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Spontaneous abortion in multiple pregnancy: Focus on fetal pathology
Pathology – Research and Practice 208 (2012) 458–461
Contents lists available at SciVerse ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Original article
Spontaneous abortion in multiple pregnancy: Focus on fetal pathology József Gábor Joó ∗ , Ákos Csaba, Zsanett Szigeti, János Rigó Jr. Semmelweis University, General Medical Faculty, 1st Department of Gynecology and Obstetrics, Hungary
a r t i c l e
i n f o
Article history: Received 29 October 2011 Received in revised form 2 January 2012 Accepted 8 May 2012 Keywords: Spontaneous abortion Multiple pregnancy Monochorionic placentation Perinatal autopsy Developmental disorders Intrauterine infection
a b s t r a c t Multiple pregnancy with its wide array of medical consequences poses an important condition during pregnancy. We performed perinatal autopsy in 49 cases of spontaneous abortion resulting from multiple pregnancies during the study period. Twenty-seven of the 44 twin pregnancies ending in miscarriage were conceived naturally, whereas 17 were conceived through assisted reproductive techniques. Each of the 5 triplet pregnancies ending in miscarriage was conceived through assisted reproductive techniques. There was a positive history of miscarriage in 22.4% of the cases. Monochorial placentation occurred more commonly in multiple pregnancies terminating with miscarriage than in multiple pregnancies without miscarriage. A fetal congenital malformation was found in 8 cases. Three of these cases were conceived through assisted reproductive techniques, and 5 were conceived naturally. Miscarriage was due to intrauterine infection in 36% of the cases. Our study confirms that spontaneous abortion is more common in multiple than in singleton pregnancies. Monochorial placentation predicted a higher fetal morbidity and mortality. In pregnancies where all fetuses were of male gender, miscarriage was more common than in pregnancies where all fetuses were female. Assisted reproductive techniques do not predispose to the development of fetal malformations. © 2012 Elsevier GmbH. All rights reserved.
Introduction Multiple pregnancy with its wide array of medical consequences poses an important condition during pregnancy. The significance of this is further increased by the recent spread of assisted reproductive techniques. In classic obstetric literature, the expected frequency of multiple pregnancy is calculated by the Hellin formula [6,8,18,23]. This formula predicts a ratio of 1 twin pregnancy in every 85 pregnancies, 1 triplet pregnancy in every 852 pregnancies, and 1 quadruplet pregnancy in every 853 pregnancies. Nowadays, with the appearance of assisted reproductive techniques (ART), the incidence of twin pregnancies has increased two-fold, triplet pregnancies approximately twelve-fold and quadruplet pregnancies approximately eighty-fold compared to expected values by the Hellin formula [16]. Furthermore, it has been suggested by some researchers that gestational folic acid supplementation may also moderately increase the risk for multiple pregnancy at least in case of natural conception. However, subsequent papers failed to confirm this [19,27].
∗ Corresponding author at: Semmelweis University, 1st Department of Gynecology and Obstetrics, 1088 Budapest, Baross utca 27, Hungary. Tel.: +36 1 266 04 73; fax: +36 1 317 61 74. E-mail address: [email protected] (J.G. Joó). 0344-0338/$ – see front matter © 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2012.05.011
Based on what factors result in the development of multiple pregnancy, different kinds of placentation may occur [1,12,20,23,24]. In dizygotic fetuses, as well as in monozygotic fetuses when separation of amniotic sacks occurs within a few hours after fertilization of the egg, dichorionic diamniotic placentation develops. If the spatial separation occurs after separation of trophoblasts from embryoblasts, monoplacental diamniotic pregnancy will develop. Monochorionic monoamniotic pregnancy develops when the embryoblasts split immediately before or immediately after implantation. The following maternal complications may be associated with multiple pregnancy: preeclampsia, anemia, cervical incompetence, abruptio placentae, and placenta previa. In terms of fetal complications with multiple pregnancy, increased perinatal morbidity and mortality and increased risk for miscarriage and premature delivery have been observed [5,18,20,23,24]. In this study, we attempted to evaluate and summarize the results of perinatal autopsies performed after spontaneous abortions that occurred in multiple pregnancies between gestational weeks 12–24. In cases of mid-term miscarriages in multiple pregnancy, perinatal autopsy may provide useful information relevant to the risk of future miscarriages. This may be especially valuable if fetal congenital malformation is diagnosed at the autopsy, providing a valuable tool in risk assessment for recurrence.
J.G. Joó et al. / Pathology – Research and Practice 208 (2012) 458–461
Materials and methods In this study, we report data from perinatal biopsies performed at The First Department of Gynecology and Obstetrics, Faculty of General Medicine, Semmelweis University, Budapest, Hungary after mid-term spontaneous abortions in multiple pregnancies during the study period of January 1, 1995–December 31st, 2010. We performed 49 perinatal autopsies from 44 twin pregnancies and 5 triplet pregnancies. Among the 17 multiple pregnancies conceived by ART, no case with the application of donor oocyte occurred. In each case, miscarriage occurred between gestational weeks 12–24. All ultrasound examinations were performed in our departmental ultrasound laboratory. Autopsies were performed in our departmental pathology laboratory based on protocols from our own department, as well as on those from other well-recognized pathology laboratories around the world [2,9,21,22,25]. During the autopsy, we were able to judge the type of placentation, the eventual presence of chorioamnionitis, as well as relevant characteristics of fetal pathology. The diagnostic criteria of chorioamnionitis were positive vaginal discharge sample taken during the pregnancy and histologically verified chorioamnionitis (the evaluation of vaginal discharge samples was performed in the departmental Chemistry Lab). We have collected detailed information about the history concerning previous obstetrical complications (spontaneous abortion, missed abortion, premature birth, intrauterine death, ectopic pregnancy – positive obstetric history), and previous pregnancies with genetic malformations (positive genetic history). If among the clinical diagnoses a likely obstetric etiology was found for the miscarriage, this was identified based on review of the medical records. If a malformation was present in previous pregnancies which was different from the condition giving rise to miscarriage in the current pregnancy, we regarded it as a nonspecific genetic risk. If, however, the malformation was identical in the present and previous pregnancies, risk was regarded specific for that condition. All relevant pieces of information were included in a computerized database. This database was then used for all subsequent analyses. For statistical significance, we used a p value of <0.05. Abbreviations used in this paper included: HC – hydrocephalus; SB – spina bifida; CAM – cysticus adenomatoid malformation; TTTS – twin to twin transfusion syndrome.
Results A total of 2141 autopsies were performed in our pathology laboratory during the study period. Out of these, 378 cases (17.6%) were perinatal autopsies due to miscarriage. During the study period of 16 years, the occurrence of spontaneous abortion was 0.91% per live birth, whereas the occurrence was higher in multiple pregnancies (7.3% per live birth). Out of the 378 miscarriage cases, miscarriage from multiple pregnancy was 49 (12.9%). Forty-four miscarriages out of the 49 (89.8%) were from twin pregnancies and 5 (10.2%) were from triplet pregnancies. Out of the 44 twin pregnancies, 27 (61.4%) were conceived naturally, while 17 (38.6%) were conceived through assisted reproductive techniques. All of the 5 triplet cases were conceived through assisted reproductive techniques. The total number of fetal samples amounted to 103. A positive obstetric history was identified in 11 out of the 49 (22.4%) multiple pregnancy miscarriage cases. In 7 out of these 11 cases (63.6%), assisted reproduction techniques were used, while 4 (36.4%) were conceived naturally. The most common obstetric history was miscarriage in a previous pregnancy (5 cases). The mean maternal age of patients undergoing ART was 33 ± 2.8 years vs. the mean median age value of pregnant women having
459
Table 1 Fetal gender distribution in twin pregnancies ending in spontaneous abortion. Gender distribution
N
%
Male/male Female/female Male/female
23 18 3
52.3 40.9 6.8
a multiple pregnancy conceived spontaneously at 29 ± 3.2 years (p < 0.05). The indication for applying ART technique was pelvic factor in 8/17 cases (47.1%), male factor in 5/17 cases (29.4%), ovulatory factor in 3/17 cases (17.6%), and unexplained infertility in 1/17 cases (5.9%). Fetal gender distribution in the multiple pregnancies resulting in spontaneous abortion is displayed in Table 1. In our series, the number of cases where fetal gender was identical was significantly higher (p < 0.05) than the number of cases with heterogenous fetal gender. In triplet pregnancies, male/male/male fetal gender distribution and female/female/female distribution were equally common (40%; 2 cases each). There was a single case with heterogenous fetal gender (20%). The type of placentation could be identified in 34 cases based on available information. These are described in Table 2. The ratio of monochorionic vs. dichorionic multiple pregnancies was 11:23. The difference in occurrence between mono- and dichorionic pregnancies was not significant (p > 0.05). Given the small number of triplet pregnancies, maternal age was analyzed for the whole multiple pregnancy group, i.e., twin and triplet pregnancies taken together. In cases where no specific fetal pathology was identified on perinatal biopsy, the median maternal age was 30 ± 3.64 years (range: 16–45 years). In cases where a specific fetal pathology was seen, the maternal median age was 29 ± 5.46 years (range: 17–44 years). The difference between these two median values was not statistically significant (p > 0.05). In terms of gestational age at the time of spontaneous abortion, there was no statistical difference between cases where a specific fetal pathology was found vs. cases where fetal pathology could not be identified. The respective values were 19.5 ± 2.77 gestational weeks in the positive fetal pathology group vs. 20 ± 2.35 gestational weeks in the group with no fetal pathology identified (p > 0.05). Fetal congenital malformation was identified in 8 out of the 44 twin pregnancy cases (18.2%); major malformations (which may explain the abortion) were verified in 6/44 (13.6%) and minor ones (not incompatible with postnatal life) in 2/44 (4.6%) cases. In the remaining 36 cases (81.8%), no specific fetal pathology could be identified. As is demonstrated in Table 3, a congenital malformation was present in both fetuses in 1 case, whereas in 7 cases, only one of the fetuses was affected (fetus A: the fetus closer to birth canal). In the cases where a congenital malformation could be identified, the pregnancy was naturally conceived in 63.5% of cases, while assisted reproduction techniques were used in 36.5% of cases. In the triplet pregnancy cases, a congenital malformation was identified in a single case. This congenital malformation was identified as spina bifida lumbosacralis. In this case, as in all other cases of triplet pregnancies, the pregnancy was conceived through assisted reproductive techniques.
Table 2 Types of placentation in multiple pregnancies ending in spontaneous abortion. Placentation
N
%
Monochorionic–monoamniotic placentation Monochorionic–diamniotic placentation Dichorionic–diamniotic placentation
1 10 23
2.9 29.4 67.7
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J.G. Joó et al. / Pathology – Research and Practice 208 (2012) 458–461
Table 3 Fetal pathology found on perinatal autopsy after spontaneous abortion in multiple pregnancy.
1 2 3 4 5 6 7 8
Affected fetus
Observed pathology
B B A B B A B A and B
Auricular aplasia, oligodactyly, pes equinovarus Hydrocephalus internus Accessory renal pelvis (double pelvis) CAM type II Renal agenesis, right-sided Single umbilical artery Single umbilical artery Lumbosacral spina bifida cystica
Table 4 describes the most likely etiologies leading to miscarriage in our study. This data tends to confirm previous reports revealing intrauterine infections as the most common etiology. Among the 16 cases of diagnosed intrauterine infection, 4 (25%) occurred due to premature rupture of membrane. Another relatively common diagnosis was twin–twin transfusion syndrome (TTTS) in 13.6% of the cases. Discussion Our findings support the widely recognized phenomenon that obstetric complications, including spontaneous abortion, are more common in multiple vs. single pregnancy. In our study population, there was an eight-fold higher incidence of miscarriage; this is somewhat higher than the previously reported two- to four-fold difference in occurrence [10,13,20,23,24]. It is remarkable that the ratio of twin pregnancies conceived naturally vs. conceived through assisted reproductive techniques (64% vs. 36%) was identical irrespective of whether miscarriage occurred vs. pregnancy was carried to term. This suggests that assisted reproductive technique does not affect the likelihood of spontaneous abortion in this context. Fitzsimmons et al. came to a similar conclusion [7], proposing that naturally conceived multiple pregnancies may even carry a higher risk for miscarriage compared to those conceived through assisted reproductive techniques. There was a positive history for spontaneous abortion in nearly 64% of multiple pregnancies conceived through assisted reproductive techniques. In some of these cases, assisted reproductive technique was employed precisely because of previous failure to produce live birth due to underlying pathology. The median age of patients undergoing ART was significantly higher than that of women having spontaneously conceived twin pregnancy. As ART is usually applied after years of several attempts to become pregnant spontaneously, this result was as was to be expected. The risk for miscarriage in multiple pregnancies is significantly higher in cases where fetal gender is identical in all fetuses within the given pregnancy [26]; this is supported by our findings. This phenomenon can be explained by the fact that when fetal gender is the same, monochorial, and monoamniotic multiple pregnancy is more likely. It is well recognized that the risk for miscarriage is higher in monochorionic forms of multiple pregnancy [1,15,20]. Table 4 Most likely clinical diagnosis resulting in spontaneous abortion in multiple pregnancy. Clinical diagnosis
N
%
Chorioamnionitis Twin–twin transfusion syndrome (TTTS) Incompetent cervix Preeclampsia Fetal malformation Etiology unclear
16 6 3 1 8 10
36.40 13.60 6.80 2.30 18.20 22.70
However, our findings suggest that the influence of fetal gender goes beyond the question of chorinicity or amnionicity. We found that in the setting where fetal gender was male–male, there was a 13% higher risk for miscarriage compared to cases where fetal gender was female–female. In the 34 cases in which chorionicity could be accurately judged based on available information, dichorionic placentation was significantly more common than monochorionic (23 vs. 11 cases or 68% vs. 32%). Considering that the ratio of monochorionic multiple pregnancies to all multiple pregnancies is expected to be between 15 and 25% [11,12], this tends to support previous beliefs that monochorionicity in multiple pregnancy is a risk factor for the development of miscarriage in this setting [4,10,17]. There is no difference in maternal age between cases where spontaneous abortion occurred through singular or multiple pregnancy. Our study shows that in multiple pregnancy there was no difference in maternal age between cases where, in the background of miscarriage, a fetal congenital malformation could be identified vs. cases in which fetal pathology was not seen. Similarly, there was no significant difference with regard to gestational age at the time of miscarriage in the cases where a fetal pathology was identified vs. cases where there was no such pathology. It is noteworthy that in singular pregnancies, miscarriage associated with congenital malformation generally takes place 3 weeks earlier, compared to cases where a malformation is not identified [14]. In multiple pregnancies, this time difference is usually not seen. In twin pregnancies ending in spontaneous abortion, we found a developmental disorder in at least 1 fetus in 18% of the cases although the rate of major fetal malformations was 13.2%. These data represent a higher incidence of fetal congenital malformation compared to miscarriage in singular pregnancies (10%) [14]. Livingston and Poland found a similar incidence of congenital malformation in at least one fetus in twin pregnancies ending in miscarriage (21%) [20]. Arteaga et al. observed substantially higher incidences; in more than 46% cases were congenital malformations identified [3]. In regard to the relationship of congenital malformations and the nature of conception, we found no difference in the incidence of malformations on the basis of whether conception was natural or induced by assisted reproductive techniques. This contradicts prior observations made by Fitzsimmons et al., demonstrating a higher fetal morbidity in spontaneously conceived multiple pregnancies [7]. In our study, disorders of the central nervous system were prominent among the type of fetal pathology identified. This represented 3 out of the 9 cases of congenital malformation. This confirms previous finding by Arteaga et al., who observed a similar prominence of central nervous system (or craniospinal) disorders in this case scenario [3]. As can be seen in Table 4, the most common clinical diagnosis found in the background of spontaneous abortion was intrauterine infection (chorioamnionitis). This underlines the importance of treatment and especially the prevention of intrauterine infection in an attempt to decrease the incidence of miscarriage. It is important to note that TTTS occurred in more than 30% of the cases, suggesting that this phenomenon deserves further attention, and future studies to evaluate the nature of this relationship are warranted. In conclusion, our study demonstrated that multiple pregnancies are associated with a higher rate of obstetric complications compared to singular pregnancies. Conception through assisted reproductive techniques does not necessarily predict a higher risk for spontaneous abortion in multiple pregnancies. In cases where fetuses have identical gender within a given pregnancy, there is a significantly higher incidence of miscarriage. Among multiple pregnancies ending in spontaneous abortion, there was no
J.G. Joó et al. / Pathology – Research and Practice 208 (2012) 458–461
difference in the incidence of fetal congenital malformations between pregnancies conceived through assisted reproductive techniques vs. naturally conceived pregnancies. References [1] J. Ando, K. Nonaka, K. Ozaki, et al., The Tokyo twin cohort project: overview and initial findings, Twin Res. Hum. Gen. 9 (2006) 817–826. [2] J.G. Archie, J.S. Collins, R.R. Lebel, Quantitative standards for fetal and neonatal autopsy, Anat. Pathol. 126 (2006) 256–265. [3] M. Arteaga, I. García-Peláez, L.R. Cornejo, et al., Fetal dysmorphism in spontaneous abortions in a Mexican population, Int. J. Obstet. Gynecol. 73 (2001) 131–140. [4] R. Bajoria, L.Y. Wee, S. Anwar, et al., Outcome of twin pregnancies complicated by single intrauterine death in relation to vascular anatomy of the monochorionic placenta, Hum. Reprod. 14 (1999) 2124–2130. [5] F.G. Cunningham, N.F. Gant, K.J. Leveno, et al., Multifetal pregnancy, in: F.G. Cunningham (Ed.), Williams Obstetrics, 21st ed., McGraw and Hill, New York, 2001, pp. 765–810. [6] J.O. Fellman, A.W. Eriksson, A mathematical model for recurrent twinning, Acta Genet. Med. Gemellol. 39 (1990) 307–316. [7] B.P. Fitzsimmons, M.W. Bebbington, F.R. Fluker, Perinatal and neonatal outcomes in multiple gestations: assisted reproduction versus spontaneous conception, Am. J. Obstet. Gynecol. 179 (1998) 1162–1167. [8] H.A. Freye, Genetic and peristatic aspects of research on twinning, Zentralbl. Gynakol. 109 (1987) 1401–1408. [9] S.J. Gordijn, J.J. Erwich, Value of perinatal autopsy: critique, Pediatr. Dev. Pathol. 5 (2002) 480–488. [10] W.A. Grobman, A.M. Peaceman, What are the rates and mechanisms of first and second trimester pregnancy loss in twins? Clin. Obstet. Gynecol. 41 (1998) 37–45. [11] A. Gul, A. Cebeci, H. Aslan, I. Polat, et al., Perinatal outcomes of twin pregnancies discordant for major fetal anomalies, Fetal Diagn. Ther. 20 (2005) 244–248.
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Contents lists available at SciVerse ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Original article
Spontaneous abortion in multiple pregnancy: Focus on fetal pathology József Gábor Joó ∗ , Ákos Csaba, Zsanett Szigeti, János Rigó Jr. Semmelweis University, General Medical Faculty, 1st Department of Gynecology and Obstetrics, Hungary
a r t i c l e
i n f o
Article history: Received 29 October 2011 Received in revised form 2 January 2012 Accepted 8 May 2012 Keywords: Spontaneous abortion Multiple pregnancy Monochorionic placentation Perinatal autopsy Developmental disorders Intrauterine infection
a b s t r a c t Multiple pregnancy with its wide array of medical consequences poses an important condition during pregnancy. We performed perinatal autopsy in 49 cases of spontaneous abortion resulting from multiple pregnancies during the study period. Twenty-seven of the 44 twin pregnancies ending in miscarriage were conceived naturally, whereas 17 were conceived through assisted reproductive techniques. Each of the 5 triplet pregnancies ending in miscarriage was conceived through assisted reproductive techniques. There was a positive history of miscarriage in 22.4% of the cases. Monochorial placentation occurred more commonly in multiple pregnancies terminating with miscarriage than in multiple pregnancies without miscarriage. A fetal congenital malformation was found in 8 cases. Three of these cases were conceived through assisted reproductive techniques, and 5 were conceived naturally. Miscarriage was due to intrauterine infection in 36% of the cases. Our study confirms that spontaneous abortion is more common in multiple than in singleton pregnancies. Monochorial placentation predicted a higher fetal morbidity and mortality. In pregnancies where all fetuses were of male gender, miscarriage was more common than in pregnancies where all fetuses were female. Assisted reproductive techniques do not predispose to the development of fetal malformations. © 2012 Elsevier GmbH. All rights reserved.
Introduction Multiple pregnancy with its wide array of medical consequences poses an important condition during pregnancy. The significance of this is further increased by the recent spread of assisted reproductive techniques. In classic obstetric literature, the expected frequency of multiple pregnancy is calculated by the Hellin formula [6,8,18,23]. This formula predicts a ratio of 1 twin pregnancy in every 85 pregnancies, 1 triplet pregnancy in every 852 pregnancies, and 1 quadruplet pregnancy in every 853 pregnancies. Nowadays, with the appearance of assisted reproductive techniques (ART), the incidence of twin pregnancies has increased two-fold, triplet pregnancies approximately twelve-fold and quadruplet pregnancies approximately eighty-fold compared to expected values by the Hellin formula [16]. Furthermore, it has been suggested by some researchers that gestational folic acid supplementation may also moderately increase the risk for multiple pregnancy at least in case of natural conception. However, subsequent papers failed to confirm this [19,27].
∗ Corresponding author at: Semmelweis University, 1st Department of Gynecology and Obstetrics, 1088 Budapest, Baross utca 27, Hungary. Tel.: +36 1 266 04 73; fax: +36 1 317 61 74. E-mail address: [email protected] (J.G. Joó). 0344-0338/$ – see front matter © 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2012.05.011
Based on what factors result in the development of multiple pregnancy, different kinds of placentation may occur [1,12,20,23,24]. In dizygotic fetuses, as well as in monozygotic fetuses when separation of amniotic sacks occurs within a few hours after fertilization of the egg, dichorionic diamniotic placentation develops. If the spatial separation occurs after separation of trophoblasts from embryoblasts, monoplacental diamniotic pregnancy will develop. Monochorionic monoamniotic pregnancy develops when the embryoblasts split immediately before or immediately after implantation. The following maternal complications may be associated with multiple pregnancy: preeclampsia, anemia, cervical incompetence, abruptio placentae, and placenta previa. In terms of fetal complications with multiple pregnancy, increased perinatal morbidity and mortality and increased risk for miscarriage and premature delivery have been observed [5,18,20,23,24]. In this study, we attempted to evaluate and summarize the results of perinatal autopsies performed after spontaneous abortions that occurred in multiple pregnancies between gestational weeks 12–24. In cases of mid-term miscarriages in multiple pregnancy, perinatal autopsy may provide useful information relevant to the risk of future miscarriages. This may be especially valuable if fetal congenital malformation is diagnosed at the autopsy, providing a valuable tool in risk assessment for recurrence.
J.G. Joó et al. / Pathology – Research and Practice 208 (2012) 458–461
Materials and methods In this study, we report data from perinatal biopsies performed at The First Department of Gynecology and Obstetrics, Faculty of General Medicine, Semmelweis University, Budapest, Hungary after mid-term spontaneous abortions in multiple pregnancies during the study period of January 1, 1995–December 31st, 2010. We performed 49 perinatal autopsies from 44 twin pregnancies and 5 triplet pregnancies. Among the 17 multiple pregnancies conceived by ART, no case with the application of donor oocyte occurred. In each case, miscarriage occurred between gestational weeks 12–24. All ultrasound examinations were performed in our departmental ultrasound laboratory. Autopsies were performed in our departmental pathology laboratory based on protocols from our own department, as well as on those from other well-recognized pathology laboratories around the world [2,9,21,22,25]. During the autopsy, we were able to judge the type of placentation, the eventual presence of chorioamnionitis, as well as relevant characteristics of fetal pathology. The diagnostic criteria of chorioamnionitis were positive vaginal discharge sample taken during the pregnancy and histologically verified chorioamnionitis (the evaluation of vaginal discharge samples was performed in the departmental Chemistry Lab). We have collected detailed information about the history concerning previous obstetrical complications (spontaneous abortion, missed abortion, premature birth, intrauterine death, ectopic pregnancy – positive obstetric history), and previous pregnancies with genetic malformations (positive genetic history). If among the clinical diagnoses a likely obstetric etiology was found for the miscarriage, this was identified based on review of the medical records. If a malformation was present in previous pregnancies which was different from the condition giving rise to miscarriage in the current pregnancy, we regarded it as a nonspecific genetic risk. If, however, the malformation was identical in the present and previous pregnancies, risk was regarded specific for that condition. All relevant pieces of information were included in a computerized database. This database was then used for all subsequent analyses. For statistical significance, we used a p value of <0.05. Abbreviations used in this paper included: HC – hydrocephalus; SB – spina bifida; CAM – cysticus adenomatoid malformation; TTTS – twin to twin transfusion syndrome.
Results A total of 2141 autopsies were performed in our pathology laboratory during the study period. Out of these, 378 cases (17.6%) were perinatal autopsies due to miscarriage. During the study period of 16 years, the occurrence of spontaneous abortion was 0.91% per live birth, whereas the occurrence was higher in multiple pregnancies (7.3% per live birth). Out of the 378 miscarriage cases, miscarriage from multiple pregnancy was 49 (12.9%). Forty-four miscarriages out of the 49 (89.8%) were from twin pregnancies and 5 (10.2%) were from triplet pregnancies. Out of the 44 twin pregnancies, 27 (61.4%) were conceived naturally, while 17 (38.6%) were conceived through assisted reproductive techniques. All of the 5 triplet cases were conceived through assisted reproductive techniques. The total number of fetal samples amounted to 103. A positive obstetric history was identified in 11 out of the 49 (22.4%) multiple pregnancy miscarriage cases. In 7 out of these 11 cases (63.6%), assisted reproduction techniques were used, while 4 (36.4%) were conceived naturally. The most common obstetric history was miscarriage in a previous pregnancy (5 cases). The mean maternal age of patients undergoing ART was 33 ± 2.8 years vs. the mean median age value of pregnant women having
459
Table 1 Fetal gender distribution in twin pregnancies ending in spontaneous abortion. Gender distribution
N
%
Male/male Female/female Male/female
23 18 3
52.3 40.9 6.8
a multiple pregnancy conceived spontaneously at 29 ± 3.2 years (p < 0.05). The indication for applying ART technique was pelvic factor in 8/17 cases (47.1%), male factor in 5/17 cases (29.4%), ovulatory factor in 3/17 cases (17.6%), and unexplained infertility in 1/17 cases (5.9%). Fetal gender distribution in the multiple pregnancies resulting in spontaneous abortion is displayed in Table 1. In our series, the number of cases where fetal gender was identical was significantly higher (p < 0.05) than the number of cases with heterogenous fetal gender. In triplet pregnancies, male/male/male fetal gender distribution and female/female/female distribution were equally common (40%; 2 cases each). There was a single case with heterogenous fetal gender (20%). The type of placentation could be identified in 34 cases based on available information. These are described in Table 2. The ratio of monochorionic vs. dichorionic multiple pregnancies was 11:23. The difference in occurrence between mono- and dichorionic pregnancies was not significant (p > 0.05). Given the small number of triplet pregnancies, maternal age was analyzed for the whole multiple pregnancy group, i.e., twin and triplet pregnancies taken together. In cases where no specific fetal pathology was identified on perinatal biopsy, the median maternal age was 30 ± 3.64 years (range: 16–45 years). In cases where a specific fetal pathology was seen, the maternal median age was 29 ± 5.46 years (range: 17–44 years). The difference between these two median values was not statistically significant (p > 0.05). In terms of gestational age at the time of spontaneous abortion, there was no statistical difference between cases where a specific fetal pathology was found vs. cases where fetal pathology could not be identified. The respective values were 19.5 ± 2.77 gestational weeks in the positive fetal pathology group vs. 20 ± 2.35 gestational weeks in the group with no fetal pathology identified (p > 0.05). Fetal congenital malformation was identified in 8 out of the 44 twin pregnancy cases (18.2%); major malformations (which may explain the abortion) were verified in 6/44 (13.6%) and minor ones (not incompatible with postnatal life) in 2/44 (4.6%) cases. In the remaining 36 cases (81.8%), no specific fetal pathology could be identified. As is demonstrated in Table 3, a congenital malformation was present in both fetuses in 1 case, whereas in 7 cases, only one of the fetuses was affected (fetus A: the fetus closer to birth canal). In the cases where a congenital malformation could be identified, the pregnancy was naturally conceived in 63.5% of cases, while assisted reproduction techniques were used in 36.5% of cases. In the triplet pregnancy cases, a congenital malformation was identified in a single case. This congenital malformation was identified as spina bifida lumbosacralis. In this case, as in all other cases of triplet pregnancies, the pregnancy was conceived through assisted reproductive techniques.
Table 2 Types of placentation in multiple pregnancies ending in spontaneous abortion. Placentation
N
%
Monochorionic–monoamniotic placentation Monochorionic–diamniotic placentation Dichorionic–diamniotic placentation
1 10 23
2.9 29.4 67.7
460
J.G. Joó et al. / Pathology – Research and Practice 208 (2012) 458–461
Table 3 Fetal pathology found on perinatal autopsy after spontaneous abortion in multiple pregnancy.
1 2 3 4 5 6 7 8
Affected fetus
Observed pathology
B B A B B A B A and B
Auricular aplasia, oligodactyly, pes equinovarus Hydrocephalus internus Accessory renal pelvis (double pelvis) CAM type II Renal agenesis, right-sided Single umbilical artery Single umbilical artery Lumbosacral spina bifida cystica
Table 4 describes the most likely etiologies leading to miscarriage in our study. This data tends to confirm previous reports revealing intrauterine infections as the most common etiology. Among the 16 cases of diagnosed intrauterine infection, 4 (25%) occurred due to premature rupture of membrane. Another relatively common diagnosis was twin–twin transfusion syndrome (TTTS) in 13.6% of the cases. Discussion Our findings support the widely recognized phenomenon that obstetric complications, including spontaneous abortion, are more common in multiple vs. single pregnancy. In our study population, there was an eight-fold higher incidence of miscarriage; this is somewhat higher than the previously reported two- to four-fold difference in occurrence [10,13,20,23,24]. It is remarkable that the ratio of twin pregnancies conceived naturally vs. conceived through assisted reproductive techniques (64% vs. 36%) was identical irrespective of whether miscarriage occurred vs. pregnancy was carried to term. This suggests that assisted reproductive technique does not affect the likelihood of spontaneous abortion in this context. Fitzsimmons et al. came to a similar conclusion [7], proposing that naturally conceived multiple pregnancies may even carry a higher risk for miscarriage compared to those conceived through assisted reproductive techniques. There was a positive history for spontaneous abortion in nearly 64% of multiple pregnancies conceived through assisted reproductive techniques. In some of these cases, assisted reproductive technique was employed precisely because of previous failure to produce live birth due to underlying pathology. The median age of patients undergoing ART was significantly higher than that of women having spontaneously conceived twin pregnancy. As ART is usually applied after years of several attempts to become pregnant spontaneously, this result was as was to be expected. The risk for miscarriage in multiple pregnancies is significantly higher in cases where fetal gender is identical in all fetuses within the given pregnancy [26]; this is supported by our findings. This phenomenon can be explained by the fact that when fetal gender is the same, monochorial, and monoamniotic multiple pregnancy is more likely. It is well recognized that the risk for miscarriage is higher in monochorionic forms of multiple pregnancy [1,15,20]. Table 4 Most likely clinical diagnosis resulting in spontaneous abortion in multiple pregnancy. Clinical diagnosis
N
%
Chorioamnionitis Twin–twin transfusion syndrome (TTTS) Incompetent cervix Preeclampsia Fetal malformation Etiology unclear
16 6 3 1 8 10
36.40 13.60 6.80 2.30 18.20 22.70
However, our findings suggest that the influence of fetal gender goes beyond the question of chorinicity or amnionicity. We found that in the setting where fetal gender was male–male, there was a 13% higher risk for miscarriage compared to cases where fetal gender was female–female. In the 34 cases in which chorionicity could be accurately judged based on available information, dichorionic placentation was significantly more common than monochorionic (23 vs. 11 cases or 68% vs. 32%). Considering that the ratio of monochorionic multiple pregnancies to all multiple pregnancies is expected to be between 15 and 25% [11,12], this tends to support previous beliefs that monochorionicity in multiple pregnancy is a risk factor for the development of miscarriage in this setting [4,10,17]. There is no difference in maternal age between cases where spontaneous abortion occurred through singular or multiple pregnancy. Our study shows that in multiple pregnancy there was no difference in maternal age between cases where, in the background of miscarriage, a fetal congenital malformation could be identified vs. cases in which fetal pathology was not seen. Similarly, there was no significant difference with regard to gestational age at the time of miscarriage in the cases where a fetal pathology was identified vs. cases where there was no such pathology. It is noteworthy that in singular pregnancies, miscarriage associated with congenital malformation generally takes place 3 weeks earlier, compared to cases where a malformation is not identified [14]. In multiple pregnancies, this time difference is usually not seen. In twin pregnancies ending in spontaneous abortion, we found a developmental disorder in at least 1 fetus in 18% of the cases although the rate of major fetal malformations was 13.2%. These data represent a higher incidence of fetal congenital malformation compared to miscarriage in singular pregnancies (10%) [14]. Livingston and Poland found a similar incidence of congenital malformation in at least one fetus in twin pregnancies ending in miscarriage (21%) [20]. Arteaga et al. observed substantially higher incidences; in more than 46% cases were congenital malformations identified [3]. In regard to the relationship of congenital malformations and the nature of conception, we found no difference in the incidence of malformations on the basis of whether conception was natural or induced by assisted reproductive techniques. This contradicts prior observations made by Fitzsimmons et al., demonstrating a higher fetal morbidity in spontaneously conceived multiple pregnancies [7]. In our study, disorders of the central nervous system were prominent among the type of fetal pathology identified. This represented 3 out of the 9 cases of congenital malformation. This confirms previous finding by Arteaga et al., who observed a similar prominence of central nervous system (or craniospinal) disorders in this case scenario [3]. As can be seen in Table 4, the most common clinical diagnosis found in the background of spontaneous abortion was intrauterine infection (chorioamnionitis). This underlines the importance of treatment and especially the prevention of intrauterine infection in an attempt to decrease the incidence of miscarriage. It is important to note that TTTS occurred in more than 30% of the cases, suggesting that this phenomenon deserves further attention, and future studies to evaluate the nature of this relationship are warranted. In conclusion, our study demonstrated that multiple pregnancies are associated with a higher rate of obstetric complications compared to singular pregnancies. Conception through assisted reproductive techniques does not necessarily predict a higher risk for spontaneous abortion in multiple pregnancies. In cases where fetuses have identical gender within a given pregnancy, there is a significantly higher incidence of miscarriage. Among multiple pregnancies ending in spontaneous abortion, there was no
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