture of membranes. 

2. Sprague AE. The evolution of bed rest as a clinical intervention. 

Little evidence supports the routine use of activity restriction for preterm birth and other obstetric conditions, and some data indicate adverse impact on obstetric outcomes. 

Joseph Biggio, MD, MS

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