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Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145

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Seminars in Fetal & Neonatal Medicine


journal homepage: www.elsevier.com/locate/siny

Interventions to prevent stillbirth


Jessica M. Page, Robert M. Silver*
University of Utah School of Medicine, Salt Lake City, UT, USA

a b s t r a c t
Keywords: Stillbirth is one of the most distressing complications of pregnancy and still occurs far too frequently. The
Stillbirth rate of stillbirth has been decreasing worldwide but room for improvement remains even in high-income
Fetal death
countries. Risk factors for stillbirth have been identified in an effort to detect those women at increased
Preterm birth
risk. However, risk factors are non-specific and do not identify most stillbirths. Strategies employed to
screen the general population such as assessment of fetal activity, fetal growth screening and biomarkers
have also been used to identify increased risk for stillbirth. As with clinical risk factors, these methods are
non-specific. Interventions to prevent stillbirth include antenatal testing of high-risk women, ultraso-
nographic assessments of fetal growth and Doppler velocimetry as well as iatrogenic preterm or term
delivery. Additional research into the role of these interventions and better identification of those at high
risk for stillbirth will help to achieve further stillbirth reduction.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction other high-income countries have been able to substantially reduce


their stillbirth rates, even with relatively low rates to begin with.
Stillbirth affects 2.6 million pregnancies annually throughout For example, the annual rate reduction in stillbirths at >28 weeks
the world, and remains far too frequent at a rate of 18.4 per 1000 between 2000 and 2015 was as high as 6.8% in the Netherlands
deliveries [1]. However, this only accounts for deliveries after 28 with a rate of 1.8 per 1000 births. In contrast, the rate reduction in
weeks of gestation. If pregnancies reaching 20 weeks are included, the USA was 0.4% and in the UK 1.4% [4] (Fig. 1). These data un-
this rate would likely be far exceeded. derscore the potential for further reduction, even in high-income
The stillbirth rate in high-income countries has decreased countries. If all high-income countries achieved the same still-
rapidly over the last one hundred years with rates as high as 60 per birth rates as the best-performing six countries (<2 per 1000
1000 deliveries to fewer than 10 by the year 2000 [2]. Much of this births), then more than 20,000 lives would be saved each year.
success is due to improvements in intrapartum care with skilled This chapter reviews strategies used to prevent stillbirth in
birth attendants and effective antibiotics to treat infection. More high-income countries. Although stillbirth reduction in low-
recently, advances in the care of diabetes, hypertension and Rhesus resource settings is critical, the topic is beyond the scope of this
alloimmunization have substantially improved outcomes in high- review. Here we place an emphasis on targeted populations at
income countries. Although these successes should be celebrated, increased risk for stillbirth as well as a discussion of tactics aimed at
many potentially preventable stillbirths occur, even in high-income low-risk pregnancies. We focus on evidence-based approaches and
countries. For example, stillbirth occurs in 5.96 per 1000 deliveries highlight knowledge gaps.
(about 23,595 stillbirths annually) in the USA [3]. Stillbirth rates
28 weeks of gestation are 3 per 1000 for the USA and 2.9 per 1000
for the UK [4]. These rates are considerably higher than in many 2. Identification of pregnancies at risk for stillbirth
other countries with comparable resources [1,4] (Fig. 1). Moreover,
Most efforts to reduce stillbirth involve the identification of
pregnancies at increased risk. Many maternal characteristics are
associated with an elevated chance of stillbirth. Examples include
* Corresponding author. Department of Obstetrics and Gynecology, University of
Utah School of Medicine, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132,
African-American race, obesity, advanced maternal age (aged >35
USA. years), tobacco use, chronic hypertension and pre-gestational dia-
E-mail address: bsilver@hsc.utah.edu (R.M. Silver). betes [5e13].

http://dx.doi.org/10.1016/j.siny.2017.02.010
1744-165X/© 2017 Elsevier Ltd. All rights reserved.
136 J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145

Fig. 1. Annual rate reduction and overall stillbirth rate per 1000 deliveries by country. (Reproduced with permission from Flenady V, Wojcieszek AM, Middleton P et al. Stillbirths:
recall to action in high-income countries. Lancet 2016;387:691e702.)

It is important to distinguish between risk factors for, and causes frequently (e.g. obesity or advanced maternal age) and are non-
of, stillbirth. Risk factors are conditions that are often present in live specific predictors for stillbirth. In many cases, the reason(s) for the
births and do not always lead to stillbirth. In some cases they occur association between the risk factor and stillbirth remains uncertain.
J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145 137

3. High-risk population screening by three-fold, gestational hypertension by 30%, and pre-eclampsia


by 60% [14].
3.1. Maternal demographics Numerous other maternal medical conditions are associated
with stillbirth. Many lead to hypertensive disorders of pregnancy
Increasing maternal age is associated with an increasing risk of and placental insufficiency such as chronic renal disease, systemic
stillbirth in a “dose-dependent” fashion; the older the woman, the lupus erythematosus, and antiphospholipid syndrome (APS).
greater the risk of stillbirth [12,14]. Typically, the risk is increased in Others such as certain maternal cardiac disorders may lead to
women aged 35 years compared to those aged 20e34 years stillbirth via severe maternal illness and decreased uterine blood
[8,14,15]. The association between advanced maternal age and flow. As with diabetes and hypertension, good prenatal and intra-
stillbirth persists, even after controlling for genetic abnormalities partum care can greatly reduce the risk of stillbirth in women with
and co-morbid medical conditions (such as hypertension and dia- other medical complications.
betes). The mechanism for stillbirth in these women is unknown.
This cohort is of particular interest as the rate of pregnancy in 3.3. Potentially modifiable risk factors
women 35 years has been increasing. From 1990 to 2009 the
pregnancy rate for women aged 35e39 years increased from 57 to Maternal obesity, defined as pre-pregnancy body mass index
77 per 1000 women and for women aged 40e44 years increased (BMI) > 30 kg/m2, represents a major and potentially modifiable
from 11 to 19 per 1000 women in the USA [16]. Given this emerging risk factor for stillbirth. In the USA the prevalence of obesity is
trend it is important to identify methods to decrease the incidence increasing: in 2014, 38.3% of women were obese including 34.4% of
of stillbirth in this group. women aged 20e39 years of age [22]. Obesity increases the risk of
Non-Hispanic black race also is a consistent risk factor for hypertensive disorders and diabetes. However, even when con-
stillbirth. In 2013 in the USA the stillbirth rate was 10.53 per 1000 trolling for these factors, there is a significant association between
for non-Hispanic black compared to 4.88 per 1000 for non-Hispanic increasing BMI and stillbirth [5,14]. Obesity confers a 1.3-fold
white women [3]. This two-fold increase in the risk of stillbirth for increased risk of stillbirth compared to that observed in normal
non-Hispanic black women persists at all gestational ages and after weight women [9]. Another study found an adjusted odds ratio of
controlling for other potential confounders including co-morbid 3.1 for stillbirth in pregnancies affected by obesity when controlling
conditions and access to medical care [12,17]. Racial and ethnic for associated co-morbidities and social factors [13,23]. The still-
disparity for stillbirth also has been noted in other high-income birth risk associated with maternal obesity is relatively weak earlier
countries [18]. in gestation, but stronger in term and postdates pregnancies
Several other demographic factors are associated with stillbirth. [13,24].
These include low maternal education, low socio-economic status, Maternal substance abuse including tobacco has also been
and suboptimal prenatal care [12,14,19]. A complete discussion of associated with stillbirth. Several studies have shown that maternal
these risk factors is beyond the scope of this chapter as they lie smoking is associated with a 30e250% increased risk of stillbirth
outside interventions which can be delivered by maternity care. [12,14,25]. In general there is a doseeresponse relationship [14,26].
However, their effect should not be overlooked. Zietlin et al. esti- Importantly, one study that measured maternal serum cotinine as
mated that 25% of stillbirths would not have occurred if stillbirth an objective measure of smoking noted an association between
rates for all women were the same as for women with post- levels associated with secondary smoke exposure and stillbirth
secondary education in their country [19]. [26]. It has been difficult to precisely assess the relationship be-
tween alcohol, illicit drugs, and stillbirth. Nonetheless, a recent
3.2. Maternal medical conditions study that measured drug exposure in umbilical cord segments
noted a weak association between marijuana and stillbirth,
Maternal medical conditions such as diabetes mellitus were although it is difficult to be sure due to confounders such as
some of the first recognized risk factors for stillbirth. Type 1 or 2 smoking [26].
pre-gestational diabetes is present in ~3e5% of pregnancies and
imparts an approximately two-fold increase in the risk for stillbirth 3.4. Clinical risk factors
when controlling for other confounders [5,9]. The pathophysiology
leading to fetal death is uncertain but in some cases may involve One of the strongest risk factors for stillbirth is a prior stillbirth.
the association between diabetes and malformations. Smith et al. Women with a previous stillbirth have an approximately 2e10-fold
noted that ~20% of fetal losses associated with diabetes had increased risk of a subsequent stillbirth [27,28]. The degree of risk
structural anomalies in a large cohort in the UK [13]. In addition, of a subsequent stillbirth is multifactorial, and is influenced by the
poor glycemic control, fetal macrosomia, and fetal growth restric- circumstances of the prior loss and maternal characteristics such as
tion are associated with stillbirth in the setting of diabetes [20]. age and race/ethnicity. Goldenberg and colleagues studied a group
Diabetes represents an important target for identification and of 95 women with a prior stillbirth between 13 and 24 weeks and
treatment in pregnancy as the incidence in the USA has increased found that 5% of this group experienced a stillbirth in the subse-
from 6.9 to 12.1 per 1000 adults from 1980 to 2014. A considerable quent pregnancy [29]. Another study by Sharma et al. found that
proportion of this population (3.2 per 1000) is of childbearing age, women with a previous stillbirth had a significantly higher rate of
and, most importantly, rates of stillbirth decrease substantially fetal loss in the subsequent pregnancy at 22.7 per 1000 vs 4.7 per
with modern obstetric management including excellent glycemic 1000, respectively. In subanalysis, this group found a 10-fold risk of
control, antenatal testing and delivery prior to 40 weeks of gesta- early stillbirth (20e28 weeks) and a 2.5-fold risk of late stillbirth
tion [16,20]. [30]. The Stillbirth Collaborative Research Network (SCRN) also
Hypertensive disorders affect 7e10% of pregnancies. Chronic found that women with a history of previous stillbirth had an
hypertension, gestational hypertension and pre-eclampsia are a adjusted odds ratio of 5.91 for recurrent stillbirth [12].
likely cause of death in ~10% of antepartum stillbirths [21]. Mothers Several other clinical risk factors are associated with stillbirth.
with hypertension are at an increased risk of placental insuffi- Multiple gestations, especially higher-order multiple gestations
ciency, fetal growth restriction, and placental abruption [5,14]. Pre- and monoamniotic or monochorionic twins, are at very high risk
existing hypertension is estimated to increase the risk of stillbirth [31]. The risk of stillbirth also is increased with a short inter-
138 J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145

pregnancy interval (<18 months) [32]. Finally, placental abruption as an early biochemical marker for placental dysfunction and thus
in the index pregnancy increases the risk of stillbirth by more than stillbirth [27,43]. The First and Second Trimester Estimation of Risk
10-fold [33]. (FASTER) trial found that patients with a PAPP-A level less than the
5th percentile were more likely to experience pregnancy loss after
4. General population screening 24 weeks of gestation with an adjusted odds ratio of 2.15. However,
the positive predictive value for stillbirth after 24 weeks of gesta-
4.1. Decreased fetal movement tion with PAPP-A <5% was low at 58% [44]. A meta-analysis of
biochemical predictors of stillbirth also identified PAPP-A as a
Decreased fetal movement is perceived by some women prior to promising marker for stillbirth. This group found that levels of
stillbirth [34]. A survey of 1714 women with stillbirth found that PAPP-A <0.4 multiples of the median (MoM) had a pretest proba-
63% perceived a decrease or change in fetal movement [35]. bility of 1.75% for antepartum stillbirth due to placental abruption
Although most women with decreased fetal movement do not have or growth restriction versus a value of 0.13% with a normal PAPP-A
stillbirth, it is estimated that women with stillbirth are four times [43]. Again, this low predictive value limits its utility for the iden-
more likely to experience decreased movement than those with tification of pregnancies at risk for stillbirth. A recent Cochrane
live birth [34]. A prospective study found that maternal perception review examined randomized controlled trials of biochemical
of decreased fetal activity was predictive of poor perinatal outcome markers for placental dysfunction including estrogen and human
in 22% of cases [36]. Another group compared women with still- placental lactogen. This review included three studies and there
birth >28 weeks of gestation to those without and examined their was no evidence that use of these biochemical markers was pre-
perception of fetal movement. They found that a perception of dictive of stillbirth or other adverse perinatal outcomes [45]. A
decreased fetal movement had an odds ratio of 2.37 for stillbirth review of 11 studies that assessed maternal serum alpha-
[37]. Nonetheless, monitoring fetal movement is an attractive fetoprotein (AFP) as a second-trimester marker for stillbirth iden-
strategy to potentially prevent stillbirth. tified an increased risk of fetal death in patients with high AFP
levels. An AFP level of 2.5 MoM correlating to the 97th percentile
4.2. Fetal growth restriction imparted a relative risk ranging from 4.4 to 21.0 for stillbirth. A
review by Reddy further discusses the nuances of the use of
Fetal growth restriction (FGR) also is an important clinical risk biochemical markers for prediction of stillbirth [27].
factor for stillbirth. FGR is defined in many regions as an estimated None of the biomarkers currently available serve as high-quality
fetal weight less than the 10th percentile for gestational age [39]. screening tests for placental insufficiency or stillbirth. Most are
FGR should be considered as a risk factor for placental insufficiency used clinically for other purposes such as screening for genetic
and stillbirth rather than as a “disease” since up to 70% of FGR fe- abnormalities. However, the potential for biomarkers as a means to
tuses are constitutionally small [40]. Constitutionally small fetuses identify pregnancies at high risk for stillbirth remains. This is
are those that are <10% weight based on the general population but currently an intensive ongoing area of investigation, and assess-
of “normal” size for them, with no evidence of placental insuffi- ment of placental genes and proteins may ultimately be useful for
ciency and no increased risk of obstetric complications [40]. This is stillbirth prediction [46].
expected since 10% of any “normal” population will be <10% in
weight. FGR is often further characterized as symmetric or asym- 5. Interventions to reduce stillbirth
metric. This symmetry refers to the relative size of the head versus
the abdomen, with asymmetric growth restriction representing Few interventions have been shown to reduce the risk of still-
fetuses with a normal head size and small abdominal circumfer- birth. For some medical conditions, appropriate medical care can
ences. Placental insufficiency is thought to result in asymmetric improve outcomes and reduce the risk of stillbirth. Examples
growth restriction with preferential supply of blood to the fetal include diabetes, hypertension, and APS. In addition, some medi-
head, thus resulting in a small abdomen. However, this is not an cations such as low-dose aspirin may improve placental function
absolute rule and symmetric growth restriction can also indicate and decrease the odds of fetal death. Antenatal surveillance such as
placental insufficiency [41]. To better characterize a patient's risk of non-stress tests also can reduce the risk of stillbirth. However, such
placental insufficiency, additional measures such as amniotic fluid tests are costly, inconvenient and prone to false-positive results,
assessment, Doppler velocimetry, and non-stress tests or bio- which may lead to iatrogenic morbidity. Thus, they are typically
physical profiles can be used. The Stillbirth Collaborative Research reserved for pregnancies at high risk of stillbirth. Finally, delivery of
Network examined the impact of growth restriction on the risk of the infant, sometimes prior to term, is an invaluable tool for the
stillbirth and found that FGR was associated with an odds ratio of reduction of stillbirth. Although this strategy is effective the risk of
3.0e4.7 for stillbirth (depending upon how FGR was defined) [42]. morbidity (and even mortality) due to preterm birth must be
A large part of antenatal care involves screening for FGR. This is weighed against the risk of stillbirth.
typically accomplished by measuring the fundal height during
prenatal visits. If the measurement is less than anticipated, an ob- 5.1. General medical and obstetric interventions
stetric sonogram is performed to exclude possible FGR and
oligohydramnios. Modifiable risk factors should be addressed, ideally prior to
conception. Smoking cessation, weight loss, optimal inter-
4.3. Biomarkers pregnancy interval, etc., should all be encouraged prior to
conception. The chances of multiple gestations, especially higher-
It would be ideal to identify a biomarker that predicts stillbirth order, should be minimized with responsible assisted reproduc-
risk and it has been an active area of investigation. It is especially tive technology (e.g. single embryo transfer for in-vitro fertiliza-
attractive since it could be utilized in pregnancies not identified as tion). Optimal control and management of medical conditions such
“high risk” based on clinical risk factors. Most work has focused on as diabetes, hypertension, systemic lupus erythematosus (SLE), and
measurement of placental proteins as a marker of placental maternal cardiac disease should be achieved. Co-management with
function. medical and/or maternal fetal medicine specialists may be useful in
Pregnancy-associated plasma protein-A (PAPP-A) has been used these cases.
J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145 139

5.2. Medical therapy thus as an indirect marker of uteroplacental function [54]. The
interpretation of oligohydramnios in an otherwise uncomplicated
Medical therapies intended to reduce the risk of stillbirth are pregnancy is somewhat uncertain and management depends on
aimed at improving placental function by improving blood flow or the gestational age at which oligohydramnios is diagnosed. The
decreasing inflammation. Some of the rationale for using these American College of Obstetricians and Gynecologists (ACOG) rec-
approaches is based on data from women with APS. Low-dose ommends that for pregnancies with oligohydramnios at <36
aspirin is the one medical therapy that appears to reduce the risk weeks, measurement of fetal growth and antenatal testing should
of stillbirth in at-risk women. Benefit may be due to reductions in be initiated with delivery at 36e37 weeks or as otherwise indicated
pre-eclampsia, spontaneous preterm birth, FGR, and placental [50].
insufficiency. In a meta-analysis of 40 trials including 33,098 Uterine artery Doppler velocimetry testing aims to identify
women treated with low-dose aspirin, a 14% reduction in fetal or abnormal placental blood flow as a marker for elevated stillbirth
neonatal deaths (40 trials; 33,098 women; relative risk: 0.86; 95% risk. The use of uterine artery Doppler studies is intended to
confidence interval: 0.76e0.98); number needed to treat: 243 (95% identify increased vascular resistance in the placental bed as a
confidence interval: 131e1666) was noted [47]. It is important to result of abnormal trophoblastic invasion of the spiral arteries. In
interpret these data with caution since pre-eclampsia rather than normal placental development, the uterine spiral arteries are
perinatal death was the primary outcome for the trials included in invaded by trophoblast cells causing a shift from a high-to low-
the meta-analysis. resistance system so as to optimize uteroplacental circulation.
In one study, low-molecular-weight heparin greatly reduced the Disorders such as early-onset pre-eclampsia and FGR are associated
chances of composite morbidity including pregnancy loss in with increased resistance to uterine artery blood flow as a result of
women with prior adverse outcomes associated with placental abnormal invasion of the trophoblast into the spiral arteries [55].
insufficiency [48]. However, it has not been effective in subsequent Other placental problems also contribute to abnormal uterine ar-
trials, and benefits remain uncertain [49]. Anti-inflammatory tery studies [55]. In unselected populations, uterine artery Doppler
medications such as prednisolone and hydroxychloroquine have velocimetry has modest predictive value for perinatal death with
been used in women with APS and chronic histocytic intervillositis. sensitivities ranging from 8% to 83% in 15 studies with heteroge-
However, data regarding their use in women without SLE or APS is neous results [56]. Another group performed uterine artery
lacking. Doppler studies in women between 22 and 24 weeks and found
that an elevated pulsatility index greater than 90th percentile had a
5.3. Antenatal testing relative risk of 5.5 for stillbirth attributed to placental causes. Most
of these stillbirths occurred earlier in gestation and were associated
Interventions to detect patients at increased risk of stillbirth with pre-eclampsia or abruption, thus making uterine artery
include antenatal testing with non-stress tests (NSTs), biophysical Doppler more useful for prediction of stillbirth prior to 33 weeks of
profiles (BPPs), amniotic fluid measurement, fetal movement as- gestation rather than maternal clinical characteristics alone.
sessments and Doppler velocimetry. These measures are based on Conversely maternal characteristics were a better predictor for
the concept that the fetal heart rate pattern and motor activity are stillbirth occurring after 33 weeks' [13]. Taken together, these data
affected by fetal hypoxemia and acidemia [50]. They are aimed at show that uterine artery Doppler studies can be helpful in the
identifying pregnancies with placental insufficiency and allowing prediction of stillbirth due to placental causes at early gestational
for delivery prior to stillbirth or irreversible fetal injury. ages, but due to the varied sensitivity of this test its use as a stan-
Non-stress testing entails monitoring of the fetal heart rate for dard assessment of low-risk patients is currently limited. Uterine
20e40 min, and the baseline, variability, and presence or absence of artery Doppler appears to perform better in pregnancies at high
accelerations or decelerations is noted. A reactive fetal heart rate risk for placental insufficiency such as hypertension and FGR [57].
tracing is considered reactive if two fetal heart rate accelerations A major dilemma is which patients should undergo antenatal
(increase by 15 beats/min for 15 s) are noted within a 20 min testing. Benefit has been demonstrated in women with chronic
period. The use of NSTs as a measure of fetal well-being takes into hypertension, gestational hypertensive disorders, pre-gestational
account the neurologic development of the fetus, sleepewake cy- diabetes, FGR, oligohydramnios, monochorionic twins, postdates
cles, maternal medications and other substances that cross the pregnancy, etc. (Box 1). However, there are several populations at
placenta. The ability to obtain a reactive NST improves with increased risk of stillbirth for whom benefits of antenatal testing
increasing gestational age with non-reactive NSTs in up to 50% of are uncertain. Examples include advanced maternal age or obesity
patients between 24 and 28 weeks and 15% between 28 and 32 without other co-morbidities. There is considerable practice vari-
weeks. The chance of obtaining a reactive test in pregnancies <32 ation with regard to antenatal testing in these women and reliable
weeks of gestation is improved by modifying the criteria (acceler- data are lacking regarding the benefits, harms, and cost-
ation threshold of 10 beats/min for 10 s) [50]. Following a reactive effectiveness of antenatal testing. Although of unproven efficacy,
NST the fetal mortality rate in the subsequent week is about 1.9 per most authorities advise antenatal testing in women with prior
1000 births [51]. stillbirth [27].
The biophysical profile expands on the NST with incorporation
of ultrasonographic measurement of fetal movement, tone, 5.4. Obstetric ultrasound
breathing and amniotic fluid. Each component receives a score of 2
and thus is scored out of a total of 10. Scores of 8 or 10 are Ultrasound is the basis for some antenatal testing such as
considered normal, 6 equivocal, and 4 abnormal. A normal BPP is Doppler velocimetry, amniotic fluid volume assessment and bio-
associated with a fetal mortality rate in the following week of 0.8 physical profile. Also and as stated earlier, ultrasound to assess fetal
per 1000. A modified BPP also predicts a fetal mortality rate of 0.8 growth is performed when there is clinical suspicion of FGR. Serial
per 1000 births and combines the use of NST and amniotic fluid sonograms to assess fetal growth also are advised for high-risk
index [51e53]. Assessment of amniotic fluid alone is also a measure conditions such as diabetes, hypertension and SLE. In theory,
of fetal well-being with oligohydramnios defined as a deepest routine third-trimester sonogram (to screen for FGR) could identify
vertical pocket of 2 cm [50]. This approach is based on using fetuses at increased risk for stillbirth. Indeed, a recent large cohort
amniotic fluid volume as a marker for fetal renal blood flow, and study of nulliparous women noted that such screening increased
140 J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145

Box 1 count on a preceding day. This study found a significant decrease in


Indications for antepartum fetal surveillance testing. the incidence of stillbirth in the intervention arm [59]. Another trial
compared women instructed to count fetal movements with
normal defined as at least 10 movements in 10 h to a group without
Maternal conditions specific fetal movement instructions. These investigators found no
difference in fetal mortality between the two arms of the trial [61].
Pregestational diabetes mellitus Given the conflicting results of these studies there is no standard-
Hypertension ized protocol for use of fetal movement assessment in antenatal
Systemic lupus erythematosus care. However, as it is an exceedingly low-cost test, with the po-
Chronic renal disease tential to reduce the incidence of fetal death, most authorities
ntiphospholipid syndrome advise educating women about fetal movement assessment [62].
Hyperthyroidism (poorly controlled) Large ongoing clinical trials including the AFFIRM (can promoting
Hemoglobinopathies (sickle cell, sickle cell-hemoglobin Awareness of Fetal movements and Focusing Interventions Reduce
C, or sickle cellethalassemia disease) fetal Mortality?) study in the UK and the My Baby's Movements
Cyanotic heart disease Study in Australia should resolve the controversy regarding wide-
spread use of screening for decreased fetal movement. Further
details including the relevance of increased fetal movements are
Pregnancy-related conditions supplied by Warland et al. [36].

Gestational hypertension 5.6. Iatrogenic delivery


Pre-eclampsia
Decreased fetal movement Intentional delivery of the fetus is a potentially effective strategy
Gestational diabetes mellitus (poorly controlled or to reduce stillbirth. Intuitively, if the infant is born alive then it
medically treated) cannot suffer a stillbirth. However, this approach, typically under-
Oligohydramnios taken by induction of labor, has several potential drawbacks. The
Fetal growth restriction largest is neonatal medical problems due to preterm birth. As an
Late term or postterm pregnancy approximate rule, the later in gestation (through 39 weeks), the
Isoimmunization lower the risk of complications due to prematurity. Other possible
Previous fetal demise (unexplained or recurrent risk) downsides of induction of labor include loss of autonomy and
Monochorionic multiple gestation (with significant satisfaction for parents regarding their birth experience, and cost.
growth discrepancy) The key to maximizing the effectiveness of this tactic is to estimate
precisely the risk of stillbirth in each case. For example, the risks of
(Reproduced with permission from American College of prematurity at 37 weeks of gestation are assuredly justified if the
Obstetricians and Gynecologists. Antepartum fetal surveil- risk of stillbirth is one in three; by contrast, they are likely not
lance. Practice Bulletin No. 145. Obstet Gynecol justified if the risk is one in 10,000.
2014;124:182e92.) It is important to evaluate gestational age as a continuum with
regard to risks of complications from preterm birth. Although risks
are greatest with decreasing gestational age, there are still
considerable neonatal risks for infants born in the late preterm
detection of small-for-gestational-age fetuses by three-fold [58]. (34e37 weeks) and even near term (37e39 weeks) periods
However, the pros, cons, and cost-effectiveness of routine third- [63e65]. Thus, delivery prior to 39 weeks of gestation is not justi-
trimester sonograms remain to be determined. fied unless the stillbirth risk is elevated over baseline. In general,
the earlier the gestational age, the higher the stillbirth risk needed
5.5. Fetal movement to justify delivery.
Sadly, evidence-based data are lacking regarding the optimal
Fetal movement assessments are a non-invasive and inexpen- gestational age for delivery in most conditions associated with
sive method for determination of fetal well-being. The recom- stillbirth. Few randomized clinical trials have been conducted
mended duration of monitoring and adequate number of fetal regarding optimal timing of delivery and none has stillbirth as its
movement is somewhat varied but in general 10 movements in a primary outcome. This is because it is difficult to have enough
2 h period is considered reassuring [59]. A prospective study of fetal statistical power to assess stillbirth as a primary outcome owing to
movement assessment as an intervention for stillbirth was per- the relative infrequency of the condition in high-income countries.
formed in an unselected group of women over a seven-month This is especially true for women enrolling in trials who are typi-
time-period. These authors compared the fetal mortality rate dur- cally receiving specialized prenatal care.
ing a control period to the rate during an intervention in which Despite these limitations, there are many conditions wherein
patients were instructed to perform fetal movement assessments expert consensus recommends delivery and even preterm birth in
and report for evaluation if fewer than 10 were noted in a 2 h time- order to reduce stillbirth and other neonatal and maternal
frame. They found that the fetal mortality rate was reduced from morbidity and mortality. For example, it is generally accepted that
8.7 to 2.1 per 1000 births with the fetal movement monitoring pregnancies in women with stable chronic hypertension should be
intervention [60]. Two randomized trials investigated the role of delivered at 39 weeks of gestation and those with severe pre-
fetal movement monitoring for the prevention of stillbirth and had eclampsia/gestational hypertension by 34 weeks [66]. Delivery of
conflicting results. The first compared a control group in which pregnancies with pre-eclampsia/gestational hypertension at 37
women were routinely asked about fetal movement at prenatal weeks of gestation is supported by results from the HYPITAT trial
visits to an intervention group in which women were instructed to [67]. Women with these conditions were randomized to delivery at
monitor fetal movement for 1 h three times weekly and present to 37 weeks of gestation or expectant management. Maternal and
their care provider if the count was less than the prior baseline neonatal outcomes were similar in both groups [67].
Table 1
Guidance regarding timing of delivery when conditions complicate pregnancy at or after 34 weeks of gestation.

Condition Gestational agea at delivery Grade of


recommendationb

Placental and uterine issues


Placenta previac 36e37 weeks B
Suspected placenta accreta, increta, or percreta with 34e35 weeks B
placenta previac
Previous classical cesarean (upper segment uterine 36e37 weeks B
incision)c
Previous myomectomy necessitating cesarean deliveryc 37e38 weeks (may require earlier delivery, similar to prior classical cesarean, in situations with more extensive or complicated B

J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145
myomectomy)
Fetal issues
Fetal growth restriction
Singleton 38e39 weeks: B
 Otherwise uncomplicated, no concurrent findings
34e37 weeks: B
 Concurrent conditions (oligohydramnios, abnormal Doppler studies, maternal risk factors, co-morbidity)
Expeditious delivery regardless of gestational age:
 Persistent abnormal fetal surveillance suggesting imminent fetal jeopardy
Twin gestation 36e37 weeks: B
 Dichorionicediamniotic twins with isolated fetal growth restriction
32e34 weeks: B
 Monochorionicediamniotic twins with isolated fetal growth restriction
 Concurrent conditions (oligohydramnios, abnormal Doppler studies, maternal risk factors, co-morbidity) B
Expeditious delivery regardless of gestational age:
 Persistent abnormal fetal surveillance suggesting imminent fetal jeopardy
Fetal congenital malformationsc 34e39 weeks: B
 Suspected worsening of fetal organ damage
 Potential for fetal intracranial hemorrhage (e.g. vein of Galen aneurysm, neonatal alloimmune thrombocytopenia)
 When delivery prior to labor is preferred (e.g. EXIT procedure)
 Previous fetal intervention
 Concurrent maternal disease (e.g. pre-eclampsia, chronic hypertension)
 Potential for adverse maternal effect from fetal condition
Expeditious delivery regardless of gestational age: B
 When intervention is expected to be beneficial
 Fetal complications develop (abnormal fetal surveillance, new-onset hydrops fetalis, progressive or new-onset organ injury)
 Maternal complications develop (mirror syndrome)
Multiple gestations
Dichorionicediamnioticc 38 weeks B
Monochorionicediamnioticc 34e37 weeks B
Dichorionicediamniotic or monochorionicediamniotic If occurs at or after 34 weeks, consider delivery (recommendation limited to pregnancies at or after 34 weeks; if occurs before 34 weeks, B
with single fetal deathc individualize based on concurrent maternal or fetal conditions
Monochorionicemonoamnioticc 32e34 weeks B
Monochorionicemonoamniotic with single fetal deathc Consider delivery; individualized according to gestational age and concurrent complications B
Oligohydramnios e isolated and persistentc 36e37 weeks B
(continued on next page)

141
142
Table 1 (continued )

Condition Gestational agea at delivery Grade of


recommendationb

Maternal issues
Chronic hypertension
No medicationsc 38e39 weeks B
Controlled on medicationc 37e39 weeks B

J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145
difficult to control (requiring frequent medication 36e37 weeks B
adjustments)c
Gestational hypertensiond 37e38 weeks B
Pre-eclampsia
Severec At diagnosis (recommendation limited to pregnancies at or after 34 weeks) C
Mildc 37 weeks B
Diabetes
Pregestational, well controlledc LPTB or ETB not recommended B
Pregestational with vascular diseasec 37e39 weeks B
Pregestational, poorly controlledc 34e39 weeks (individualized to situation) B
Gestational, well controlled on dietc LPTB or ETB not recommended B
Gestational, well controlled on medicationc LPTB or ETB not recommended B
Gestational, poorly controlled on medicationc 34e39 weeks (individualized to situation) B
Obstetric issues
Prior stillbirth e unexplainedc LPTB or ETB not recommended. B
Consider amniocentesis for fetal pulmonary maturity if delivery planned at <39 weeks C
Spontaneous preterm birth
Preterm premature rupture of membranesc 34 weeks (recommendation limited to pregnancies at or after 34 weeks) B
Active preterm laborc Delivery if progressive labor or additional maternal or fetal indication B

EXIT, ex-utero intrapartum treatment; LPTB, late-preterm birth at 340/7 weeks through 366/7 weeks; ETB, early-term birth at 370/7 weeks through 386/7 weeks.
(Reprinted with permission from Spong CY, Mercer BM, D'Alton M et al. Timing of indicated late-preterm and early-term birth. Obstet Gynecol 2011;118:323e33.).
a
Gestational age is in completed weeks; thus, 34 weeks includes 340/7 weeks through 346/7 weeks.
b
Grade of recommendations are based on the following: recommendations or conclusions or both are based on good and consistent scientific evidence (A); limited or inconsistent scientific evidence (B); primarily consensus
and expert opinion (C). The recommendations regarding expeditious delivery for imminent fetal jeopardy were not given a grade. The recommendation regarding severe pre-eclampsia is based largely on expert opinion;
however, higher-level evidence is not likely to be forthcoming because this condition is believed to carry significant maternal risk with limited potential fetal benefit from expectant management after 34 weeks.
c
Uncomplicated, thus no fetal growth restriction, superimposed pre-eclampsia, etc. If these are present, then the complicating conditions take precedence and earlier delivery may be indicated.
d
Maintenance antihypertensive therapy should not be used to treat gestational hypertension.
J.M. Page, R.M. Silver / Seminars in Fetal & Neonatal Medicine 22 (2017) 135e145 143

Similar recommendations are available for other conditions management in nulliparous women at 39 weeks of gestation. The
with increased risk for stillbirth. Women with well-controlled ARRIVE trial is expected to be completed by midelate 2017 and
diabetes and otherwise uncomplicated pregnancies should be should inform the pros and cons of this strategy for stillbirth
delivered at 39 weeks of gestation [68]. However, those with poor prevention.
glycemic control, renal disease, or other complications may benefit
from earlier delivery [68]. Most fetuses with FGR can be expectantly 5.7. Knowledge gaps
managed until there is abnormal fetal testing. The DIGITAT trial
compared induction of labor after 36 weeks of gestation to The ability to better discriminate between pregnancies at high
expectant management with close surveillance in FGR pregnancies and low risk for stillbirth will facilitate stillbirth prevention. This
[69]. Neonatal and maternal outcomes including cesarean rates may include biomarker discovery, clinical risk factors and obstetric
were similar among groups, including infant follow-up at 2 years of imaging, including the fetus and placental function and blood flow.
age [69,70]. The authors concluded that induction at 37 weeks or The Human Placental Project of the NICHD is focused on improved
expectant management until abnormal fetal testing are reasonable assessment of placental function during pregnancy. In turn, this
options [69,70]. Early delivery is indicated in many other conditions will inform which patients benefit from antenatal testing and iat-
including some cases of multiple gestation, abnormal placentation, rogenic delivery. Many studies have focused on first-trimester
previous classical uterine incision, and fetal malformations. They prediction of adverse outcomes but third-trimester markers also
are summarized in an NICHD workshop on the timing of indicated deserve study. The role as well as the best method for assessment of
late preterm and early term birth [71] (Table 1). fetal movement should be determined. Finally, the efficacy of
The optimal gestational age for delivery remains uncertain for therapies to improve placental function warrants investigation.
many conditions. For example, previous analytical models
concluded that women aged 35 years should be delivered at 38 or 6. Summary and clinical recommendations
39 weeks of gestation [72,73]. However, a recent randomized
controlled trial (RCT) showed no difference in outcomes in women A reduction in stillbirth, particularly in high-income countries,
35 years of age who were induced at 39 weeks of gestation has been one of the great success stories in modern obstetrics.
compared to those expectantly managed [74]. These data illustrate However, it is clear that we can do better. Clinicians should be
the limitations of decision analyses as well as RCTs. cognizant of risk factors for stillbirth. Modifiable risk factors should
Some authors have suggested that all pregnancies be delivered be optimized and medical problems treated so that they are stable
at 38 weeks of gestation in hopes of avoiding stillbirths [75]. Indeed or in remission. Antenatal surveillance and serial sonograms should
there is concern that recent public health efforts intended to be performed in at-risk pregnancies such as those with diabetes,
decrease the rate of elective deliveries prior to 39 weeks of gesta- hypertension, FGR, etc. Induction of labor or cesarean delivery
tion (the “39-week rule”) will increase the rate of stillbirth [75]. should be considered at term and even preterm in pregnancies at
One study noted an increase in stillbirths post 38 weeks gestation increased risk for stillbirth.
since the implementation of the 39-week rule [75]. However, this
may be an artifact since the mortality ratio of deaths per ongoing 6.1. Practice points
pregnancy has remained unchanged from 2006 to 2012 [76].
Another US cohort study also noted no increase in term stillbirths  Identification of demographic and clinical risk factors for
from 39-week rule despite reductions in late preterm and early stillbirth.
term births [77]. Similar observations were noted after a quality  Optimization of modifiable risk factors for stillbirth.
improvement initiative in a large health care corporation [78].  Antenatal testing and serial ultrasonographic assessment of at-
There was a reduction in elective deliveries at <39 weeks from 9.6% risk pregnancies.
to 4.3% with a 16% reduction in neonatal intensive care admissions  Delivery at an appropriate gestational age based on risk factors.
and no increase in stillbirth [78]. Further data are needed regarding
this important issue. Meanwhile, clinicians should be reassured
that entirely elective delivery can and should be delayed until 39
6.2. Research directions
weeks gestation without apparent harm. They should also be
cognizant that the 39-week rule applies only to normal pregnancies
 Improved assessment of placental function.
and that there are many sound indications for iatrogenic preterm
 Identification of third-trimester markers for increased stillbirth
birth [71].
risk.
Another approach would involve delivering all women at 39
 Better protocol for fetal movement assessment.
weeks of gestation. This might decrease stillbirths as well as other
 Identification of therapies to improve placental function.
adverse maternal and neonatal outcomes. However, it might lead to
an increase in cesarean delivery, cost, etc. In fact, the two-fold in-
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