Hum. Reprod. Advance Access originally published online on February 23, 2006
Human Reproduction 2006 21(5):1285-1290; doi:10.1093/humrep/dei494
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Abnormal placental cord insertion may induce intrauterine growth restriction in IVF-twin pregnancies
Department of Obstetrics and Gynecology, Tokai University School of Medicine, Bohseidai, Isehara, 259–1193, Japan
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan, E-mail: s-izumi{at}is.icc.u-tokai.ac.jp
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Abstract |
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BACKGROUND: This study determined whether twins conceived through assisted reproduction technology (ART) have an increased risk of perinatal complications compared with natural twin pregnancies and investigated potential associated major risk factors. METHODS: This retrospective study consisted of 199 twins born between 1994 and 2003. There were four groups according to conception modalities: 97 twins after spontaneous pregnancy, 24 after induced ovulation, 28 after intrauterine insemination (IUI) and 50 after IVF with embryo transfer. Analysis included preterm birth, Caesarean delivery, weight discordance, intrauterine growth restriction (IUGR), low-birth-weight, Apgar score, chorionicity, gross placental pathology and placental umbilical cord insertion (UCI) site. RESULTS: A significant difference was found in IUGR between the IVF group (7.0%) and spontaneous pregnancy group (14.9%). When maternal age was >30 years there was a 2.86-fold increase in the risk of IUGR. There was a 3.69-fold increased risk of IUGR in the presence of abnormal UCI (odds ratio 3.69, 95% CI 1.62–8.42) and a 2.18-fold increased risk of abnormal UCI in monochorionic twins when compared with dichorionic twins (odds ratio 2.18, 95% CI 1.30–3.66). CONCLUSION: Twins conceived through ART are not at an increased risk of perinatal complications. A relationship has been found between abnormal UCI and IUGR.
Key words: assisted reproduction technique/intrauterine growth restriction (IUGR)/IVF/twins/umbilical cord insertion
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Introduction |
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With increasing rates of infertility and delayed age of first pregnancy, assisted reproduction technology (ART) is apt to be employed more widely in our modern society. Hence, multiple pregnancies are frequently observed because of this technique, and some studies have demonstrated that 20 to 25% of all multiple pregnancies are conceived using this procedure (MRC, 1990
; SART/ASRM, 1995; Koudstaal et al., 2000; Nygren and Nyboe, 2001). Recently, multiple pregnancies have been limited to twin pregnancies by adjusting the number of embryos transferred. However, management of pregnancy and delivery is still troublesome even in twin pregnancy. Some studies have reported an increase in perinatal mortality (Moise et al., 1998; Lambalk and van Hooff, 2001), preterm labour (Moise et al., 1998; Lambalk et al., 2001; Nassar et al., 2003) and low birth weight (Moise et al., 1998; Lambalk et al., 2001; Pinborg et al., 2004) by IVF with embryo transfer. Other reports have found no difference in perinatal outcome (Olivennes et al., 1996; Dhont et al., 1999). Nassar et al. (2003) reported a higher incidence of intrauterine growth restriction (IUGR) in spontaneous twins than in IVF twins and explained that this finding attributed to a higher incidence of monochorionic twins in the spontaneous group. The purpose of this retrospective analysis was to investigate pregnancy outcome of ART-related twins compared with spontaneous twins. Particular attention has been given to IUGR with an attempt to elucidate the factor(s) that determine poor outcomes.
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Materials and methods |
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In the present retrospective study, 199 pairs of twins delivered at 25 gestational weeks or more over a 10-year period (1994 through to 2003) at our University Hospital were analysed. Cases were assigned to one of four groups according to the different conception modalities as follows: spontaneous group (Spnt; 97 pairs after spontaneous conception), induced ovulation group (28 pairs after induced ovulation), intrauterine insemination group (IUI; 24 pairs after intrauterine insemination), IVF with embryo transfer group (IVF; 50 pairs after IVF and embryo transfer). A total of 14 patients of 50 in the IVF group were referred from an affiliated hospital in the first trimester of twin pregnancy. Analysed maternal information included maternal age, BMI, parity, method for conception, mode of delivery (vaginal delivery, Caesarean section), preterm labour, pregnancy induced hypertension (PIH), IUGR and maternal hospital stay. In terms of ‘Hospital stay’, we considered summed hospitalized days after 2nd trimester and excluded days after delivery. (Hence, the hospitalization for oocyte pickup in ART cycle and side effect(s) such as ovarian hyper–stimulation syndrome was not included.) Additional data included fetal and placental information: birth weight, gender, gestational age at birth, chorionicity, growth discordance, Apgar score, need for oxygen administration and admission to intensive care unit (NICU), gross placental pathology with cord condition such as twist, spiral and, especially, placental umbilical cord insertion (UCI) site. UCI into the placenta is described as centric, eccentric, marginal, or velamentous, as it relates to the chorionic plate. Centric and eccentric insertions are defined as UCI into the disc of the placenta, whereas marginal is UCI within 2 cm of the disc edge. Velamentous is UCI directly into the membranes. With regard to UCI, centric or eccentric insertion is considered normal, whereas marginal or velamentous insertion is abnormal.
Preterm birth was defined as delivery occurring at 36-week gestation or less. IUGR was defined as birth weight below the 10th percentile of curves for Japanese singletons at delivered gestational age (Minakami et al., 1999). Twin discordance was defined as a birth weight difference of 25% or more. Low birth weight was considered <2500 g and very low birth weight was <1500 g. PIH was defined as blood pressure >140/90 mmHg after 20 weeks of gestation in a previously normotensive women with or without proteinuria.
For statistical analysis, the 
2 test and ANOVA with Kruskal–Wallis test as post hoc analysis were used for comparing maternal characteristics and neonatal outcomes where applicable. Multiple logistic regression analysis was performed to evaluate the impact on IUGR in twins for the following variables: maternal age, BMI, PIH, maternal hospital stay, chorionicity, parity and placental UCI site. A difference where P < 0.05 was considered statistically significant.
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Results |
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The maternal characteristics of four groups are summarized in Table I. As expected, the patients in the IVF group were significantly older than the other groups (P < 0.001). Moreover, the IVF group showed a greater proportion of primiparous women and Caesarean section rate as well as longer maternal hospital stay than the other groups (P < 0.05, 0.001, and 0.001, respectively). Regarding BMI, PIH, and preterm delivery, no significant difference was found among the four groups. Three ICSI and 6 natural ovulation cases were included in IVF (n = 50) and IUI (n = 28) group, respectively.
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The neonatal outcomes of the four groups are summarized in Table II. With regard to twin chorionicity, as expected, the dichorionic placentation in the Spnt group (46.4%) was significantly lower (P < 0.001) than the other assisted twin groups (induced ovulation group, 100%; IUI group, 89.7%; IVF group, 94.0%). We did not observe any significant difference in gestational age, birth weight, Apgar scores on 1 min, discordant twins, and low birth weight among the four groups. The total placental weight was significantly lower in spontaneous twins than the other three groups (P < 0.05) with consistent results on total placental area (P < 0.001). The rate of very low birth weight in the Spnt group was consistently the highest (P < 0.05), with a significantly higher incidence of neonatal intensive care unit (NICU) admission in spontaneous twins compared with the other groups (P < 0.05).
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IUGR in Spnt group (14.9%) was more frequent than in IVF (7.0%) group (P < 0.05). The distribution of IUGR in Spnt and IVF groups, classified according to their chorionicity is summarized in Figure 1. While there was a higher incidence of IUGR in monochorionic twins than dichorionic twins (P < 0.05) overall, this tendency was not significant either in Spnt or in IVF group. Thus, dichorionic twins were analysed precisely in Spnt and IVF groups (Table III). Multivariable logistic regression analysis was used to identify the risk of IUGR. The analysis of maternal age, BMI, PIH, maternal hospital stay, chorionicity, parity and placental UCI site are presented in Table IV. Only abnormal UCI and maternal age are risk factors for IUGR. In the presence of abnormal UCI, the risk of IUGR increases (odds ratio 3.69, 95% CI 1.62–8.42). When maternal age was over 30 years, there was a 2.86-fold increase in the risk of IUGR. Those results suggested that maternal age and abnormal UCI were significantly associated with IUGR. The patients with IVF were significantly older than those in the Spnt group, whereas monochorionical IUGR fetuses were more frequent in spontaneous twins. Lastly, the association between the chorionicity and abnormal UCI was evaluated. Table V shows 30.2% of monochorionic twins had abnormal UCI, while that in dichorionic twins was only 17.7%. The distribution of the abnormal UCI was significantly different between the monochorionic twins and dichorionic twins (OR 2.18, 95% CI 1.30–3.66, P < 0.05).
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Discussion |
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In our modern society the demand for ART is growing considerably. Previous studies have shown that ART has caused an increased incidence rate of multiple pregnancies, which have been limited to twin pregnancies in recent years by adjustment of the number of embryos transferred. In this context, it becomes more important to know whether twin pregnancies conceived through ART have an increased risk of neonatal complications compared with natural twin pregnancies. On the contrary, it has been reported that sub-infertile status itself brings about obstetrical complications (Williams et al., 1991
; Wang et al., 1994). In the present study, we took a sub-infertile group without IVF into consideration, trying to include an IUI group and induced ovulation group. While both obstetric complications and neonatal problems have been taken into account, special attention has been focused on fetal growth. The abnormal UCI is mentioned as a common finding in twins (Fries et al., 1993; Hanley et al., 2002). The velamentous insertion reportedly occurs in approximately 13–21% of multiple gestation (Fries et al., 1993), while a 13-fold increase in the risk of birth weight discordance in monochorionic twins occurs in the presence of velamentous UCI (Hanley et al., 2002). A previous study also showed that fetuses with velamentously or marginally inserted cords presented more frequently in IUGR than in twins with centrally inserted umbilical cords (Bjoro and Bjoro, 1985). Bruner et al. (1998) evaluated a series of twins and found that abnormal UCI into the placenta appears to be an important risk factor for twin–twin transfusion syndrome, presumably because of deprived condition of placental flow. Hence, we also analysed gross placental pathology and placental UCI site in conjunction with IUGR.
In terms of population characteristics, ART patients were older and more often primiparous than the Spnt group, which concurs with other study findings (Agustsson et al., 1997; Nassar et al., 2003). Older women are more prone to be sub-infertile and have obstetrical complications (Seoud et al., 2002). As our retrospective analysis was not successful in matching maternal age and parity, comparisons between IVF and spontaneous pregnancies were carefully made, taking this intrinsic bias into account. Moreover, this bias could be corrected by the multiple logistic regression analysis which we utilized. Anyhow, in our study, as far as dichorionic twins concern, no statistical difference was found between IVF twins and spontaneous twins concerning the incidences of preterm birth, birth weight, birth weight discordance, Apgar score or PIH. There are a few studies where IVF-twin pregnancies have been compared with spontaneous twin pregnancies with (Fitzsimmons et al., 1998; Moise et al., 1998; Dhont et al., 1999; Koudstaal et al., 2000; Isaksson et al., 2002; Nassar et al., 2003) and without (Olivennes et al., 1996; Agustsson et al., 1997; Bernasko et al., 1997) matching. In the latter three non-matched studies, an increased incidence of Caesarean section in the IVF group was found, and an increased rate of birth weight discordance was indicated in one study (Bernasko et al., 1997). In general, the perinatal outcome of IVF twins was shown to be comparable with that of spontaneous twins. While in the matching studies, the matching criteria showed considerable variations, and the results were inconsistent. Because monozygotic twins are known to be associated with an increase in preterm delivery, low birth weight and birth weight discordance (Kovacs et al., 1989; Rydhstroem, 1996), in two studies where zygosity was taken into account, a higher rate of preterm delivery (Moise et al., 1998; Dhont et al., 1999) and a lower birth weight (Moise et al., 1998) in IVF twins were noted. We analysed the data in terms of chorionicity, and it would be interesting to do the analysis in terms of zygosity as well. Moreover, according to Weinberg’s rule (Blickstein, 2005), we could estimate dizygotic twins were 160 neonates, hence the monozygotic twins might be 134. However, we have no tool to distinguish the same-sex twins into monozygotic or dizygotic. Whereas it might be difficult to make another table (similar to Table V) in terms of zygosity as described above, we assume that dizygotic twin might have more chance to have normal UCI site than dichorionic (88.8 versus 82.3%).
When zygosity was not taken into account, a better outcome of IVF was reported, as described by Fitzsimmons et al. (1998) and Isaksson et al. (2002). However, Nassar et al. (2003) found higher rates of preterm delivery and lower birth weight in IVF twins.
It was reported that sub-infertile status itself brought upon obstetrical complications (Agustsson et al., 1997; Koudstaal et al., 2000). However, these were not found in our study; only the infertile groups had an earlier and longer maternal hospital stay than spontaneous twins. This implies that successful obstetric management played an important role in obstetrical outcome. In our study, a higher Caesarean delivery rate was found in the IVF group. This finding was also reported in several studies (Olivennes et al., 1996; Fitzsimmons et al., 1998; Seoud et al., 2002; Nassar et al., 2003). Taking previous studies into consideration, it was suggested that obstetricians intervened in most IVF twin Caesarean sections, expecting better neonatal outcome which may not be evidenced.
In our present study, almost 30% of spontaneous twins were admitted into the NICU. This result can be attributed to prematurity and a higher incidence of very low birth weight in natural twin pregnancies. It is worth mentioning that a significant difference was found in IUGR between the IVF group (7.0%) and Spnt pregnancy group (14.9%), where P < 0.05. By now only one report (Nassar et al., 2003) has mentioned a higher incidence rate of IUGR in spontaneous twins than in IVF twins, which has not been previously reported in monochorionic twins of the Spnt group. The difference in risk factor for IUGR between IVF twins and spontaneous twins has not been investigated. Certainly, in our study, 53.6% of spontaneous twins had a monochorionic placenta, whereas in IVF twins this was only 6%. Similar data was shown in the Koudstaal’s study group (23.3 versus 2.3%) (Koudstaal et al., 2000). Our multiple logistic regression analysis showed that only maternal age and placental UCI site were significantly associated with IUGR. There was a 3.69-fold increase in the risk of IUGR in the presence of abnormal UCI, whereas maternal age over 30 years increases the risk of IUGR by 2.86-fold. Moreover, abnormal UCI increased 2.18-fold in monochorionic twins than dichorionic twins. Our findings demonstrated that a substantial increase in abnormal UCI in monochorionic twins induced the increase in incidence of IUGR of spontaneous twins than IVF twins.
Previous studies (Fries et al., 1993; Hanley et al., 2002) reported that abnormal UCI is a common finding in twins, which is consistent with our results. Hanley et al. (2002) demonstrated that abnormal UCI into placenta is a risk factor for birth weight discordance in twin gestation. Doppler technology helps to identify UCI much earlier and easier (Nomiyama et al., 1998; Sepulveda et al., 2003). Nomiyama et al. (1998) prospectively evaluated placental UCI at 18–20 weeks. Sepulveda et al. (2003) described that abnormal UCI can reliably be detected parentally by grey-scaled or coloured Doppler ultrasound. Because the abnormal UCI of placenta markedly impacts fetal growth in monochorionic twins, systematic assessment of the placental UCI site at routine obstetric prenatal ultrasounds should be performed.
We chose 25 gestational weeks as the lower limit of our study, because this limit was selected in majority of published papers. Even though it would be interesting to know the incidence of such events as miscarriages, medical abortions or early stillbirth, it is impossible to evaluate those earlier events in our study. However, as far as we know, malformation of 5, 2, 0, 2 cases and stillbirth of 8, 0, 1, 1 case(s) were included in Spnt, induced ovulation, IUI, IVF group, respectively, without statistical significance.
In conclusion, our study confirms twins from IVF or from subfertile patients do not have an increased risk for preterm delivery, fetal growth, or neonatal complications. Abnormal UCI in monochorionic twins may be closely related with the IUGR in spontaneous twins compared with that in IVF twins. Generally, IVF patients are older than spontaneous patients, on the contrary, the Spnt group has a higher proportion of monochorionic twins than the IVF group. Moreover, abnormal UCI is the highest risk factor for IUGR. Taking these intrinsic characteristics into consideration, obstetricians should pay more attention to twin chorionicity versus the method of conception or sub-infertility.
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The authors thank Ms. Kei Mori and Ms. Yoshimi Fujita for their technical assistance.
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Agustsson T, Geirsson RT and Mires G (1997) Obstetric outcome of natural and assisted conception twin pregnancies is similar. Acta Obstet Gynecol Scand 76,45–49.[Web of Science][Medline]
Bernasko J, Lynch L, Lapinski R and Berkowitz RL (1997) Twin pregnancies conceived by assisted reproductive techniques: maternal and neonatal outcomes. Obstet Gynecol 89,368–372.[CrossRef][Web of Science][Medline]
Bjoro K Jr and Bjoro K (1985) Disturbed intrauterine growth in twins: etiological aspects. Acta Genet Med Gemellol (Roma) 34,73–79.[Medline]
Blickstein I (2005) Estimation of iatrogenic monozygotic twinning rate following assisted reproduction: pitfalls and caveats. Am J Obstet Gynecol 192,365–368.[CrossRef][Web of Science][Medline]
Bruner JP, Anderson TL and Rosemond RL (1998) Placental pathophysiology of the twin oligohydramnios-polyhydramnios sequence and the twin–twin transfusion syndrome. Placenta 19,81–86.[CrossRef][Web of Science][Medline]
Dhont M, De Sutter P, Ruyssinck G, Martens G and Bekaert A (1999) Perinatal outcome of pregnancies after assisted reproduction: a case-control study. Am J Obstet Gynecol 181,688–695.[CrossRef][Web of Science][Medline]
Fitzsimmons BP, Bebbington MW and Fluker MR (1998) Perinatal and neonatal outcomes in multiple gestations: assisted reproduction versus spontaneous conception. Am J Obstet Gynecol 179,1162–1167.[CrossRef][Web of Science][Medline]
Fries MH, Goldstein RB, Kilpatrick SJ, Golbus MS, Callen PW and Filly RA (1993) The role of velamentous cord insertion in the etiology of twin–twin transfusion syndrome. Obstet Gynecol 81,569–574.[Web of Science][Medline]
Hanley ML, Ananth CV, Shen-Schwarz S, Smulian JC, Lai YL and Vintzileos AM (2002) Placental cord insertion and birth weight discordancy in twin gestations. Obstet Gynecol 99,477–482.[CrossRef][Web of Science][Medline]
Isaksson R, Gissler M and Tiitinen A (2002) Obstetric outcome among women with unexplained infertility after IVF: a matched case-control study. Hum Reprod 17,1755–1761.
Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP, Willemsen WN and Visser GH (2000) Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch university hospitals. Hum Reprod 15,935–940.
Kovacs BW, Kirschbaum TH and Paul RH (1989) Twin gestations. I. Antenatal care and complications. Obstet Gynecol 74,313–317.[Web of Science][Medline]
Lambalk CB and van Hooff M (2001) Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries. Fertil Steril 75,731–736.[CrossRef][Web of Science][Medline]
Minakami H, Izumi A and Sato I (1999) Gestational age-specific normal birth weight for Japanese twins. Risk of early neonatal death in small-for-gestational-age and large-for-gestational-age twins. J Reprod Med 44,625–629.[Web of Science][Medline]
Moise J, Laor A, Armon Y, Gur I and Gale R (1998) The outcome of twin pregnancies after IVF. Hum Reprod 13,1702–1705.
MRC Working Party on Children Conceived by In Vitro Fertilisation. (1990) Births in Great Britain resulting from assisted conception, 1978–87. BMJ 300,1229–1233.
Nassar AH, Usta IM, Rechdan JB, Harb TS, Adra AM and Abu-Musa AA (2003) Pregnancy outcome in spontaneous twins versus twins who were conceived through in vitro fertilization. Am J Obstet Gynecol 189,513–518.[CrossRef][Web of Science][Medline]
Nomiyama M, Toyota Y and Kawano H (1998) Antenatal diagnosis of velamentous umbilical cord insertion and vasa previa with color Doppler imaging. Ultrasound Obstet Gynecol 12,426–429.[CrossRef][Web of Science][Medline]
Nygren KG and Nyboe A (2001) Assisted reproductive technology in Europe, 1998. Results Generated from European Registers ESHRE. Hum Reprod 16,2459–2471.
Olivennes F, Kadhel P, Rufat P, Fanchin R, Fernandez H and Frydman R (1996) Perinatal outcome of twin pregnancies obtained after in vitro fertilization: comparison with twin pregnancies obtained spontaneously or after ovarian stimulation. Fertil Steril 66,105–109.[Web of Science][Medline]
Pinborg A, Loft A, Schmidt L, Langhoff-Roos J and Andersen AN (2004) Maternal risks and perinatal outcome in a Danish national cohort of 1005 twin pregnancies: the role of in vitro fertilization. Acta Obstet Gynecol Scand 83,75–84.[CrossRef][Web of Science][Medline]
Rydhstroem H (1996) Pregnancy with stillbirth of both twins. Br J Obstet Gynaecol 103,25–32.[Web of Science][Medline]
Seoud MA, Nassar AH, Usta IM, Melhem Z, Kazma A and Khalil AM (2002) Impact of advanced maternal age on pregnancy outcome. Am J Perinatol 1,1–8.[Medline]
Sepulveda W, Rojas I, Robert JA, Schnapp C and Alcalde JL (2003) Prenatal detection of velamentous insertion of the umbilical cord: a prospective color Doppler ultrasound study. Ultrasound Obstet Gynecol 21,564–569.[CrossRef][Web of Science][Medline]
Society for Assisted Reproductive Technology, American Society for Reproductive Medicine. (1995) Assisted reproductive technology in the United States and Canada: 1993 results generated from the American Society for Reproductive Medicine. Fertil Steril 64,13–21.[Web of Science][Medline]
Wang JX, Clark AM, Kirby CA, Philipson G, Petrucco O, Anderson G and Matthews CD (1994) The obstetric outcome of singleton pregnancies following in-vitro fertilization/gamete intra-fallopian transfer. Hum Reprod 9,141–146.
Williams MA, Goldman MB, Mittendorf R and Monson RR (1991) Subfertility and the risk of low birth weight. Fertil Steril 56,668–671.[Web of Science][Medline]
Submitted on October 15, 2005; resubmitted on December 9, 2005; accepted on December 20, 2005.
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