IJG-08055; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Outcome of pregnancy following second- or third-trimester intrauterine fetal death Chloé Maignien a, Amélie Nguyen a, Chloé Dussaux a, Evelyne Cynober a, Marie Gonzales b, Bruno Carbonne a,⁎ a b
Department of Obstetrics, Hôpital Trousseau, Assistance Publique—Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France Department of Cytogenetics and Fetopathology, Hôpital Trousseau, Assistance Publique—Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
a r t i c l e
i n f o
Article history: Received 31 January 2014 Received in revised form 4 June 2014 Accepted 22 July 2014 Keywords: Intrauterine fetal death Obstetric outcome Preterm birth Recurrence Small for gestational age Stillbirth Vascular complications
a b s t r a c t Objective: To investigate the outcomes of a pregnancy after a second- or third-trimester intrauterine fetal death (IUFD). Methods: A prospective observational study was conducted at Trousseau Hospital (Paris, France) between 1996 and 2011. The first ongoing pregnancy in women who had had a previous IUFD was monitored. Management of their treatment was according to a standardized protocol. Recurrence of fetal death was the main outcome criterion. Results: The subsequent pregnancies of 87 women who had experienced at least one previous IUFD were followed up. The cause of previous IUFD was placental in 50 (57%) women, unknown in 19 (22%), adnexal in 12 (14%), metabolic in 2 (2%), and malformative in 4 (5%). Three (3%) participants had another stillbirth. Overall, obstetric complications occurred in 34 (39%) pregnancies (including 22 [25%] preterm births, 5 [6%] small for gestational age, and 6 [7%] maternal vascular complications). Obstetric complications were significantly more common among women whose previous stillbirth had been due to placental causes than among those affected by other causes (P = 0.02). Conclusion: Most pregnancies after IUFD resulted in a live birth; however, adverse obstetric outcomes were more common when the previous stillbirth was due to placental causes. © 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
1. Introduction Between five and seven stillbirths occur in every 1000 pregnancies [1,2]. This dramatic event engenders a high degree of anxiety about the next pregnancy for women, their partners, and caregivers. However, according to published data [3–9], the risk of another stillbirth ranges from nil to a 20-fold increase compared with that for primigravidas. Although some studies have shown an increase in the incidence of stillbirth and obstetric complications (e.g. placental abruption, preterm delivery, and low birth weight) in women who have had a previous stillbirth [10,11], others have found that the risk of stillbirth in these women is no higher than that in the general population [12]. Moreover, the definition of fetal loss is particularly heterogeneous in the literature, including late spontaneous abortions as well as intrapartum stillbirths. Finally, many studies are population-based, lacking information about the etiology of stillbirth and details of the follow-up [8,12,13]. Because of the conflicting evidence in the literature about stillbirth recurrence rates, the objective of the present study was to conduct an investigation of a cohort of pregnancies after a second- or thirdtrimester stillbirth at one healthcare center, using a standardized protocol for the etiologic investigations, and where the management of the next pregnancy involved only a limited number of obstetricians. The ⁎ Corresponding author at: Department of Obstetrics, Hôpital Trousseau, 26 Avenue du Dr Arnold Netter, 75012 Paris, France. Tel.: +33 1 44 73 53 42; fax: +33 1 44 73 63 82. E-mail address: [email protected] (B. Carbonne).
main aim of the study was to investigate the occurrence of subsequent intrauterine fetal death (IUFD), preterm birth, small for gestational age (SGA) neonates, and any vascular complication of pregnancy (preeclampsia, HELLP syndrome [hemolysis, elevated liver enzymes, and low platelet count], and placental abruption) in women with a history of IUFD. The secondary objective was to determine whether the cause of fetal death in the index pregnancy affected the occurrence of complications during a subsequent pregnancy. 2. Materials and methods A prospective observational study was conducted at Trousseau Hospital (Paris, France) between January 1, 1996, and December 31, 2011. Eligible women had their first ongoing pregnancy (past 12 weeks) after a previous second- or third-trimester stillbirth. Only women followed up for the whole pregnancy and who went on to deliver at Trousseau Hospital were included. The study was approved by the National Ethics Committee for Research in Obstetrics and Gynecology. Informed consent was obtained from all study participants. Stillbirth was defined as an intrauterine death after 15 weeks of gestation. A systematic work-up to try to identify the cause of the intrauterine death was done after the IUFD if it occurred at Trousseau Hospital, or when a woman subsequently presented to the hospital for the first time (while planning a pregnancy or when already pregnant again). The work-up involved a systematic examination of the fetal autopsy, the macroscopic and microscopic placental conditions,
http://dx.doi.org/10.1016/j.ijgo.2014.06.015 0020-7292/© 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
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C. Maignien et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
fetal karyotyping, and laboratory testing (blood type; Rhesus factor; Kleihauer–Betke test; serologic screening for recent toxoplasma, rubella, cytomegalovirus, and parvovirus B19; and bacteriologic, hematologic, and biochemical screening). The cause of death was classified into five possible categories according to the local classification system, which was devised in agreement with obstetricians and fetopathologists: (1) placental [14] when at least one of a list of problems was identified (pre-eclampsia, HELLP syndrome, placental abruption, intrauterine growth retardation, uterine artery Doppler anomalies, or histologic evidence of placental vascular dysfunction); (2) malformative when severe structural anomalies were identified by ultrasound or fetal autopsy; (3) adnexal in case of cord accidents, fetal maternal hemorrhage confirmed by positive Kleihauer–Betke test, or red-blood-cell alloimmunization; (4) metabolic in the case of diabetes mellitus or an obstetric cholestasis; or (5) unknown when, despite all the investigations or because of a lack of information, no cause was identified. If the cause of the stillbirth appeared to be placental or remained unexplained, further investigations were undertaken to determine whether the stillbirth could have been due to inherited thrombophilias (deficiencies of proteins C or S, factor V Leiden mutation, prothrombin G20210A gene mutation, antithrombin III deficiency, or hyperhomocysteinemia), circulating antiphospholipid antibodies (anticardiolipin antibodies, antiβ2GP1, and lupus anticoagulant), or antinuclear factor if there was clinical evidence of lupus. If the stillbirth had occurred in another hospital, efforts were made to obtain all prenatal care records. The standardized protocol of management for these patients included: first-trimester ultrasonography with uterine artery Doppler; monthly ultrasonography with uterine and umbilical artery Dopplers, fetal weight estimation, and screening for fetal malformations in the second or third trimester; prenatal care visits at least once a month; and weekly monitoring of blood pressure, proteinuria, and fetal heart rate during the third trimester. A psychological follow-up was offered to all women during pregnancy as part of standard management; however, these data are not included in the present study. Some aspects of the protocol were slightly modified according to the cause and the timing of the stillbirth. In women whose previous stillbirth was due to placental causes, specific treatments were prescribed to prevent the recurrence of placental vascular pathology. From early diagnosis of pregnancy to 35–36 weeks, the patients received a daily dose of 100–160 mg aspirin. Aspirin was also given to women whose previous stillbirth was not obviously due to a placental cause but in whom uterine artery Doppler at 12 weeks of pregnancy showed elevated resistance indices and bilateral notches. If the screening for thrombophilia was positive, a daily prophylactic dose of 4000 IU enoxaparin—a lowmolecular-weight heparin—was prescribed as soon as the pregnancy test was positive until 6 weeks after delivery, with an interruption of treatment during labor and until 12 hours postpartum [15]. Women whose stillbirth had been due to placental causes but in whom screening for thrombophilia was negative were also given a low-molecularweight heparin if the first-trimester uterine artery Doppler was highly pathologic (i.e. bilateral resistance index N80% and/or bilateral notches). Women with hyperhomocysteinemia were supplemented with daily doses of 10 mg vitamin B9 and 0.25 mg vitamin B12, and were checked for normal homocysteine rates under treatment. In the case of an uneventful pregnancy, labor was usually induced at the beginning of the ninth month (i.e. 37–38 weeks of pregnancy) according to the cause of the first stillbirth, the gestational age at the time that it occurred, and the medical history of the patient. The main outcome criteria were: a recurrence of IUFD and the occurrence of pregnancy complications such as preterm birth (b 37 weeks); a SGA fetus or neonate (birthweight b10th percentile using Leroy–Lefort birth weight curves); vascular complications of pregnancy such as preeclampsia, placental abruption, or HELLP syndrome; and a composite outcome called “any complication”, which included any of the aforementioned obstetric outcomes.
Statistical analyses were performed using Medcalc version 12 (Ostend, Belgium; http://www.medcalc.org). Categorical data were compared using the Pearson χ2 test and the Fisher exact test, as appropriate. Continuous variables were compared using the Student t test. P b 0.05 was considered statistically significant. 3. Results The subsequent pregnancies of 87 patients who had experienced at least one prior IUFD were followed up. The characteristics of the patients at the time of the previous stillbirth are shown in Table 1. The mean age of the patients was 31 ± 5 years. At the time of the previous IUFD, 58 (67%) women had been nulliparous. The cause of stillbirth was classified as placental for 50 (57%) patients (Table 2), of whom 27 (54%) were found to have a positive result when screened for thrombophilia (Table 3). More than half of these 27 women had antiphospholipid syndrome (Table 3). Of the 12 IUFDs with adnexal causes, seven were due to cord accidents, two to fetal–maternal hemorrhage, one to amniotic bonds, one to extrachorial placenta, and one to red-blood-cell alloimmunization. Of the four stillbirths that were due to malformative causes, one was due to hydrocephalus, one to diaphragmatic hernia, and two to polymalformative syndromes. Both stillbirths due to metabolic causes involved obstetric cholestasis. Fifty-six (64%) stillbirths occurred during the third trimester, among which 28 (50%) occurred during the last month of the pregnancy (between 37 and 42 weeks). The mean age of the participants at the time of their next pregnancy was 33 ± 5 years, median gravidity was three (range 2–9), and median parity was two (range 0–6). Fifty-four (62%) women had had no live births at the time of this pregnancy. Among 69 (79%) participants given at least low doses of aspirin, the cause of previous IUFD had been placental in 49 (71%). Among the 37 patients whose previous stillbirth was not due to placental causes, 20 (54%) received treatment with aspirin. These patients either had severe anomalies of uterine artery Doppler at the first-trimester ultrasound, mild fetal growth retardation, or multiple previous stillbirths. Six participants were given aspirin before the results of the complete etiologic work-up were obtained, but were then stopped when no placental cause was found. Among the cohort, 84 (97%) went on to have a live birth. The obstetric complications, according to the etiology of the index IUFD, are shown in Table 4, and the obstetric outcomes among women whose previous stillbirth had been due to placental causes (the placental group) and
Table 1 Characteristics of the patients at the time of the index IUFD. Characteristic
Median (range)
Age, y Gravidity Parity Number of previous live births Number of previous IUFDs
31 (21–43)a 2 (1–8) 1 (0–5) 0 (0–3) 0 (0–2)
Abbreviation: IUFD, intrauterine fetal death. a Mean (range).
Table 2 Cause of index intrauterine fetal death (n = 87). Cause
No. (%)
Placental Malformative Metabolic Adnexal Unexplained
50 (57) 4 (5) 2 (2) 12 (14) 19 (22)
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
C. Maignien et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx Table 3 Thrombophilia screening among women whose previous stillbirth was due to placental causes (n = 50). Result
No. (%)
Negative Positive Antiphospholipid syndrome Protein C deficiency Protein S deficiency Hyperhomocysteinemia Factor V mutation Factor II mutation
23 (46) 27 (54) 16 (59) 1 (4) 4 (15) 2 (7) 3 (11) 1 (4)
those whose previous stillbirth had been due to other causes (the nonplacental group) are compared in Table 5. Only three (3%) women had another stillbirth, all of whom were in the placental group. However, the difference between the groups was not statistically significant (P = 0.26). All three recurrent stillbirths were associated with fetal growth retardation and were considered to be of placental origin. Obstetric complications (including preterm birth, pre-eclampsia, HELLP syndrome, placental abruption, and SGA) occurred in 34 (39%) pregnancies (Table 4). Significantly more obstetric complications occurred in the placental group than in the nonplacental group (P = 0.02). Among 22 (25%) women who delivered preterm, 14 (64%) had induced vaginal delivery or elective cesarean delivery, 5 (23%) had SGA neonates, and 6 (27%) had placental vascular complications of pregnancy. There were a greater number of preterm deliveries among the placental group than among the nonplacental group, although the difference was not significant (P = 0.15). Placental vascular diseases (pre-eclampsia, HELLP syndrome, and placental abruption) occurred in the placental group only (P = 0.036). Subsequent obstetric outcomes according to the gestational age at the time of the index IUFD are shown in Fig. 1. Obstetric complications were slightly more common among the pregnancies following a thirdtrimester IUFD (affecting 34 [61%]) than among those after a secondtrimester IUFD (affecting 17 [55%]). However, of the three recurrent IUFD, two occurred in women whose previous IUFD had been in the second trimester. 4. Discussion In the present study, the frequency of IUFD recurrence was 3%, but more than 40% of subsequent pregnancies were complicated by preterm birth, SGA neonates, or placental vascular complications (preeclampsia, HELLP syndrome, or placental abruption). There was a significant difference in the number of adverse obstetric outcomes experienced during the subsequent pregnancy between women whose previous IUFD had and had not been due to placental causes: participants in the placental group had a significantly greater number of adverse obstetric outcomes and maternal vascular complications.
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Table 5 Comparison of the obstetric outcomes of the placental and the nonplacental group.a Obstetric complications
Placental group (n = 50)
Nonplacental group (n = 37)
P value
IUFD Preterm birth SGA Maternal vascular complicationb Any complicationc
3 (6) 16 (32) 2 (4) 6 (12) 27 (54)
0 6 (16) 1 (3) 0 7 (19)
0.26 0.15 N0.99 0.036 0.02
Abbreviations: IUFD, intrauterine fetal death; SGA, small for gestational age. a Values are given as number (percentage) unless otherwise stated. b Pre-eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), or placental abruption. c Composite outcome including IUFD and/or preterm birth and/or SGA and/or maternal vascular complication.
Most of the available data on pregnancy after stillbirth comes from large cohorts. Getahun et al. [12] reported a 3.5-fold increased risk of stillbirth after a previous IUFD, with 21% of 71 315 pregnancies ending with a stillbirth. Battacharya et al. [13] showed a 4.5-fold increased risk of recurrence among a population of 3094 women. Such populationbased studies enable many cases to be studied; however, little, if anything, is known about each individual case. Usually, no data are available about the cause of fetal death, the clinical context, the follow-up of the next pregnancy, and/or the treatment administered. The findings of the present study seem to differ slightly from those of previous studies. Indeed, in this high-risk population, the recurrence rate of IUFD was much lower than that described in the previous larger series for which details of follow-up are unavailable [12,13]. One potential explanation is that the patients in the present study had a complete and standardized etiologic work-up, as well as homogenous management by a small number of obstetricians, which could account for the low incidence of stillbirth recurrence. Another series of 73 pregnancies after IUFD [16], with a protocol similar to that of the present study, had a recurrence rate of 6.8%, and the risk of IUFD was 22.2 times higher than in a control group (n = 10 370). Further large, controlled studies in a hospital setting are needed to evaluate precisely the individual prognosis of pregnancies after stillbirth. A high incidence of adverse obstetric outcomes was observed in the present study population, which is consistent with the findings of previous reports: Black et al. [8] showed a 2.8-fold increased risk of low birth weight and prematurity after a previous stillbirth, and Getahun et al. [12] reported that ischemic placental disease was increased by 1.6-fold and extreme preterm birth by 4.2-fold. However, in the present study, almost two-thirds of the preterm deliveries were due to medical intervention (induction of labor or elective cesarean delivery), which suggests that prematurity in women with a history of IUFD is rarely spontaneous but mainly associated with adverse obstetric conditions. One explanation for the significant difference in number of adverse outcomes between the placental and nonplacental groups in the present study could be that placental causes were the most common
Table 4 Obstetric complications by cause of previous IUFD.a Cause
IUFD
Preterm birth
SGA
Maternal vascular complications of pregnancyb
Any complicationc,d
Placental (n = 50) Adnexal (n = 12) Malformative (n = 4) Metabolic (n = 2) Unexplained (n = 19) Total (n = 87)
3 (6) 0 0 0 0 3 (3)
16 (32) 1 (8) 0 1 (50) 4 (21) 22 (25)
2 (4) 1 (8) 0 0 2 (11) 5 (6)
6 (12) 0 0 0 0 6 (7)
27 (54) 2 (17) 0 1 (50) 4 (21) 34 (39)
Abbreviations: IUFD, intrauterine fetal death; SGA, small for gestational age. a Values are given as number (percentage). b Pre-eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), or placental abruption. c Composite outcome including IUFD and/or preterm birth and/or SGA and/or maternal vascular complications of pregnancy. d More than one complication could occur in the same pregnancy.
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
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Fig. 1. Obstetric outcomes according to gestational age at the time of the index IUFD. Abbreviations: IUFD, intrauterine fetal death; PTB, preterm birth; SGA, small for gestational age; MVC, maternal vascular complications of pregnancy (preeclampsia, HELLP syndrome, placental abruption).
reasons for previous IUFD, probably owing to a referral bias. Indeed, several women were referred by the pathologist to the Department of Obstetrics at Trousseau Hospital for their next pregnancy when there were signs of ischemic placental disease. Nevertheless, the adverse obstetric outcomes reported in the present study also support the findings of a recent study [16] that showed that the risk of intrauterine growth retardation was increased in a pregnancy following a prior placental stillbirth (odds ratio 10.5; 95% confidence interval 1.12–245.6; P = 0.016). However, Surkan et al. [17] reported that the risk of a subsequent stillbirth is increased when the first pregnancy has been complicated by pre-eclampsia and a SGA birth, even when it ended with a live birth. Such data suggest that women with a history of placental IUFD have a greater risk of complications during the next pregnancy, probably because the etiology of the impaired placental condition that was involved in the initial stillbirth is still present at the second pregnancy despite preventive treatments (e.g. aspirin and lowmolecular-weight heparin). Among the three recurrent IUFDs, two occurred during the second trimester. Although no definitive conclusions can be drawn from a small series, these findings support those from other studies [6,9] showing a higher risk of stillbirth recurrence for early IUFD (b28 weeks). The main limitations of our study are the lack of a control group and the fairly limited number of pregnancies after stillbirth. In conclusion, the overall prognosis of pregnancies following a second- or third- trimester IUFD was favorable in most cases in the present study, with only a low level of recurrence; however, there were a high number of adverse obstetric outcomes among women with a previous placental stillbirth. Further large controlled studies are needed to confirm these findings and to help physicians to counsel patients. Conflict of interest
References [1] Salihu HM, Kinniburgh BA, Aliyu MH, Kirby RS, Alexander GR. Racial disparity in stillbirth among singleton, twin, and triplet gestations in the United States. Obstet Gynecol 2004;104(4):734–40. [2] Goldenberg RL, Kirby R, Culhane JF. Stillbirth: a review. J Matern Fetal Neonatal Med 2004;16(2):79–94. [3] Greenwood R, Samms-Vaughan M, Golding J, Ashley D. Past obstetric history and risk of perinatal death in Jamaica. Paediatr Perinat Epidemiol 1994;8(Suppl. 1):40–53. [4] Samueloff A, Xenakis EM, Berkus MD, Huff RW, Langer O. Recurrent stillbirth. Significance and characteristics. J Reprod Med 1993;38(11):883–6. [5] Lurie S, Eldar I, Glezerman M, Sadan O. Pregnancy outcome after stillbirth. J Reprod Med 2007;52(4):289–92. [6] Onwude JL, Eisman V, Selo-Ojeme DO. Recurrent stillbirths: a matched case-control study of unexplained stillbirths at term. J Obstet Gynaecol 2006;26(3):205–7. [7] Nijkamp JW, Korteweg FJ, Holm JP, Timmer A, Erwich JJ, van Pampus MG. Subsequent pregnancy outcome after previous foetal death. Eur J Obstet Gynecol Reprod Biol 2013;166(1):37–42. [8] Black M, Shetty A, Bhattacharya S. Obstetric outcomes subsequent to intrauterine death in the first pregnancy. BJOG 2008;115(2):269–74. [9] Sharma PP, Salihu HM, Kirby RS. Stillbirth recurrence in a population of relatively low-risk mothers. Paediatr Perinat Epidemiol 2007;21(Suppl. 1):24–30. [10] Heinonen S, Kirkinen P. Pregnancy outcome after previous stillbirth resulting from causes other than maternal conditions and fetal abnormalities. Birth 2000;27(1):33–7. [11] Sharma PP, Salihu HM, Oyelese Y, Ananth CV, Kirby RS. Is race a determinant of stillbirth recurrence? Obstet Gynecol 2006;107(2 Pt 1):391–7. [12] Getahun D, Lawrence JM, Fassett MJ, Strickland D, Koebnick C, Chen W, et al. The association between stillbirth in the first pregnancy and subsequent adverse perinatal outcomes. Am J Obstet Gynecol 2009;201(4):378.e1–6. [13] Bhattacharya S, Prescott GJ, Black M, Shetty A. Recurrence risk of stillbirth in a second pregnancy. BJOG 2010;117(10):1243–7. [14] Flenady V, Middleton P, Smith GC, Duke W, Erwich JJ, Khong TY, et al. Stillbirths: the way forward in high-income countries. Lancet 2011;377(9778):1703–17. [15] Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G, Mercier E, Fabbro-Peray P, Balducchi JP, et al. Comparative incidence of pregnancy outcomes in thrombophiliapositive women from the NOH-APS observational study. Blood 2014;123(3):414–21. [16] Ofir K, Kalter A, Moran O, Sivan E, Schiff E, Simchen MJ. Subsequent pregnancy after stillbirth: obstetrical and medical risks. J Perinat Med 2013;41(5):543–8. [17] Surkan PJ, Stephansson O, Dickman PW, Cnattingius S. Previous preterm and smallfor-gestational-age births and the subsequent risk of stillbirth. N Engl J Med 2004; 350(8):777–85.
The authors have no conflicts of interest.
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Outcome of pregnancy following second- or third-trimester intrauterine fetal death Chloé Maignien a, Amélie Nguyen a, Chloé Dussaux a, Evelyne Cynober a, Marie Gonzales b, Bruno Carbonne a,⁎ a b
Department of Obstetrics, Hôpital Trousseau, Assistance Publique—Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France Department of Cytogenetics and Fetopathology, Hôpital Trousseau, Assistance Publique—Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
a r t i c l e
i n f o
Article history: Received 31 January 2014 Received in revised form 4 June 2014 Accepted 22 July 2014 Keywords: Intrauterine fetal death Obstetric outcome Preterm birth Recurrence Small for gestational age Stillbirth Vascular complications
a b s t r a c t Objective: To investigate the outcomes of a pregnancy after a second- or third-trimester intrauterine fetal death (IUFD). Methods: A prospective observational study was conducted at Trousseau Hospital (Paris, France) between 1996 and 2011. The first ongoing pregnancy in women who had had a previous IUFD was monitored. Management of their treatment was according to a standardized protocol. Recurrence of fetal death was the main outcome criterion. Results: The subsequent pregnancies of 87 women who had experienced at least one previous IUFD were followed up. The cause of previous IUFD was placental in 50 (57%) women, unknown in 19 (22%), adnexal in 12 (14%), metabolic in 2 (2%), and malformative in 4 (5%). Three (3%) participants had another stillbirth. Overall, obstetric complications occurred in 34 (39%) pregnancies (including 22 [25%] preterm births, 5 [6%] small for gestational age, and 6 [7%] maternal vascular complications). Obstetric complications were significantly more common among women whose previous stillbirth had been due to placental causes than among those affected by other causes (P = 0.02). Conclusion: Most pregnancies after IUFD resulted in a live birth; however, adverse obstetric outcomes were more common when the previous stillbirth was due to placental causes. © 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
1. Introduction Between five and seven stillbirths occur in every 1000 pregnancies [1,2]. This dramatic event engenders a high degree of anxiety about the next pregnancy for women, their partners, and caregivers. However, according to published data [3–9], the risk of another stillbirth ranges from nil to a 20-fold increase compared with that for primigravidas. Although some studies have shown an increase in the incidence of stillbirth and obstetric complications (e.g. placental abruption, preterm delivery, and low birth weight) in women who have had a previous stillbirth [10,11], others have found that the risk of stillbirth in these women is no higher than that in the general population [12]. Moreover, the definition of fetal loss is particularly heterogeneous in the literature, including late spontaneous abortions as well as intrapartum stillbirths. Finally, many studies are population-based, lacking information about the etiology of stillbirth and details of the follow-up [8,12,13]. Because of the conflicting evidence in the literature about stillbirth recurrence rates, the objective of the present study was to conduct an investigation of a cohort of pregnancies after a second- or thirdtrimester stillbirth at one healthcare center, using a standardized protocol for the etiologic investigations, and where the management of the next pregnancy involved only a limited number of obstetricians. The ⁎ Corresponding author at: Department of Obstetrics, Hôpital Trousseau, 26 Avenue du Dr Arnold Netter, 75012 Paris, France. Tel.: +33 1 44 73 53 42; fax: +33 1 44 73 63 82. E-mail address: [email protected] (B. Carbonne).
main aim of the study was to investigate the occurrence of subsequent intrauterine fetal death (IUFD), preterm birth, small for gestational age (SGA) neonates, and any vascular complication of pregnancy (preeclampsia, HELLP syndrome [hemolysis, elevated liver enzymes, and low platelet count], and placental abruption) in women with a history of IUFD. The secondary objective was to determine whether the cause of fetal death in the index pregnancy affected the occurrence of complications during a subsequent pregnancy. 2. Materials and methods A prospective observational study was conducted at Trousseau Hospital (Paris, France) between January 1, 1996, and December 31, 2011. Eligible women had their first ongoing pregnancy (past 12 weeks) after a previous second- or third-trimester stillbirth. Only women followed up for the whole pregnancy and who went on to deliver at Trousseau Hospital were included. The study was approved by the National Ethics Committee for Research in Obstetrics and Gynecology. Informed consent was obtained from all study participants. Stillbirth was defined as an intrauterine death after 15 weeks of gestation. A systematic work-up to try to identify the cause of the intrauterine death was done after the IUFD if it occurred at Trousseau Hospital, or when a woman subsequently presented to the hospital for the first time (while planning a pregnancy or when already pregnant again). The work-up involved a systematic examination of the fetal autopsy, the macroscopic and microscopic placental conditions,
http://dx.doi.org/10.1016/j.ijgo.2014.06.015 0020-7292/© 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
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C. Maignien et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
fetal karyotyping, and laboratory testing (blood type; Rhesus factor; Kleihauer–Betke test; serologic screening for recent toxoplasma, rubella, cytomegalovirus, and parvovirus B19; and bacteriologic, hematologic, and biochemical screening). The cause of death was classified into five possible categories according to the local classification system, which was devised in agreement with obstetricians and fetopathologists: (1) placental [14] when at least one of a list of problems was identified (pre-eclampsia, HELLP syndrome, placental abruption, intrauterine growth retardation, uterine artery Doppler anomalies, or histologic evidence of placental vascular dysfunction); (2) malformative when severe structural anomalies were identified by ultrasound or fetal autopsy; (3) adnexal in case of cord accidents, fetal maternal hemorrhage confirmed by positive Kleihauer–Betke test, or red-blood-cell alloimmunization; (4) metabolic in the case of diabetes mellitus or an obstetric cholestasis; or (5) unknown when, despite all the investigations or because of a lack of information, no cause was identified. If the cause of the stillbirth appeared to be placental or remained unexplained, further investigations were undertaken to determine whether the stillbirth could have been due to inherited thrombophilias (deficiencies of proteins C or S, factor V Leiden mutation, prothrombin G20210A gene mutation, antithrombin III deficiency, or hyperhomocysteinemia), circulating antiphospholipid antibodies (anticardiolipin antibodies, antiβ2GP1, and lupus anticoagulant), or antinuclear factor if there was clinical evidence of lupus. If the stillbirth had occurred in another hospital, efforts were made to obtain all prenatal care records. The standardized protocol of management for these patients included: first-trimester ultrasonography with uterine artery Doppler; monthly ultrasonography with uterine and umbilical artery Dopplers, fetal weight estimation, and screening for fetal malformations in the second or third trimester; prenatal care visits at least once a month; and weekly monitoring of blood pressure, proteinuria, and fetal heart rate during the third trimester. A psychological follow-up was offered to all women during pregnancy as part of standard management; however, these data are not included in the present study. Some aspects of the protocol were slightly modified according to the cause and the timing of the stillbirth. In women whose previous stillbirth was due to placental causes, specific treatments were prescribed to prevent the recurrence of placental vascular pathology. From early diagnosis of pregnancy to 35–36 weeks, the patients received a daily dose of 100–160 mg aspirin. Aspirin was also given to women whose previous stillbirth was not obviously due to a placental cause but in whom uterine artery Doppler at 12 weeks of pregnancy showed elevated resistance indices and bilateral notches. If the screening for thrombophilia was positive, a daily prophylactic dose of 4000 IU enoxaparin—a lowmolecular-weight heparin—was prescribed as soon as the pregnancy test was positive until 6 weeks after delivery, with an interruption of treatment during labor and until 12 hours postpartum [15]. Women whose stillbirth had been due to placental causes but in whom screening for thrombophilia was negative were also given a low-molecularweight heparin if the first-trimester uterine artery Doppler was highly pathologic (i.e. bilateral resistance index N80% and/or bilateral notches). Women with hyperhomocysteinemia were supplemented with daily doses of 10 mg vitamin B9 and 0.25 mg vitamin B12, and were checked for normal homocysteine rates under treatment. In the case of an uneventful pregnancy, labor was usually induced at the beginning of the ninth month (i.e. 37–38 weeks of pregnancy) according to the cause of the first stillbirth, the gestational age at the time that it occurred, and the medical history of the patient. The main outcome criteria were: a recurrence of IUFD and the occurrence of pregnancy complications such as preterm birth (b 37 weeks); a SGA fetus or neonate (birthweight b10th percentile using Leroy–Lefort birth weight curves); vascular complications of pregnancy such as preeclampsia, placental abruption, or HELLP syndrome; and a composite outcome called “any complication”, which included any of the aforementioned obstetric outcomes.
Statistical analyses were performed using Medcalc version 12 (Ostend, Belgium; http://www.medcalc.org). Categorical data were compared using the Pearson χ2 test and the Fisher exact test, as appropriate. Continuous variables were compared using the Student t test. P b 0.05 was considered statistically significant. 3. Results The subsequent pregnancies of 87 patients who had experienced at least one prior IUFD were followed up. The characteristics of the patients at the time of the previous stillbirth are shown in Table 1. The mean age of the patients was 31 ± 5 years. At the time of the previous IUFD, 58 (67%) women had been nulliparous. The cause of stillbirth was classified as placental for 50 (57%) patients (Table 2), of whom 27 (54%) were found to have a positive result when screened for thrombophilia (Table 3). More than half of these 27 women had antiphospholipid syndrome (Table 3). Of the 12 IUFDs with adnexal causes, seven were due to cord accidents, two to fetal–maternal hemorrhage, one to amniotic bonds, one to extrachorial placenta, and one to red-blood-cell alloimmunization. Of the four stillbirths that were due to malformative causes, one was due to hydrocephalus, one to diaphragmatic hernia, and two to polymalformative syndromes. Both stillbirths due to metabolic causes involved obstetric cholestasis. Fifty-six (64%) stillbirths occurred during the third trimester, among which 28 (50%) occurred during the last month of the pregnancy (between 37 and 42 weeks). The mean age of the participants at the time of their next pregnancy was 33 ± 5 years, median gravidity was three (range 2–9), and median parity was two (range 0–6). Fifty-four (62%) women had had no live births at the time of this pregnancy. Among 69 (79%) participants given at least low doses of aspirin, the cause of previous IUFD had been placental in 49 (71%). Among the 37 patients whose previous stillbirth was not due to placental causes, 20 (54%) received treatment with aspirin. These patients either had severe anomalies of uterine artery Doppler at the first-trimester ultrasound, mild fetal growth retardation, or multiple previous stillbirths. Six participants were given aspirin before the results of the complete etiologic work-up were obtained, but were then stopped when no placental cause was found. Among the cohort, 84 (97%) went on to have a live birth. The obstetric complications, according to the etiology of the index IUFD, are shown in Table 4, and the obstetric outcomes among women whose previous stillbirth had been due to placental causes (the placental group) and
Table 1 Characteristics of the patients at the time of the index IUFD. Characteristic
Median (range)
Age, y Gravidity Parity Number of previous live births Number of previous IUFDs
31 (21–43)a 2 (1–8) 1 (0–5) 0 (0–3) 0 (0–2)
Abbreviation: IUFD, intrauterine fetal death. a Mean (range).
Table 2 Cause of index intrauterine fetal death (n = 87). Cause
No. (%)
Placental Malformative Metabolic Adnexal Unexplained
50 (57) 4 (5) 2 (2) 12 (14) 19 (22)
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
C. Maignien et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx Table 3 Thrombophilia screening among women whose previous stillbirth was due to placental causes (n = 50). Result
No. (%)
Negative Positive Antiphospholipid syndrome Protein C deficiency Protein S deficiency Hyperhomocysteinemia Factor V mutation Factor II mutation
23 (46) 27 (54) 16 (59) 1 (4) 4 (15) 2 (7) 3 (11) 1 (4)
those whose previous stillbirth had been due to other causes (the nonplacental group) are compared in Table 5. Only three (3%) women had another stillbirth, all of whom were in the placental group. However, the difference between the groups was not statistically significant (P = 0.26). All three recurrent stillbirths were associated with fetal growth retardation and were considered to be of placental origin. Obstetric complications (including preterm birth, pre-eclampsia, HELLP syndrome, placental abruption, and SGA) occurred in 34 (39%) pregnancies (Table 4). Significantly more obstetric complications occurred in the placental group than in the nonplacental group (P = 0.02). Among 22 (25%) women who delivered preterm, 14 (64%) had induced vaginal delivery or elective cesarean delivery, 5 (23%) had SGA neonates, and 6 (27%) had placental vascular complications of pregnancy. There were a greater number of preterm deliveries among the placental group than among the nonplacental group, although the difference was not significant (P = 0.15). Placental vascular diseases (pre-eclampsia, HELLP syndrome, and placental abruption) occurred in the placental group only (P = 0.036). Subsequent obstetric outcomes according to the gestational age at the time of the index IUFD are shown in Fig. 1. Obstetric complications were slightly more common among the pregnancies following a thirdtrimester IUFD (affecting 34 [61%]) than among those after a secondtrimester IUFD (affecting 17 [55%]). However, of the three recurrent IUFD, two occurred in women whose previous IUFD had been in the second trimester. 4. Discussion In the present study, the frequency of IUFD recurrence was 3%, but more than 40% of subsequent pregnancies were complicated by preterm birth, SGA neonates, or placental vascular complications (preeclampsia, HELLP syndrome, or placental abruption). There was a significant difference in the number of adverse obstetric outcomes experienced during the subsequent pregnancy between women whose previous IUFD had and had not been due to placental causes: participants in the placental group had a significantly greater number of adverse obstetric outcomes and maternal vascular complications.
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Table 5 Comparison of the obstetric outcomes of the placental and the nonplacental group.a Obstetric complications
Placental group (n = 50)
Nonplacental group (n = 37)
P value
IUFD Preterm birth SGA Maternal vascular complicationb Any complicationc
3 (6) 16 (32) 2 (4) 6 (12) 27 (54)
0 6 (16) 1 (3) 0 7 (19)
0.26 0.15 N0.99 0.036 0.02
Abbreviations: IUFD, intrauterine fetal death; SGA, small for gestational age. a Values are given as number (percentage) unless otherwise stated. b Pre-eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), or placental abruption. c Composite outcome including IUFD and/or preterm birth and/or SGA and/or maternal vascular complication.
Most of the available data on pregnancy after stillbirth comes from large cohorts. Getahun et al. [12] reported a 3.5-fold increased risk of stillbirth after a previous IUFD, with 21% of 71 315 pregnancies ending with a stillbirth. Battacharya et al. [13] showed a 4.5-fold increased risk of recurrence among a population of 3094 women. Such populationbased studies enable many cases to be studied; however, little, if anything, is known about each individual case. Usually, no data are available about the cause of fetal death, the clinical context, the follow-up of the next pregnancy, and/or the treatment administered. The findings of the present study seem to differ slightly from those of previous studies. Indeed, in this high-risk population, the recurrence rate of IUFD was much lower than that described in the previous larger series for which details of follow-up are unavailable [12,13]. One potential explanation is that the patients in the present study had a complete and standardized etiologic work-up, as well as homogenous management by a small number of obstetricians, which could account for the low incidence of stillbirth recurrence. Another series of 73 pregnancies after IUFD [16], with a protocol similar to that of the present study, had a recurrence rate of 6.8%, and the risk of IUFD was 22.2 times higher than in a control group (n = 10 370). Further large, controlled studies in a hospital setting are needed to evaluate precisely the individual prognosis of pregnancies after stillbirth. A high incidence of adverse obstetric outcomes was observed in the present study population, which is consistent with the findings of previous reports: Black et al. [8] showed a 2.8-fold increased risk of low birth weight and prematurity after a previous stillbirth, and Getahun et al. [12] reported that ischemic placental disease was increased by 1.6-fold and extreme preterm birth by 4.2-fold. However, in the present study, almost two-thirds of the preterm deliveries were due to medical intervention (induction of labor or elective cesarean delivery), which suggests that prematurity in women with a history of IUFD is rarely spontaneous but mainly associated with adverse obstetric conditions. One explanation for the significant difference in number of adverse outcomes between the placental and nonplacental groups in the present study could be that placental causes were the most common
Table 4 Obstetric complications by cause of previous IUFD.a Cause
IUFD
Preterm birth
SGA
Maternal vascular complications of pregnancyb
Any complicationc,d
Placental (n = 50) Adnexal (n = 12) Malformative (n = 4) Metabolic (n = 2) Unexplained (n = 19) Total (n = 87)
3 (6) 0 0 0 0 3 (3)
16 (32) 1 (8) 0 1 (50) 4 (21) 22 (25)
2 (4) 1 (8) 0 0 2 (11) 5 (6)
6 (12) 0 0 0 0 6 (7)
27 (54) 2 (17) 0 1 (50) 4 (21) 34 (39)
Abbreviations: IUFD, intrauterine fetal death; SGA, small for gestational age. a Values are given as number (percentage). b Pre-eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), or placental abruption. c Composite outcome including IUFD and/or preterm birth and/or SGA and/or maternal vascular complications of pregnancy. d More than one complication could occur in the same pregnancy.
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
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C. Maignien et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
Fig. 1. Obstetric outcomes according to gestational age at the time of the index IUFD. Abbreviations: IUFD, intrauterine fetal death; PTB, preterm birth; SGA, small for gestational age; MVC, maternal vascular complications of pregnancy (preeclampsia, HELLP syndrome, placental abruption).
reasons for previous IUFD, probably owing to a referral bias. Indeed, several women were referred by the pathologist to the Department of Obstetrics at Trousseau Hospital for their next pregnancy when there were signs of ischemic placental disease. Nevertheless, the adverse obstetric outcomes reported in the present study also support the findings of a recent study [16] that showed that the risk of intrauterine growth retardation was increased in a pregnancy following a prior placental stillbirth (odds ratio 10.5; 95% confidence interval 1.12–245.6; P = 0.016). However, Surkan et al. [17] reported that the risk of a subsequent stillbirth is increased when the first pregnancy has been complicated by pre-eclampsia and a SGA birth, even when it ended with a live birth. Such data suggest that women with a history of placental IUFD have a greater risk of complications during the next pregnancy, probably because the etiology of the impaired placental condition that was involved in the initial stillbirth is still present at the second pregnancy despite preventive treatments (e.g. aspirin and lowmolecular-weight heparin). Among the three recurrent IUFDs, two occurred during the second trimester. Although no definitive conclusions can be drawn from a small series, these findings support those from other studies [6,9] showing a higher risk of stillbirth recurrence for early IUFD (b28 weeks). The main limitations of our study are the lack of a control group and the fairly limited number of pregnancies after stillbirth. In conclusion, the overall prognosis of pregnancies following a second- or third- trimester IUFD was favorable in most cases in the present study, with only a low level of recurrence; however, there were a high number of adverse obstetric outcomes among women with a previous placental stillbirth. Further large controlled studies are needed to confirm these findings and to help physicians to counsel patients. Conflict of interest
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The authors have no conflicts of interest.
Please cite this article as: Maignien C, et al, Outcome of pregnancy following second- or third-trimester intrauterine fetal death, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.06.015
