http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–4 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.923394
ORIGINAL ARTICLE
Perinatal outcomes of women with a prior history of unexplained recurrent miscarriage
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
Mark A. Dempsey1, Karen Flood1, Naomi Burke1, Patricia Fletcher2, Colin Kirkham2, Michael P. Geary2, and Fergal D. Malone1 1
Department of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland, Rotunda Hospital, Dublin, Ireland and 2Department of Obstetrics and Gynaecology, Rotunda Hospital, Dublin, Ireland Abstract
Keywords
Objective: We sought to determine subsequent pregnancy outcomes in a cohort of women with a history of unexplained recurrent miscarriage (RM) who were not receiving medical treatment. Study design: This was a prospective cohort study, of women with a history of three unexplained consecutive first trimester losses, who were recruited and followed in their subsequent pregnancy. Control patients were healthy pregnant patients with no previous adverse perinatal outcome. Results: A total of 42 patients with a history of unexplained RM were recruited to the study. About nine (21.4%) experienced a further first trimester miscarriage, one case of ectopic and one case of partial molar pregnancy. About 74% (23/31) of the RM cohort had a vaginal delivery. There was one case of severe pre-eclampsia. The RM group delivered at a mean gestational age of 38 + 2 weeks and with a mean birthweight of 3.23 kg. None of the neonates were under the 10th centile for gestational age. Overall, there was no significant difference in pregnancy outcomes between the two cohorts. Conclusion: Our study confirms the reassuring prognosis for achieving a live birth in the unexplained RM population with a very low incidence of adverse events with the majority delivering appropriately grown fetuses at term.
Aggregation, platelets, recurrent miscarriage
Introduction Recurrent miscarriage (RM) with three or more consecutive pregnancy losses occurs in 1–3% of couples trying to conceive [1–5]. It has been documented that at least half of these will remain unexplained after investigation [6]. The major known causes include antiphospholipid syndrome, abnormal parental karyotype, endocrine disorders and abnormal uterine pathology. Women with acquired and congenital thrombophilia have been shown to have increased rates of RM and adverse pregnancy outcomes across all gestational ages [7–9]. Some earlier studies have suggested that in patients with a history of RM subsequent ongoing pregnancies may be at an increased risk of obstetric complications. Rai et al. [10] performed a detailed review of RM patients and identified specific reproductive characteristics associated with subsequent poor pregnancy prognosis such as stillbirth, intrauterine
Address for correspondence: Mark A. Dempsey, Royal College of Surgeons in Ireland, OBGYN, Rotunda Hospital, Parnell Street, Dublin 1, Dublin, Ireland. E-mail: [email protected]
History Received 6 January 2014 Revised 14 April 2014 Accepted 8 May 2014 Published online 4 June 2014
growth restriction and prematurity. More recently, Trogstad et al. [11] performed a large population-based study of RM and found a trend towards an increased risk of pre-eclampsia (PET) in patients with a history of RM. This association became significant with the additive effect of a history of fertility treatment, producing an adjusted odds ratio for PET of 2.40 (95% CI – 1.11–5.18). Jivraj et al. [12] looked at 162 RM-associated pregnancies that progressed beyond 24 weeks’ gestation and found a significantly higher percentage of preterm labor (PTL), small for gestational age (SGA), perinatal loss and caesarean delivery. They advised that RM-associated pregnancies should be managed as high risk pregnancies and require close antenatal surveillance. However, these studies included all cases of RM, not distinguishing between patients with a known causative factor for RM. There is a dearth of literature describing subsequent perinatal outcomes in those select patients with a history of unexplained RM. Clifford et al. [13] retrospectively evaluated the miscarriage rate in subsequent pregnancies of 201 patients with a history of unexplained RM and found a 25% rate of subsequent repeat miscarriage in women under 30 years of age, rising to 52% in those over the age of 40 years. Their study showed better live birth outcomes for those patients who attend a dedicated RM clinic despite no pharmaceutical intervention. However, their
2
M. A. Dempsey et al.
study failed to address later obstetrical and neonatal outcomes which our study attempts to address. Overall, there are limited clinical data available regarding subsequent pregnancy outcome in patients who achieve a viable pregnancy after a background history of unexplained RM. Our study aimed to prospectively evaluate pregnancy outcomes beyond the first trimester to determine whether additional specific obstetric risks exist and thus more appropriately counsel and target management in patients with a history of unexplained RM.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
Materials and methods This was a prospective cohort study which included a study group of patients attending for antenatal care at the RM clinic in the Rotunda Hospital prior to 9 weeks’ gestation. Patients with a history of either primary or secondary recurrent miscarriage (at least three consecutive miscarriages) were referred to our specialized tertiary referral centre for investigations. Patients were screened for endometrial cavity abnormalities by ultrasound and also by either hysteroscopy or hysterosalphingogram. Structural abnormality of the endometrial cavity included septated uterus, bicornate uterus or presence of Asherman’s syndrome. Blood tests were performed to screen for medical disorders including thyroid dysfunction (thyroid stimulating antibody and thyroxine levels), pituitary dysfunction (LH, FSH and prolactin), ovarian dysfunction (estradiol and progesterone) and for abnormal platelet count. Patients were only screened for diabetes mellitus if they had symptoms, PCOS or previous gestational diabetes. Blood analysis for the presence of antiphospholipid syndrome included lupus anticoagulant, anticardiolipin antibodies and anti-b2 glycoportein-1. A thrombophila screen was performed, and included testing for deficiencies of protein C, protein S and antithrombin III, activated protein C resistance, activated partial thromboplastin time (APTT) and prothombin time (PT). Couples were also offered karotype analysis for both parents to identify a structural chromosomal anomaly. Patient were then given the results and classified as unexplained RM if all of the above tests were normal. They were invited back to the clinic to attend as soon as they were pregnant to monitor their pregnancy from early gestational age. Recruitment to this trial took place when patients with a diagnosis of unexplained RM first attended the clinic with a positive pregnancy test, no evidence of miscarriage and were not on any medical intervention or on anti-platelet therapy. The inclusion criteria for the control cohort of healthy pregnant patients included only those with a viable pregnancy at their initial antenatal visit and who were willing to participate in the study. Exclusion criteria for the control cohort included a personal or family history of venous thromboembolism, a prior history of stillbirth, intrauterine growth restriction, preeclampsia or preterm labor, a history of more than one prior first trimester miscarriage, the presence of medical disorders such as thyroid disease, abnormal platelet count 5140 000 mm3, or use of aspirin or LMWH. Consecutive patients with a prior diagnosis of unexplained RM were asked to participate in this study. No patient with a history of unexplained RM refused inclusion to the study.
J Matern Fetal Neonatal Med, Early Online: 1–4
Five patients during this time period were not included in the study as they were already taking or planning to take aspirin (of which two were taking LMWH plus aspirin). Of the nine patients who had a repeat miscarriage in the study, seven of the patients had normal parental karotype analysis and the other two had normal karotypes on products of conception. Of the 31 who had successful live birth outcomes, 23 had either normal parental or product of conception karotypes, or both. Eight patients did not agree to karyotyping of products of conception. Patients were recruited over 1 year, and all patients within that year that were eligible for analysis were included. We used very strict inclusion criteria to classify patients as having unexplained RM, which is why only 42 patients satisfied these inclusion criteria despite the Rotunda Hospital being a major tertiary referral centre, delivering over 9000 patients per year. Controls were invited to participate consecutively at the general antenatal booking clinics and were recruited later than the unexplained RM group due to the fact that they typically only booked to the hospital after 12 weeks’ gestation. Patients were followed up in the RM clinic and their obstetrical outcomes were noted as they progressed through their pregnancies. Antepartum and obstetrical outcomes were recorded in a Microsoft Excel file for statistical analysis.
Results During the study period, 42 study patients were recruited from the recurrent miscarriage clinic prior to 9 weeks’ gestation. Within this cohort, there were 11 subsequent first trimester pregnancy losses, which included 9 miscarriages (21.4%), 1 ectopic and 1 molar pregnancy. The average age in this group was 35.4 years (range 30–42) and they had a median of four miscarriages prior to the index pregnancy. Only two out of the nine patients with a subsequent repeat miscarriage had a previous successful pregnancy outcome. Of these nine miscarriages, three were anembryonic and six had a visible embryo on early ultrasound. Two of these six had initially visible cardiac activity which subsequently stopped. There was one ectopic pregnancy managed surgically with a salpingectomy and one partial molar pregnancy diagnosed after evacuation of retained products. Within the RM study cohort, the remaining 31 pregnancies continued into the second trimester and ultimately all had successful pregnancy outcomes. Of the 11 women who did not have a successful obstetric outcome pregnancy in this study, 6 patients subsequently have had a successful pregnancy after this study was completed in a later pregnancy. Thirty-one healthy pregnant controls were recruited during their booking visit to allow comparison of the pregnancy outcomes. Matching was based on age, ethnicity, body mass index and smoking status. There was no statistically significant difference in baseline characteristics between the RM group with successful pregnancies and the healthy pregnant controls (Table 1). Table 2 demonstrates the perinatal outcomes of the RM and control groups. While the RM group had twice as many elective cesarean deliveries compared with controls, this did not reach statistical significance (p ¼ 0.553). There was 100% live-birth outcome in the RM cohort with ongoing
Obstetric outcomes following a history of unexplained recurrent miscarriage
DOI: 10.3109/14767058.2014.923394
3
Table 1. Baseline characteristics of each cohort. Characteristic
RM with repeat miscarriage
RM with successful pregnancy
Healthy pregnant controls
Number Mean age (range) Ethnic origin (No.)
9 35.4 years (30–42) 9 Caucasian 100%
31 33.65 (27–39) 29 Caucasian (93.5%) 2 Asian (6.5%)
At least one previous live birth Smoker Mean BMI (range) No. of miscarriages
2 (22.2%) 0 (0%) 23.9 (18–28) median 4 (range 3–5)
31 33.5 years (27–42) 28 Caucasian (90.3%) 2 African (6.5%) 1 Asian (3.2%) 16 (51.6%) 1 (3.2%) 25.4 (19–39) Median 4 (range 3–9)
16 (51.6%) 0 (0%) 24.94 (20–39) 8 (25.8%) had 1
RM, recurrent miscarriage; No, number; BMI, body mass index. Table 2. Perinatal outcomes.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
Characteristic Live birth Birthweight – mean (range) Gestational age at delivery Mean (range) Birth centiles (mean) Mode of delivery Emergency LSCS Elective LSCS Vaginal delivery Gestational diabetes Pre-eclampsia IUGR 510th centile Aneuploidy Structural abnormality Induction of labor
RM with successful pregnancy 31 (100%) 3230 (660–4500) 38 + 2 weeks (25–41 + 10) 56.4 2 6 23 1 1 0 0 1 12
(6.5%) (19.4%) (74.2%) (3.2%) (3.2%) (0%) (0%) (3.2%) duodenal atresia (38.7%)
Healthy pregnant controls 30 (96.8%) 3581 (1300–4380) 39 + 4 (31 + 2–40 + 11) 59.7 2 3 26 1 0 1 1 0 13
(6.5%) (9.7%) (83.9%) (3.2%) (0%) (3.2%) (3.2%) Trisomy 21 (0%) (41.9%)
p value (*test) 1.000 0.086 0.004 0.800
(3) (1) (2) (1)
0.553 1.000 1.000 1.000 1.000 1.000 1.000
(2) (3) (3) (3) (3) (3) (3)
*Statistical test used: 1, Mann–Whitney U test; 2, Pearson chi-squared; 3, Fisher’s exact test; RM, recurrent miscarriage; LSCS, lower segment caesarean section; IUGR, intra-uterine growth restriction.
pregnancies after the first trimester. There was one case of stillbirth in the healthy pregnant control group, and this was the only fetus with an estimated fetal weight less than the 10th centile in either group. Overall, there was no significant difference in birthweight centiles between the groups (p ¼ 0.8), with a mean birthweight of 3230 g (56th centile for gestational age) in the RM cohort compared to 3581 g (59th centile) in the healthy controls. However, there was a statistically significant difference in gestational age at delivery between the two groups with the RM group having a mean gestational age at delivery of 38 + 2 weeks, while the controls had a mean gestational age at delivery of 39 + 4 weeks (p ¼ 0.004). Three obstetric complications occurred in the RM group, with one episode of severe early onset pre-eclampsia, one prenatal diagnosis of a structural anomaly (isolated duodenal atresia) and one case of insulin-requiring gestational diabetes. There were also three cases of obstetric complications in the control group with one episode of aneuploidy (Trisomy 21), one stillbirth in an IUGR pregnancy and one case of insulinrequiring gestational diabetes. There were two infants born before 37 weeks’ gestation in the RM group: one delivered at 25 weeks’ gestation for severe pre-eclampsia and one delivered at 30 weeks’ gestation following preterm rupture of membranes due to polyhydramnios secondary to duodenal atresia. There were also two infants born before 37 weeks’ gestation in the control group: one delivered at 31 weeks’ gestation following unexplained stillbirth, and one delivered
at 35 weeks’ gestation due to spontaneous preterm labor. See Table 2 for a table of results.
Comment Our study clearly demonstrates reassuring clinical outcomes for women with a history of unexplained RM who achieve pregnancy beyond the first trimester. The adverse pregnancy outcomes typically associated with the heterogeneous causes of RM, such as stillbirth, pre-eclampsia, intrauterine growth restriction, preterm labor and perinatal loss, were not seen in this specific cohort of unexplained RM cases. The successful live birth outcome of 31/42 (73.8%) in women with unexplained RM was similar to that described by Clifford et al. [13] who found a live birth rate of 74% in a retrospective study with a history of unexplained RM attending their dedicated clinic. Our study went a step further and evaluated the perinatal outcomes of these live birth outcomes which was failed to be addressed by other studies. This made our study one of the few studies addressing perinatal outcomes in the unexplained RM patient. The American College of Obstetricians and Gynecologists has suggested that a subsequent live birth rate of 80% can be expected after a single miscarriage and 60% after three consecutive unexplained RM [14]. Our study therefore gives reassuring evidence for couples trying to achieve their goal of a live birth despite a background of unexplained RM.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
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Previous studies have suggested mixed results for perinatal outcomes after a background history of RM. Reginald et al. [15] in 1987 looked at 118 women with RM and found a 30% rate of small for gestational age (less than or equal to the 10th centile) fetuses, a preterm delivery rate of 28% and a perinatal mortality rate of 1.6% in fetuses after 28 weeks’ gestation. Jivraj et al. [12] reported similar findings with small for gestational age rates of 13%, preterm delivery rates of 13% and perinatal loss of 2.5%. These high rates of adverse outcomes were not seen in our study. Our study showed a preterm delivery rate of 2/31 (6.5%), with no cases of small for gestational age and no pregnancy losses after 12 weeks’ gestation. However, each of these prior studies combined both unexplained and explained RM cases. In our study, the unexplained RM patients delivered at a mean gestational age of 38 + 2 weeks’ gestation, 9 days earlier than that of healthy pregnant controls, which likely explains their smaller size (3.23 versus 3.58 kg).This finding might be explained by the fact that the RM patients may have been electively induced earlier in the pregnancy due to their previous poor obstetrical history and may have been less likely to accept progression to postmaturity. When birthweight is corrected for gestational age there was no difference in weight between the groups. In summary, little data are available to counsel patients regarding subsequent perinatal outcomes in the specific setting of prior unexplained RM. Earlier studies on perinatal outcomes of RM patients have been limited by their inclusion of all subgroups of RM for analysis. Our study demonstrates that women with unexplained RM who are found to have no identifiable underlying cause of miscarriage have an excellent live birth rate and can be expected to have normal perinatal outcomes with appropriately grown fetuses. Although our study numbers are small, this was due to the strict inclusion criteria used. Ideally, larger scale studies may be helpful in confirming our findings.
J Matern Fetal Neonatal Med, Early Online: 1–4
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Ware Branch D, Gibson M, Silver RM. Recurrent miscarriage. N Engl J Med 2010;363:1740–7. 2. Royal College of Obstetricians and Gynaecologists; Green-Top Guideline No. 17. Recurrent Miscarriage, Investigation and Treatments of Couples. Published April 2011. 3. Stirrat GM. Recurrent miscarriage. Lancet 1990;336:673–5. 4. Stirrat GM. Recurrent miscarriage II: clinical associations, causes and management. Lancet 2003;336:728–33. 5. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidencebased guidelines for the investigation and treatment of recurrent miscarriage. Hum Reprod 2006;21:2216–22. 6. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994;9:1328–32. 7. Rai RS, Regan L, Clifford K, et al. Antiphospholipid antibodies and b2-glycoprotein-1 in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995;10: 2001–5. 8. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913–16. 9. Kupferminc, MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9–13. 10. Rai RS, Regan L. Recurrent miscarriage. Lancet 2006;368:601–11. 11. Trogstad L, Magnus P, Moffett A, Stoltenberg C. The effect of recurrent miscarriage and infertility on the risk of pre-eclampsia. BJOG 2009;116:108–13. 12. Jivraj S, Anstie A, Cheong Y, et al. Obstetric and neonatal outcomes in women with a history of recurrent miscarriage: a cohort study. Hum Reprod 2001;16:102–6. 13. Clifford K, Rai R, Regan L. Future pregnancy outcomes in unexplained recurrent first trimester miscarriage. Hum Reprod 1997;12:387–9. 14. ACOG Practice Bulletin. Management of recurrent pregnancy loss. No. 24, February 2001. Int J Gynaecol Obstet 2002;78:179–90. 15. Reginald PW, Beard RW, Chapple J, et al. Outcomes of pregnancies progressing beyond 28 weeks gestation in women with a history of recurrent miscarriage. Br J Obstet Gynaecol 1987;94:643–8.
ORIGINAL ARTICLE
Perinatal outcomes of women with a prior history of unexplained recurrent miscarriage
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
Mark A. Dempsey1, Karen Flood1, Naomi Burke1, Patricia Fletcher2, Colin Kirkham2, Michael P. Geary2, and Fergal D. Malone1 1
Department of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland, Rotunda Hospital, Dublin, Ireland and 2Department of Obstetrics and Gynaecology, Rotunda Hospital, Dublin, Ireland Abstract
Keywords
Objective: We sought to determine subsequent pregnancy outcomes in a cohort of women with a history of unexplained recurrent miscarriage (RM) who were not receiving medical treatment. Study design: This was a prospective cohort study, of women with a history of three unexplained consecutive first trimester losses, who were recruited and followed in their subsequent pregnancy. Control patients were healthy pregnant patients with no previous adverse perinatal outcome. Results: A total of 42 patients with a history of unexplained RM were recruited to the study. About nine (21.4%) experienced a further first trimester miscarriage, one case of ectopic and one case of partial molar pregnancy. About 74% (23/31) of the RM cohort had a vaginal delivery. There was one case of severe pre-eclampsia. The RM group delivered at a mean gestational age of 38 + 2 weeks and with a mean birthweight of 3.23 kg. None of the neonates were under the 10th centile for gestational age. Overall, there was no significant difference in pregnancy outcomes between the two cohorts. Conclusion: Our study confirms the reassuring prognosis for achieving a live birth in the unexplained RM population with a very low incidence of adverse events with the majority delivering appropriately grown fetuses at term.
Aggregation, platelets, recurrent miscarriage
Introduction Recurrent miscarriage (RM) with three or more consecutive pregnancy losses occurs in 1–3% of couples trying to conceive [1–5]. It has been documented that at least half of these will remain unexplained after investigation [6]. The major known causes include antiphospholipid syndrome, abnormal parental karyotype, endocrine disorders and abnormal uterine pathology. Women with acquired and congenital thrombophilia have been shown to have increased rates of RM and adverse pregnancy outcomes across all gestational ages [7–9]. Some earlier studies have suggested that in patients with a history of RM subsequent ongoing pregnancies may be at an increased risk of obstetric complications. Rai et al. [10] performed a detailed review of RM patients and identified specific reproductive characteristics associated with subsequent poor pregnancy prognosis such as stillbirth, intrauterine
Address for correspondence: Mark A. Dempsey, Royal College of Surgeons in Ireland, OBGYN, Rotunda Hospital, Parnell Street, Dublin 1, Dublin, Ireland. E-mail: [email protected]
History Received 6 January 2014 Revised 14 April 2014 Accepted 8 May 2014 Published online 4 June 2014
growth restriction and prematurity. More recently, Trogstad et al. [11] performed a large population-based study of RM and found a trend towards an increased risk of pre-eclampsia (PET) in patients with a history of RM. This association became significant with the additive effect of a history of fertility treatment, producing an adjusted odds ratio for PET of 2.40 (95% CI – 1.11–5.18). Jivraj et al. [12] looked at 162 RM-associated pregnancies that progressed beyond 24 weeks’ gestation and found a significantly higher percentage of preterm labor (PTL), small for gestational age (SGA), perinatal loss and caesarean delivery. They advised that RM-associated pregnancies should be managed as high risk pregnancies and require close antenatal surveillance. However, these studies included all cases of RM, not distinguishing between patients with a known causative factor for RM. There is a dearth of literature describing subsequent perinatal outcomes in those select patients with a history of unexplained RM. Clifford et al. [13] retrospectively evaluated the miscarriage rate in subsequent pregnancies of 201 patients with a history of unexplained RM and found a 25% rate of subsequent repeat miscarriage in women under 30 years of age, rising to 52% in those over the age of 40 years. Their study showed better live birth outcomes for those patients who attend a dedicated RM clinic despite no pharmaceutical intervention. However, their
2
M. A. Dempsey et al.
study failed to address later obstetrical and neonatal outcomes which our study attempts to address. Overall, there are limited clinical data available regarding subsequent pregnancy outcome in patients who achieve a viable pregnancy after a background history of unexplained RM. Our study aimed to prospectively evaluate pregnancy outcomes beyond the first trimester to determine whether additional specific obstetric risks exist and thus more appropriately counsel and target management in patients with a history of unexplained RM.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
Materials and methods This was a prospective cohort study which included a study group of patients attending for antenatal care at the RM clinic in the Rotunda Hospital prior to 9 weeks’ gestation. Patients with a history of either primary or secondary recurrent miscarriage (at least three consecutive miscarriages) were referred to our specialized tertiary referral centre for investigations. Patients were screened for endometrial cavity abnormalities by ultrasound and also by either hysteroscopy or hysterosalphingogram. Structural abnormality of the endometrial cavity included septated uterus, bicornate uterus or presence of Asherman’s syndrome. Blood tests were performed to screen for medical disorders including thyroid dysfunction (thyroid stimulating antibody and thyroxine levels), pituitary dysfunction (LH, FSH and prolactin), ovarian dysfunction (estradiol and progesterone) and for abnormal platelet count. Patients were only screened for diabetes mellitus if they had symptoms, PCOS or previous gestational diabetes. Blood analysis for the presence of antiphospholipid syndrome included lupus anticoagulant, anticardiolipin antibodies and anti-b2 glycoportein-1. A thrombophila screen was performed, and included testing for deficiencies of protein C, protein S and antithrombin III, activated protein C resistance, activated partial thromboplastin time (APTT) and prothombin time (PT). Couples were also offered karotype analysis for both parents to identify a structural chromosomal anomaly. Patient were then given the results and classified as unexplained RM if all of the above tests were normal. They were invited back to the clinic to attend as soon as they were pregnant to monitor their pregnancy from early gestational age. Recruitment to this trial took place when patients with a diagnosis of unexplained RM first attended the clinic with a positive pregnancy test, no evidence of miscarriage and were not on any medical intervention or on anti-platelet therapy. The inclusion criteria for the control cohort of healthy pregnant patients included only those with a viable pregnancy at their initial antenatal visit and who were willing to participate in the study. Exclusion criteria for the control cohort included a personal or family history of venous thromboembolism, a prior history of stillbirth, intrauterine growth restriction, preeclampsia or preterm labor, a history of more than one prior first trimester miscarriage, the presence of medical disorders such as thyroid disease, abnormal platelet count 5140 000 mm3, or use of aspirin or LMWH. Consecutive patients with a prior diagnosis of unexplained RM were asked to participate in this study. No patient with a history of unexplained RM refused inclusion to the study.
J Matern Fetal Neonatal Med, Early Online: 1–4
Five patients during this time period were not included in the study as they were already taking or planning to take aspirin (of which two were taking LMWH plus aspirin). Of the nine patients who had a repeat miscarriage in the study, seven of the patients had normal parental karotype analysis and the other two had normal karotypes on products of conception. Of the 31 who had successful live birth outcomes, 23 had either normal parental or product of conception karotypes, or both. Eight patients did not agree to karyotyping of products of conception. Patients were recruited over 1 year, and all patients within that year that were eligible for analysis were included. We used very strict inclusion criteria to classify patients as having unexplained RM, which is why only 42 patients satisfied these inclusion criteria despite the Rotunda Hospital being a major tertiary referral centre, delivering over 9000 patients per year. Controls were invited to participate consecutively at the general antenatal booking clinics and were recruited later than the unexplained RM group due to the fact that they typically only booked to the hospital after 12 weeks’ gestation. Patients were followed up in the RM clinic and their obstetrical outcomes were noted as they progressed through their pregnancies. Antepartum and obstetrical outcomes were recorded in a Microsoft Excel file for statistical analysis.
Results During the study period, 42 study patients were recruited from the recurrent miscarriage clinic prior to 9 weeks’ gestation. Within this cohort, there were 11 subsequent first trimester pregnancy losses, which included 9 miscarriages (21.4%), 1 ectopic and 1 molar pregnancy. The average age in this group was 35.4 years (range 30–42) and they had a median of four miscarriages prior to the index pregnancy. Only two out of the nine patients with a subsequent repeat miscarriage had a previous successful pregnancy outcome. Of these nine miscarriages, three were anembryonic and six had a visible embryo on early ultrasound. Two of these six had initially visible cardiac activity which subsequently stopped. There was one ectopic pregnancy managed surgically with a salpingectomy and one partial molar pregnancy diagnosed after evacuation of retained products. Within the RM study cohort, the remaining 31 pregnancies continued into the second trimester and ultimately all had successful pregnancy outcomes. Of the 11 women who did not have a successful obstetric outcome pregnancy in this study, 6 patients subsequently have had a successful pregnancy after this study was completed in a later pregnancy. Thirty-one healthy pregnant controls were recruited during their booking visit to allow comparison of the pregnancy outcomes. Matching was based on age, ethnicity, body mass index and smoking status. There was no statistically significant difference in baseline characteristics between the RM group with successful pregnancies and the healthy pregnant controls (Table 1). Table 2 demonstrates the perinatal outcomes of the RM and control groups. While the RM group had twice as many elective cesarean deliveries compared with controls, this did not reach statistical significance (p ¼ 0.553). There was 100% live-birth outcome in the RM cohort with ongoing
Obstetric outcomes following a history of unexplained recurrent miscarriage
DOI: 10.3109/14767058.2014.923394
3
Table 1. Baseline characteristics of each cohort. Characteristic
RM with repeat miscarriage
RM with successful pregnancy
Healthy pregnant controls
Number Mean age (range) Ethnic origin (No.)
9 35.4 years (30–42) 9 Caucasian 100%
31 33.65 (27–39) 29 Caucasian (93.5%) 2 Asian (6.5%)
At least one previous live birth Smoker Mean BMI (range) No. of miscarriages
2 (22.2%) 0 (0%) 23.9 (18–28) median 4 (range 3–5)
31 33.5 years (27–42) 28 Caucasian (90.3%) 2 African (6.5%) 1 Asian (3.2%) 16 (51.6%) 1 (3.2%) 25.4 (19–39) Median 4 (range 3–9)
16 (51.6%) 0 (0%) 24.94 (20–39) 8 (25.8%) had 1
RM, recurrent miscarriage; No, number; BMI, body mass index. Table 2. Perinatal outcomes.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.
Characteristic Live birth Birthweight – mean (range) Gestational age at delivery Mean (range) Birth centiles (mean) Mode of delivery Emergency LSCS Elective LSCS Vaginal delivery Gestational diabetes Pre-eclampsia IUGR 510th centile Aneuploidy Structural abnormality Induction of labor
RM with successful pregnancy 31 (100%) 3230 (660–4500) 38 + 2 weeks (25–41 + 10) 56.4 2 6 23 1 1 0 0 1 12
(6.5%) (19.4%) (74.2%) (3.2%) (3.2%) (0%) (0%) (3.2%) duodenal atresia (38.7%)
Healthy pregnant controls 30 (96.8%) 3581 (1300–4380) 39 + 4 (31 + 2–40 + 11) 59.7 2 3 26 1 0 1 1 0 13
(6.5%) (9.7%) (83.9%) (3.2%) (0%) (3.2%) (3.2%) Trisomy 21 (0%) (41.9%)
p value (*test) 1.000 0.086 0.004 0.800
(3) (1) (2) (1)
0.553 1.000 1.000 1.000 1.000 1.000 1.000
(2) (3) (3) (3) (3) (3) (3)
*Statistical test used: 1, Mann–Whitney U test; 2, Pearson chi-squared; 3, Fisher’s exact test; RM, recurrent miscarriage; LSCS, lower segment caesarean section; IUGR, intra-uterine growth restriction.
pregnancies after the first trimester. There was one case of stillbirth in the healthy pregnant control group, and this was the only fetus with an estimated fetal weight less than the 10th centile in either group. Overall, there was no significant difference in birthweight centiles between the groups (p ¼ 0.8), with a mean birthweight of 3230 g (56th centile for gestational age) in the RM cohort compared to 3581 g (59th centile) in the healthy controls. However, there was a statistically significant difference in gestational age at delivery between the two groups with the RM group having a mean gestational age at delivery of 38 + 2 weeks, while the controls had a mean gestational age at delivery of 39 + 4 weeks (p ¼ 0.004). Three obstetric complications occurred in the RM group, with one episode of severe early onset pre-eclampsia, one prenatal diagnosis of a structural anomaly (isolated duodenal atresia) and one case of insulin-requiring gestational diabetes. There were also three cases of obstetric complications in the control group with one episode of aneuploidy (Trisomy 21), one stillbirth in an IUGR pregnancy and one case of insulinrequiring gestational diabetes. There were two infants born before 37 weeks’ gestation in the RM group: one delivered at 25 weeks’ gestation for severe pre-eclampsia and one delivered at 30 weeks’ gestation following preterm rupture of membranes due to polyhydramnios secondary to duodenal atresia. There were also two infants born before 37 weeks’ gestation in the control group: one delivered at 31 weeks’ gestation following unexplained stillbirth, and one delivered
at 35 weeks’ gestation due to spontaneous preterm labor. See Table 2 for a table of results.
Comment Our study clearly demonstrates reassuring clinical outcomes for women with a history of unexplained RM who achieve pregnancy beyond the first trimester. The adverse pregnancy outcomes typically associated with the heterogeneous causes of RM, such as stillbirth, pre-eclampsia, intrauterine growth restriction, preterm labor and perinatal loss, were not seen in this specific cohort of unexplained RM cases. The successful live birth outcome of 31/42 (73.8%) in women with unexplained RM was similar to that described by Clifford et al. [13] who found a live birth rate of 74% in a retrospective study with a history of unexplained RM attending their dedicated clinic. Our study went a step further and evaluated the perinatal outcomes of these live birth outcomes which was failed to be addressed by other studies. This made our study one of the few studies addressing perinatal outcomes in the unexplained RM patient. The American College of Obstetricians and Gynecologists has suggested that a subsequent live birth rate of 80% can be expected after a single miscarriage and 60% after three consecutive unexplained RM [14]. Our study therefore gives reassuring evidence for couples trying to achieve their goal of a live birth despite a background of unexplained RM.
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M. A. Dempsey et al.
Previous studies have suggested mixed results for perinatal outcomes after a background history of RM. Reginald et al. [15] in 1987 looked at 118 women with RM and found a 30% rate of small for gestational age (less than or equal to the 10th centile) fetuses, a preterm delivery rate of 28% and a perinatal mortality rate of 1.6% in fetuses after 28 weeks’ gestation. Jivraj et al. [12] reported similar findings with small for gestational age rates of 13%, preterm delivery rates of 13% and perinatal loss of 2.5%. These high rates of adverse outcomes were not seen in our study. Our study showed a preterm delivery rate of 2/31 (6.5%), with no cases of small for gestational age and no pregnancy losses after 12 weeks’ gestation. However, each of these prior studies combined both unexplained and explained RM cases. In our study, the unexplained RM patients delivered at a mean gestational age of 38 + 2 weeks’ gestation, 9 days earlier than that of healthy pregnant controls, which likely explains their smaller size (3.23 versus 3.58 kg).This finding might be explained by the fact that the RM patients may have been electively induced earlier in the pregnancy due to their previous poor obstetrical history and may have been less likely to accept progression to postmaturity. When birthweight is corrected for gestational age there was no difference in weight between the groups. In summary, little data are available to counsel patients regarding subsequent perinatal outcomes in the specific setting of prior unexplained RM. Earlier studies on perinatal outcomes of RM patients have been limited by their inclusion of all subgroups of RM for analysis. Our study demonstrates that women with unexplained RM who are found to have no identifiable underlying cause of miscarriage have an excellent live birth rate and can be expected to have normal perinatal outcomes with appropriately grown fetuses. Although our study numbers are small, this was due to the strict inclusion criteria used. Ideally, larger scale studies may be helpful in confirming our findings.
J Matern Fetal Neonatal Med, Early Online: 1–4
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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