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Journal of Perinatology (2010) 30, 305–310 r 2010 Nature Publishing Group All rights reserved. 0743-8346/10 $32 www.nature.com/jp STATE-OF-THE-ART Management of subsequent after an unexplained stillbirth

SJ Robson1 and LR Leader2 1Department of and , Australian National University, Canberra, Australia and 2School of Women’s and Children’s Health, University of New South Wales, Royal Hospital for Women, Randwick, Australia

they face in a subsequent pregnancy, as well as potential Purpose: To review the management of pregnancy after an unexplained management strategies to optimize future pregnancy outcomes.2–4 stillbirth. Unfortunately, as many as one-third of such cases remain Epidemiology: Approximately 1 in 200 will end in ‘unexplained’ and unexplained stillbirth is now the commonest stillbirth, of which about one-third will remain unexplained. Unexplained single contributor to . stillbirth is the largest single contributor to perinatal mortality. There is no evidence that extensive research efforts over the last Subsequent pregnancies do not appear to have an increased risk of two decades have yielded a reduction in the incidence of this 2,5 stillbirth, but are characterized by increased rates of intervention distressing outcome. Virtually all of the published literature is (induction of labor, elective cesarean section) and iatrogenic adverse concerned with population-based strategies for primary prevention outcomes (low birth weight, prematurity, emergency cesarean section and of unexplained stillbirth. However, the commonest situation in post-partum hemorrhage). which clinicians will find themselves is management of women in their next pregnancy after an unexpected unexplained stillbirth. Conclusions: There is no level-one evidence to guide management in Effective care of women in their next pregnancy after an this situation. Pre-pregnancy counseling is very important to detect and unexplained stillbirth presents major management challenges, and correct potential risk factors such as , smoking and maternal there is no level-one evidence available to guide clinicians in this disease. As timely delivery is the mainstay of management, early accurate setting. Although the odds ratio for recurrence of stillbirths from all determination of gestational age is vital. There is controversy regarding causes is almost five,6 studies of pregnancy outcomes subsequent to the pattern of surveillance, but evidence exists only for and not unexplained stillbirth have not reported any increase in the risk of for regular non-stress testing, nor formal charting. There perinatal death.7–10 However, those studies found that pregnancy is an urgent need for more studies in this important area. after stillbirth is characterized by increased rates of induced labor, Journal of Perinatology (2010) 30, 305–310; doi:10.1038/jp.2009.133; elective and emergency cesarean section, and low published online 24 September 2009 birth weight. These adverse outcomes might be at least partly the Keywords: pregnancy; unexplained stillbirth; management; review result of obstetricians having a low threshold for intervention. A study of the management plans in pregnancy after unexplained stillbirth revealed that obstetricians commonly offer induction of Introduction labor and elective cesarean delivery, sometimes as early as 36 11 More than three million babies are stillborn across the world each weeks, irrespective of any other obstetric considerations. In view year, the majority in developing countries.1 Even in developed of the obvious potential for iatrogenic prematurity and maternal nations stillbirth remains a common adverse outcome of complications with these interventions, it is important to minimize pregnancy, affecting about one in 200 pregnancies in countries the risk of another stillbirth while avoiding unnecessary such as the United States and Australia.2 In the majority of cases interventions. diligent investigation will reveal one or more likely causes for a fetal death. Accurate knowledge of the etiology of a stillbirth will Pre-pregnancy then allow the woman and her family to be counseled about risks Different classification systems for stillbirth are used by various Correspondence: Dr SJ Robson, Department of Obstetrics and Gynaecology, Australian population-based perinatal data collections around the world. It is National University, The Canberra Hospital, PO Box 11, Woden, ACT, 2600, Australia. likely that much of the reported geographical variation in the rates E-mail: [email protected] Received 22 February 2009; revised 5 July 2009; accepted 12 July 2009; published online 24 of unexplained stillbirth results from the use of different 12 September 2009 classification procedures. Many coding systems used to classify Pregnancy after unexplained stillbirth SJ Robson and LR Leader 306 stillbirths do not distinguish between cases where no cause of death for stillbirth.26 Obesity is notoriously difficult to manage, and many was found despite thorough investigation, and those where obstetricians feel inadequately prepared to supervise weight incomplete investigation made final diagnosis impossible.13 This normalization programs.27 Treatment of obesity is best managed in latter group, often referred to as ‘unexplored’ stillbirths, are likely a multidisciplinary setting and will take time, as optimal weight to represent a large proportion of unexplained stillbirths.14 loss is about 1 kg per week.28 The issue of importance for clinicians is that couples seeking The other modifiable risk factor for stillbirth is smoking. It pre-pregnancy counseling after ‘unexplained’ stillbirth, actually would be unusual to encounter a woman who is not aware that may have been incompletely investigated. Principles of the smoking is deleterious in pregnancy. Nonetheless, adverse investigation of stillbirth have been reviewed in detail elsewhere.3,4 outcomes in a previous pregnancy do not necessarily motivate It may be useful to describe a previous stillbirth as unexplained but women to cease smoking.29 Again, specialized smoking cessation low recurrence risk (that is, sufficient investigation was performed programs that include support groups and counsellors, combined to exclude all the causes of stillbirth known to be associated with a with the use of replacement therapies, are most likely to risk of recurrence), or unexplained but potentially recurrent (where succeed.30 a lack of information makes it impossible to tell what the risk of Many women will be highly motivated to try for another child recurrence is). after stillbirth, with studies showing that as many as half of all Faced with a woman for whom a previous stillbirth was bereaved couples become pregnant within 6 months.31 Timing of unexplained because of incomplete investigation, it is obviously the next pregnancy is important as women who conceive within 12 impossible to obtain information that would have been provided by months of a perinatal loss have higher rates of and a perinatal , karyotyping of the or examination of the anxiety in their next pregnancy than women who conceive later.32 and membranes. In this situation the next pregnancy is There is evidence that these emotional states can influence best considered ‘high risk’, and before the woman attempts pregnancy outcome: diagnosis and management of maternal pregnancy again maternal conditions associated with an increased anxiety and depression may reduce the risk of preterm birth and risk of adverse pregnancy outcomes should be tested for, including possibly other adverse pregnancy outcomes.33–36 In view of this, , thyroid and chronic renal disease. Other conditions formal assessment of the woman’s (and probably her partner’s) to be excluded include ,15 inherited or acquired level of depression and anxiety to identify pathological ,16,17 lupus,18 blood group antibodies and responses is worthwhile. Simple self-administered instruments such hyperhomocysteinemia.19 If diagnosed, these conditions should be as the Edinburgh Postnatal Depression Scale37 and the treated and stabilized. Most infectious events associated with Spielberger State-Trait Anxiety Inventory32 are readily available stillbirth are acute and hence unlikely to recur, but empirically it is and allow accurate assessment of women who might benefit from important to exclude chronic infectious conditions such as referral for further psychological assessment before embarking on toxoplasmosis, and possibly Chlamydia.20 There is some another pregnancy. It is important not to underestimate the effect evidence that chronic periodontal disease increases the risk of of a previous pregnancy loss, and even couples who appear to have adverse pregnancy outcomes,21 and evidence from animal models made a good emotional recovery should be offered counseling. suggests that these effects could include stillbirth.22 If there is any history suggestive of periodontal disease (typically from the gums with vigorous tooth brushing) then examination and management by a dentist is prudent. Early pregnancy A number of ‘demographic’ risk factors for stillbirth are difficult Many women who have had a previous unexplained stillbirth will or impossible to modify. These include low socioeconomic status first seek care once they are pregnant. One of the most important and increased maternal age.2 There is also some evidence that management steps in the next pregnancy is accurate establishment certain racial groups face increased risks of stillbirth not accounted of gestational age. This is because the most effective intervention for by factors such as decreased access to medical services.23 In for reducing the rate of stillbirth in subsequent pregnancies is these situations it would seem reasonable to offer additional social likely to be timely delivery once the fetus is mature, ideally no later support if possible, although evidence of the effectiveness of such than 39 weeks gestation.2,38–40 Most of the reported increases in strategies is equivocal.24 adverse maternal and perinatal outcome rates associated with In contrast, obesity and smoking are important risk factors for induction of labor (emergency cesarean delivery, instrumental stillbirth that may be modified before the next pregnancy. Obesity delivery and post-partum hemorrhage) are related to either is of special significance as the prevalence of obesity on obstetric attempted induction at an early gestation or in older age populations is increasing rapidly.25 Although obesity is associated groups.41–43 Accurate determination of gestational age with with pre- and , after adjustment for ultrasound as early as possible reduces the risk of inadvertent these conditions it remains an important independent risk factor premature delivery and failed induction,44 the major contributors

Journal of Perinatology Pregnancy after unexplained stillbirth SJ Robson and LR Leader 307 to adverse outcomes in subsequent pregnancy after unexplained reassurance and comfort, and the potential benefits of this simple stillbirth. intervention strategy have been noted by previous authors.52 As previously stated, many stillbirths remain unexplained Regular fetal surveillance by ultrasound is commonly because of insufficient investigation and an important cause that recommended in pregnancy after stillbirth.4,11 This is because may have been overlooked is an abnormal fetal karyotype. Even growth restriction is a final common pathway for many with careful work-up at the time of stillbirth, chromosomal pathological processes in pregnancy. Fetal growth restriction may abnormalities in the fetus can also remain undiagnosed with be a factor in many unexplained stillbirths53 and studies have failure of cell culture, which is common when there has been a suggested that failure to identify growth restriction during delay between intrauterine death and delivery. It may still be antenatal care is one of the commonest associations with stillbirth, possible to offer comparative genomic hybridization using stored and that a discrepancy of 3 cm or more between gestational age formalin-fixed tissues from stillbirth to exclude aneuploidy, and and symphysio-fundal height is a predictor of stillbirth.54,55 this should be considered. Although low birth weight is more common in the next pregnancy The commonest conditions associated with fetal death are after an unexplained stillbirth, it has been difficult to determine trisomies 21, 18 and 13.45 In the absence of a parental whether this results from a trend to early delivery or a true increase translocation, these aneuploidies impart an empirical recurrence in the incidence of pathological growth restriction.8,56,57 A study risk of less than 5%, but the risk can be as high as 18% in some from South Australia reported an increase in the odds for very low cases depending on the age of the women.46–49 Invasive birth weight (that is, below 1500 g) that would not be accounted karyotyping by villus sampling or amniocentesis obviously for by very preterm birth in the post-stillbirth group, suggesting a increases the risk of early pregnancy loss, so care must be taken in true increase in the number of growth-restricted babies.8 giving such advice to younger women. In case investigation of a Frequent ultrasound examination is commonly undertaken in previous stillbirth did not include an attempt at karyotyping, or in the next pregnancy after unexplained stillbirth, but it is important case attempted karyotyping failed, young women should be offered to advise women about the potential limitations of such tests. a risk estimation using combined first trimester screening (such as Abnormal uterine artery Doppler studies in the second trimester are nuchal translucency measurement, nasal bone ossification and associated with adverse pregnancy outcomes, and a finding of PAPP-A/hCG biochemistry), with resort to formal karyotyping if increased uterine artery flow impedance before 24 weeks gestation indicated by the results of the screening. can predate a clinical suspicion of growth restriction.58 Uterine Lastly, the odds for being diagnosed with diabetes in the next artery flow has been shown to be a useful predictor of stillbirth pregnancy after an unexplained stillbirth is approximately four related to growth restriction up to 32 weeks gestation, but such times that for other women.8 Undiagnosed diabetes is associated testing is of limited value in later pregnancy.59 The authors of that with a number of adverse outcomes of pregnancy, including fetal study speculated that the lack of sensitivity in later pregnancy was demise. This risk increases adequately high such that the condition due, again, to a Hawthorne effect as clinicians were not blinded to should be sought early in the next pregnancy. the results of the Doppler studies. In later pregnancy clinical methods of evaluation of fetal growth such as abdominal examination and measurement of the Later pregnancy management symphysio-fundal height are of limited value in screening for Studies of women who have had an unexplained stillbirth report growth restriction, and a systematic review concluded that there that a great majority seek increased fetal surveillance and ‘early was insufficient evidence to evaluate their usefulness.60 For this delivery’ in subsequent pregnancy, although a desire for elective reason, many obstetricians maintain surveillance by regular cesarean delivery is uncommon.50,51 These wishes for management ultrasound, non-stress tests and formal fetal movement counts in coincide with the recommendations of many obstetricians.11 All the third trimester.4,11 It is important to be aware of the clinical studies of pregnancy outcome subsequent to unexplained stillbirth effectiveness of these surveillance modalities in pregnancy. are reassuring in terms of perinatal mortality, but report increased Although ultrasound-based estimates of fetal weight are rates of intervention and iatrogenic adverse outcomes such as commonly undertaken, their value in screening for growth prematurity, emergency cesarean section and post-partum restriction is actually unproven and they can be falsely hemorrhage.7–10 There is likely to be a strong Hawthorne effect in reassuring.61 Because many normal will be constitutionally such studies as the history of a previous stillbirth increases levels of small, use of customized centile charts has been found to be a surveillance in the next pregnancy and lowers the threshold to better predictor of fetal growth restriction and stillbirth, but there is intervene. Optimizing fetal surveillance while minimizing the risk no evidence yet that prospective use of such charts reduces the rate of false-positive results that might prompt unnecessary intervention of perinatal death in a screened population.62 As a screening tool, a presents the major challenge in this setting. However, simply seeing measurement of fetal abdominal circumference within the normal women for antenatal visits more commonly can provide range effectively excludes growth restriction,63 whereas

Journal of Perinatology Pregnancy after unexplained stillbirth SJ Robson and LR Leader 308 is suggestive of growth restriction.64 However, of denominator, increases almost exponentially after 39 weeks greatest value is an umbilical artery Doppler study: screening of gestation.74 If surveillance detects adverse fetal status then clinical high-risk populations using this method is the only surveillance management and timing of delivery would be individualized. method associated with a trend toward improvement in perinatal However, the great majority of these pregnancies will be mortality.65 The optimal frequency of such remains uncomplicated. Many authorities now concede that the single most uncertain, but as a screening strategy they should probably only be important aspect of management of uncomplicated pregnancies performed at 28 and 34 weeks gestation unless clinical suspicions after an unexplained stillbirth may be delivery by 39 weeks.3–5,11 If dictate more frequent surveillance. The effect of regular ultrasound delivery is delayed beyond this gestation the fetus should be surveillance on maternal anxiety should not be underestimated.66 reassessed by ultrasound to measure amniotic fluid volume and The use of regular non-stress testing to confirm ‘fetal abdominal circumference, and to assess umbilical artery flow. Only well-being’ is widespread, yet this practice has remarkably little a small number of women will request elective cesarean delivery in evidence to support it. One study of regular non-stress testing from this setting, unless they have had a previous cesarean or were 32 weeks gestation in pregnancies after stillbirth showed no effect advised at the time of the stillbirth to have a cesarean birth in their on perinatal mortality.55 An analysis of pooled data from studies of next pregnancy.51 regular non-stress testing in ‘high or intermediate risk’ pregnancies showed no significant reduction in perinatal morbidity or mortality, and a paradoxical trend to increased perinatal Directions for future research deaths.67 That systematic review made the important point that no The population-based studies that have provided prognostic high quality-controlled trials of non-stress testing as a screening information rely on heterogeneous case groups that contain both tool in ‘high-risk’ pregnancies were undertaken for many years. On truly unexplained stillbirths and ‘unexplored’ losses. These studies the basis of current evidence routine non-stress testing undertaken also take no account of delays and early pregnancy losses. as a screening strategy in the absence of specific clinical concerns There is thus an urgent need for a large prospective cohort study of such as reduced fetal movement is unlikely to benefit the woman, women after unexplained stillbirth. Such a study could more and has the potential to be very inconvenient and time consuming. closely examine the emotional consequences of unexplained loss, Formal charting of fetal movements (the use of ‘kick charts’) is as well as decision-making for future pregnancies. Fertility delays widely recommended to women in the next pregnancy after and early pregnancy complications could be quantified for the first unexplained stillbirth.11 Indeed, maternal perception of fetal time. It would also be possible to examine the effects of movements is one of the commonest and longest used methods of surveillance and intervention strategies in the next pregnancy in assessing fetal status.68 Many intrauterine fetal deaths are preceded terms of obstetric outcome, maternal satisfaction and cost-benefit. by a decrease in fetal movements for up to 24 h69 and a wide It is unlikely that formal controlled trials of antenatal variety of adverse pregnancy outcomes are associated with reduced management will ever be undertaken, because of the large sample fetal movements.68 However, prospective trials of the use of ‘kick sizes required. In addition, the set of interventions that would charts’ have failed to show any effect on the rate of perinatal constitute a ‘treatment’ arm in such a trial remains uncertain. mortality.69,70 As many as 15% of women will present with reported reduction in fetal movements during a pregnancy, making this a very common symptom.71 Maternal perception is highly variable Conclusion with ultrasound studies showing that only a small proportion of Dealing with a couple who have experienced an unexplained fetal fetal movements are actually felt by the woman.72 The negative death in late pregnancy is distressing and challenging. Many conclusions of trials of ‘kick charts’ have been challenged,73 but as couples will try to become pregnant again, and will seek guidance yet there is no convincing evidence that use of formal fetal on the risks they face, and an optimal plan of management. movement charting improves pregnancy outcomes.68 Still, it is Careful surveillance and early delivery are likely to have an obviously important to encourage women to report abnormal important role in minimizing the risk of another perinatal death, patterns of fetal movement early, and to ensure that staff who but with the consequence that many adverse outcomes (low birth undertake non-routine antenatal assessment evaluate this symptom weight, preterm delivery, emergency cesarean section and post- without delay. partum hemorrhage) might actually result from the interventions and not the innate biology of the pregnancy. The risk of inadvertent prematurity can be reduced with early ultrasound. Delivery Such pregnancies are also characterized by high levels of anxiety Early delivery in pregnancies after an unexplained stillbirth is very and it is important that women and their families are provided commonly requested by women,51,52 and promoted by many with reassurance and support. There is an obvious and pressing obstetricians.11 The risk of stillbirth, using undelivered fetuses as a need for more research in the area of unexplained stillbirth.

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