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Impact of induced pregnancies in the obstetrical outcome of twin pregnancies
ORIGINAL ARTICLES: EARLY PREGNANCY
Impact of induced pregnancies in the obstetrical outcome of twin pregnancies Ana Patrícia Domingues, M.D., M.Sc.,a Sofia Raposo Dinis, M.D.,a Adriana Belo, M.Sc.,c Daniela Couto, M.D.,b Etelvina Fonseca, M.D.,a and Paulo Moura, M.D., Ph.D.a,d a c
Obstetrics-A Department and b Human Reproduction Department, Coimbra Hospital and University Center; Biostatistician; d Obstetrical Clinic, Faculty of Medicine, Coimbra University, Coimbra, Portugal
Objective: To compare obstetric outcomes of induced twins with those spontaneously conceived. Design: A prospective observational study was conducted in twin pregnancies delivered over 16 years. Setting: A tertiary obstetric center with differentiated perinatal support. Patient(s): A total of 180 induced twins and 698 spontaneously conceived were included. Intervention(s): None. Main Outcome Measure(s): Comparison of demographic factors, obstetrical complications, gestational age at delivery, mode of delivery, birth weight, and immediate newborn outcome. Result(s): First-trimester bleeding was higher in the induced group (6.0% vs. 12.2%), as were gestational diabetes (4.4% vs. 8.3%) and discordant intrauterine growth (4.3% vs. 11.1%). Preterm premature rupture of membranes was less frequent (23.9% vs. 12.8%) as was preterm delivery %32 weeks (22.5% vs. 14.0%). Cesarean section rate was higher (50.6% vs. 63.9%). Other obstetrical complications, newborn data, and puerperal complications were not statistically different. Except for first-trimester bleeding (significantly associated with monochorionicity), these results were independent from chorionicity. Regarding the induced method (ovulation induction, IVF, or ICSI), IVF is a predictor for first-trimester bleeding and IVF or ICSI a predictor for cesarean section. Conclusion(s): The higher rates found with induced twins of first-trimester bleeding, gestational diabetes, and discordant growth do not contribute to different neonatal immediate outcomes and do not contribute to higher rates Use your smartphone of prematurity, low birth weight, or other major perinatal complications. (Fertil SterilÒ to scan this QR code 2014;101:172–7. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: Twins, induced reproduction, obstetrical outcomes Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/dominguesap-induced-pregnancy-obstetric-outcome-twins/
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ince 1980 there has been a worldwide increase in multiple births. This seems to be due to an increase in the age of women at reproduction, the use of ovulation induction (OI), and the use of assisted reproduction techniques (ART), such as in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI). ART has become a widespread option for the treatment of human infertility,
and data show that 22% of all deliveries after ART occur in pregnancies with more than one fetus: 20.7% of twins and 1% of triplets (1). It is well known that maternal and obstetrical complications are more frequent in twin pregnancies than in singleton pregnancies. However, it is not yet clear if induced twin pregnancies must be considered to be at higher obstetrical risk than spontaneously
Received May 31, 2013; revised September 13, 2013; accepted September 18, 2013; published online October 17, 2013. A.P.D. has nothing to disclose. S.R.D. has nothing to disclose. A.B. has nothing to disclose. D.C. has nothing to disclose. E.F. has nothing to disclose. P.M. has nothing to disclose. Reprint requests: Ana Patrícia Domingues, M.D., M.Sc., Maternidade Dr Daniel de Matos, Servic¸o de rio de Coimbra, Rua Miguel Torga, 3030-165 Obstetrícia-A, Centro Hospitalar e Universita Coimbra, Portugal (E-mail: [email protected]). Fertility and Sterility® Vol. 101, No. 1, January 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2013.09.026 172
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conceived ones. Studies comparing the outcome of induced twin pregnancies and those of spontaneous conception report inconsistent findings; some report similar perinatal outcomes (2– 5), whereas others report a higher risk of adverse perinatal outcomes, such as gestational diabetes, hypertension, intrauterine growth discordance, preterm birth and cesarean section, low birth weight, and higher neonatal intensive care unit (NICU) admissions (6–14), and others find a better perinatal outcome after IVF/ICSI (15). In most studies, however, only IVF/ ICSI are evaluated, leaving out OI, and chorionicity, considered to be a confounding factor in predicting the perinatal outcomes of twin pregnancies, has not been determined or evaluated. VOL. 101 NO. 1 / JANUARY 2014
Fertility and Sterility® The aim of the present study was to compare obstetrical outcomes of induced twin pregnancies with those spontaneously conceived, and to evaluate the impact of chorionicity and the type of induction (OI, IVF, or ICSI) on the results.
MATERIALS AND METHODS Data from files of all twin pregnancies that were delivered in our tertiary obstetrics center with differentiated perinatal support over a period of 16 years (from January 1996 to December 2011) were prospectively collected and analyzed. No intervention was done besides the normal twin surveillance protocol in those with surveillance in our center. This study was included in an investigation project approved by the Ethics Committee of the University Hospitals of Coimbra. We excluded triplets, higher orders, and monoamniotic multiple gestations from the analysis. All twin pregnancies (dichorionic and monochorionic) that were spontaneously conceived and those obtained following an induction method/technique—OI, IVF, or ICSI—were included. In a first analysis, two groups were formed: one of all spontaneously conceived twin pregnancies and the other of all induced twin pregnancies. In both groups the following parameters were analyzed and compared: maternal age (categorized in the following classes <18, 18–25, 26–35, 36–40, and >40 years), parity, personal or family history of twins, personal disease history, and habits (current or earlier use of smoking, drugs, or alcohol). Obstetrical complications included were first-trimester bleeding; urinary, genital, or other infections; anemia; fetal malformations; hypertensive diseases of the pregnancy (gestational hypertension, preeclampsia, eclampsia, and HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome); gestational diabetes [GD]; preterm delivery [PTD], defined as delivery after 24 and before 37 weeks of gestation; preterm premature rupture of membranes (PPROM), defined as the occurrence of premature rupture of membranes after 24 and before 37 weeks of gestation; intrauterine growth restriction [IUGR], defined as fetal measure of abdominal perimeter <10th percentile; discordant growth, defined as 20% difference between fetal birthweights; and fetal death. Birth data analyzed included gestational age at delivery (categorized in the following classes: <28, 28–32, 33–34, 35–36, and >36 weeks), mode of delivery (categorized as vaginal, cesarean section during delivery, elective cesarean section, and cesarian section of the second twin), birthweights of both twins, Apgar (American Pediatric Gross Assessment Record) score at 1st and 5th minute of both twins, and admission of the neonates in the NICU. Puerperal complication occurrences were also analyzed: anemia, hemorrhage, hypertension complications, and endometritis. Gestational age was calculated from the date of embryo transfer for the induced pregnancies obtained from ART and from the date of the last menstrual period in the spontaneously conceived group, both confirmed and corrected by the time of the first-trimester ultrasound. Chorionicity was also determined in the first-trimester scan (by lambda and T signs). VOL. 101 NO. 1 / JANUARY 2014
In a second phase we went on to analyze the influence of chorionicity and of the type of induced technique (IO, IVF, or ICSI) in the above conditions. A global characterization of the sample (180 induced and 698 spontaneously conceived twin pregnancies) was performed considering the above listed parameters. Categoric variables were characterized by absolute frequencies and relative frequencies, and continuous variables were characterized with the use of mean, standard deviation, quartiles, minimum, and maximum. For categoric variables, differences in proportions between the two groups were evaluated with the use of the chi-square test or Fisher exact test. For continuous variables, the t test was used to compare means between the two groups and, when the assumptions for use of the t test were not satisfied, the Mann-Whitney test to compare the distribution of values. The normal distribution of values for continuous variables and the equality of their variances were tested with the use of the Kolmogorov-Smirnov and Levene tests, respectively. To analyze the stratification of risks according to age and chorionicity, the Breslow-Day test was used. A logistic regression model adjusted for age and chorionicity was made to look for predictors of the significantly different results found previously. The variables assumed as potential predictors were the type of pregnancy, induced method/ technique, and all other variables included in the personal history and obstetrical complications. The significance level used in this analysis was 5%. The statistical software SPSS v19.0.0.2 was used.
RESULTS During the period in study—January 1996 to December 2011— there were 878 deliveries of twin pregnancies in our center. Regarding the type of conception, 698 were spontaneous (79.5%) and 180 were induced (20.5%). Over the period studied we found a significant growing trend for induced twin pregnancies (P¼ .001), which represented 20.3% of twin deliveries in our center. This trend is no longer observed regarding the mode of conception individually over the years, which remained stable: OI accounting for 31.5% of the induced pregnancies, IVF 41%, and ICSI 27.5%. Maternal characteristics in both groups were analyzed (Table 1). As expected, women in the induced group were significantly older, had higher rates of infertility, and most were nulliparous. There were no significant differences regarding personal medical histories (hypertensive, endocrine, renal, or other systemic disease) or habits (tobacco, alcohol, drugs). The analysis of obstetrical complications (Table 2; anemia, infections, hypertensive disorders of pregnancy, fetal malformations, intrauterine fetal death, and IUGR) revealed no major statistically significant differences between the two groups. First-trimester bleeding was higher in the induced group [6.0% vs. 12.2%; P¼ .004; odds ratio [OR] 2.18 (95% confidence interval [CI] 1.26–3.75)], as were gestational diabetes [4.4% vs. 8.3%; P¼ .037; OR 1.96 (1.03–3.71)] and intrauterine discordant growth [4.3% vs. 11.1%, P< .001; OR 2.78 (1.54–5.03)]. 173
ORIGINAL ARTICLE: EARLY PREGNANCY
TABLE 1 Maternal characteristics of both groups, n (%).
Age >35 y <35 y Twins history Medical history Renal Hypertensive Endocrine Systemic Psychiatric STD Tobacco/alcohol Infertility history Nulliparity
Spontaneous pregnancy
Induced pregnancy
565 (81.1) 132 (18.9) 282 (41.4)
167 (92.8)a 13 (7.2)a 32 (18)
8 (1.1) 13 (1.9) 23 (3.3) 30 (4.3) 8 (1.1) 4 (0.6) 9 (1.3) 12 (1.7) 345 (49.9)
1 (0.6) 3 (1.7) 8 (4.4) 4 (2.2) 1 (0.6) 2 (1.1) 2 (1.1) 166 (92.2)a 159 (88.3)a
Note: Chi-square test used to compare categoric variables, t test for continuous variables. STD ¼ sexually transmitted disease. a P< .001. Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
PPROM was less frequent in the induced group [23.9% vs. 12.8%; P< .001; OR 0.47 (0.29–0.75)] as was preterm delivery at gestational age %32 weeks [22.5% vs. 14.0%; P¼ .012; OR 0.56 (0.35–0.88)].
TABLE 2 Obstetrical results of both groups, n (%).
Complications 1st-trimester bleeding Anemia Infections Hypertension induced by pregnancy Preeclampsia HELLP syndrome Gestational diabetes PPROM Preterm delivery %32 wk Preterm delivery <35 wk Fetal malformations IUFD TTTS IUGR Growth discordance 20% Cesarean section rate Puerperium complications NICU admission F1 and/or F2 Fetus data Birthweight F1 Birthweight F2 Apgar F1 1st min Apgar F1 5th min Apgar F2 1st min Apgar F2 5th min
Spontaneous pregnancy
Induced pregnancy
545 (78.1) 42 (6.0) 27 (3.9) 53 (7.6) 26 (3.7)
138 (76.7) 22 (12.2)a 9 (5.0) 16 (8.9) 6 (3.3)
32 (4.6) 6 (0.9) 31 (4.4) 166 (23.9) 157 (22.5) 283 (40.6) 11 (1.6) 17 (2.4) 15 (2.1) 89 (12.8) 30 (4.3) 353 (50.6) 131 (18.9) 173 (41.1)
6 (3.3) 1 (0.6) 15 (8.3)a 23 (12.8)b 25 (14)a 58 (32.4)a 3 (1.7) 6 (3.3) 2 (1.1) 25 (13.9) 20 (11.1)b 115 (63.9)b 36 (20.5) 54 (43.2)
2,176 611 g 2,136 620 g 8.3 3.4 9.7 7.8 7.9 9.7 9.6 6.9
2,211 187 g 2,187 738 g 8.3 3.2 9.6 6.9 7.8 8.6 9.6 6.7
Note: Chi-square test used to compare categoric variables, t test for continuous variables. F1, F2 ¼ fetuses 1 and 2; HELLP ¼ hemolysis, elevated liver enzymes, and low platelet count; IUFD ¼ intrauterine fetal death; IUGR ¼ intrauterine growth restriction; NICU ¼ neonatal intensive care unit; PPROM ¼ preterm premature rupture of membranes; TTTS ¼ twin-totwin transfusion syndrome. a P< .05. b P< .001. Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
174
Over the years, we found a significant decreasing trend for obstetrical complications in general (P¼ .001; 81.4% in 1996 to 58.9% in 2011 with an overall mean of 77.9%) and for PPROM and fetal death in particular (P¼ .001 [28.8% in 1996 to 16.1% in 2011 with an overall mean of 21.6%] and P¼ .011 [5.1% in 1996 to 0% in 2011 with an overall mean of 2.6%], respectively). A significantly growing tendency was observed in cases of first-trimester bleeding (P< .001; 1.7% in 1996 to 5.4% in 2011 with an overall mean of 7.2%), anemia (P¼ .009; 3.4% in 1996 to 5.4% in 2011 with an overall mean of 4%), IUGR (P¼ .001; 8.5% in 1996 to 14.3% in 2011 with an overall mean of 13%), and growth discordance (P< .001; 0% in 1996 to 8.9% in 2011 with an overall mean of 5.7%). All other parameters had a stable tendency over the years. Regarding delivery, the induced group had higher cesarean section rates (50.6% vs. 63.9%; P< .001; risk ratio [RR] 1.26 [95% CI 1.11–1.44]). Birth weight, Apgar scores at 1st and 5th minutes, admissions to NICU, and puerperal complications were not statistically different in both groups (Table 2). Analyzing the influence of the induction methods/techniques in pregnancy complications, we found that the results were also independent of the induced method (OI, IVF, or ICSI; Table 3). The only differences found were in maternal characteristics. As expected, we found that OI was significantly associated with younger maternal ages (<35 years; P¼ .047; 94.6% OI vs. 78% of IVF vs. 75.5% of ICSI). This subgroup of OI was also associated with lower rates of puerperal complications (P¼ .037), mainly due to postpartum anemia. When stratifying the risk of significantly obstetrical complications by chorionicity, we found that only first-trimester bleeding had a significantly association with monochorionicity (P¼ .006); this complication occurred in 5.7% of monochorionic spontaneous twin pregnancies vs. 35.7% of monochorionic induced pregnancies. Gestational diabetes occurred in 6.1% of monochorionic spontaneous twin pregnancies vs. none of the monochorionic induced pregnancies (P¼ .14); discordant growth restriction occurred in 4.7% of monochorionic spontaneous twin pregnancies vs. 28.6% of monochorionic induced pregnancies (P¼ .15); PPROM occurred in 26.4% of monochorionic spontaneous twin pregnancies vs. 28.6% in of monochorionic induced pregnancies (P¼ .21); and preterm delivery %32 weeks occurred in 27.8% of monochorionic spontaneous twin pregnancies vs. 23.1% of monochorionic induced pregnancies (P¼ .85). When stratifying the risk of obstetrical complications by age, we found that except for first-trimester bleeding, which had a significant association with age >35 years (P¼ .009), all other results were independent from the women's ages. Applying a logistic regression model adjusted for age and chorionicity, to look in the induced twin pregnancies group for predictors of the significant results obtained, we found that IVF was a predictor for first-trimester bleeding, endocrine pathology was a predictor for the occurrence of gestational diabetes, all types of induction methods/techniques were predictors risk factors for discordant growth, and both IVF and ICSI were predictors for cesarean section occurrence (Table 4). VOL. 101 NO. 1 / JANUARY 2014
Fertility and Sterility®
TABLE 3 Obstetrical results of both groups according to mode of conception. Spontaneous pregnancy
Ovulation induction
IVF
ICSI
565 (81.1) 132 (18.9)
49 (87.5) 7 (12.5)
68 (93.1) 5 (6.8)
48 (97.9)a 1 (2)a
13 (1.9) 23 (1.9) 30 (4.3) 4 (0.6) 12 (1.7) 345 (49.9) 545 (78.1) 42 (6.0) 27 (3.9) 53 (7.6) 26 (3.7) 32 (4.6) 6 (0.9) 31 (4.4) 166 (23.9) 157 (22.5) 11 (1.6) 17 (2.4) 15 (2.1) 89 (12.8) 30 (4.3) 353 (50.6) 131 (18.9) 173 (41.1)
2 (3.6) 2 (3.6) 0 1 (1.8) 48 (85.7) 48 (85.7) 42 (75) 5 (8.9) 2 (3.6) 4 (7.1) 1 (1.8) 2 (3.6) 0 48 (7.1) 9 (16.1) 6 (10.7) 1 (1.8) 1 (1.8) 1 (1.8) 10 (17.9) 7 (12.5) 32 (57.2) 5 (9.3) 15 (38.5)
0 4 (5.5) 2 (2.7) 1 (1.4) 70 (95.9) 63 (86.3) 58 (78.1) 11 (13.7) 4 (4.1) 8 (11) 2 (2.7) 1 (1.4) 0 6 (8.2) 11 (13.9) 12 (16.7) 0 5 (6.8) 0 10 (13.7) 6 (8.2) 49 (67.1) 21 (27.8) 23 (54.8)
1 (2) 2 (4.1) 2 (4.1) 0 46 (93.9) 47 (95.9) 38 (77.6) 6 (12.2) 3 (6.1) 4 (8.2) 3 (6.1) 3 (6.1) 1 (2) 5 (10.2) 3 (6.1) 7 (14.3) 2 (4.1) 0 1 (2) 5 (10.2) 7 (14.3) 34 (67.3) 10 (20.8)a 16 (38.1)
Age >35 y <35 y Medical history Hypertensive Endocrine Systemic STD Infertility history Nulliparity Complications 1st-trimester bleeding Anemia Infections Hypertension induced by pregnancy Preeclampsia HELLP syndrome Gestational diabetes PPROM Preterm delivery %32 wk Fetal malformations IUFD TTTS IUGR Growth discordance 20% Cesarean section rate Puerperium complications NICU admission, F1 and/or F2
Note: Fisher test used to compare categoric variables, Mann-Whitney test for continuous variables. Abbreviations as in Tables 1 and 2. a P< .05. Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
DISCUSSION/COMMENT The increasing use of ART has led to an increase in the incidence of multiple pregnancy. Currently in Europe, 21% of pregnancies resulting from these techniques are twins (1). A twin pregnancy is a high-risk situation that is generally associated with greater maternal morbidity (higher frequency of hypertension induced by pregnancy, anemia, thromboembolic phenomena, sepsis associated with premature rupture of membranes, and postpartum hemorrhage) and increased perinatal morbidity and mortality (higher frequency of preterm labor, premature rupture of membranes, and fetal growth restriction). Consequently, it has been suggested that the higher rates of prematurity, low birth weight, and perinatal complications in newborns resulting from pregnancy induction techniques may result from the higher prevalence of multiple pregnancy in this population. These facts support the need to increase the use of single-embryo transfer (SET) after IVF or ICSI, which among most European countries is still low—22% (1, 16). The impact of induced pregnancies on the adverse outcome of twin pregnancies is still unknown. Unlike studies of single-fetus pregnancies— a comparison that is well established—and its association with an increased risk of preterm delivery, low birth weight, need for induction of labor, cesarean section, and pregnancy-induced hypertension (3, 8, 17–19), studies comparing the obstetrical and neonatal results of twin pregnancies after induced methods or techniques with VOL. 101 NO. 1 / JANUARY 2014
those of spontaneous conception are quite contradictory. Some describe higher perinatal mortality rate, higher prematurity, and low birth weight (6, 7, 9, 20, 21). Others show no significant differences (3–5, 17). Fitzsimmons et al. (15) even showed a lower risk of adverse outcomes, including a lower rate of perinatal mortality, compared with spontaneous pregnancies. In most studies, however, only IVF and/or ICSI are evaluated (leaving out OI), and chorionicity, considered to be a confounding factor for predicting the perinatal outcomes of twin pregnancies, has not been determined or evaluated. The heterogeneous results reported can also depend on differences in studied populations and/or in the management approach to twin pregnancy. Unlike most of the studies published, we included all twin pregnancies, and we analyzed the impact or influence on the results of the usually considered confounding variables, namely, chorionicity and age. We also included all types of induced pregnancies—OI, IVF, and ICSI—and evaluated their influence in the global results. Our results showed, as expected, a more advanced maternal age and a higher proportion of nulliparity in the group of induced pregnancies over the years, which agrees with the literature, because women who need assisted procreation are usually older (4, 10, 18). We found this group to be at higher risk when pregnant from some obstetrical complications, namely, first-trimester 175
ORIGINAL ARTICLE: EARLY PREGNANCY
TABLE 4 Logistical regression for predictors of obstetric complications in induced twin pregnancies. P valuea Predictors for 1st-trimester bleeding OI .53 IVF .018 ICSI .19 Predictors for gestational diabetes OI .312 IVF .153 ICSI .076 Endocrine pathology .049 Predictors for discordant growth OI .003 IVF .034 ICSI .006 Predictors for preterm rupture of membranes Ovulation induction .091 IVF .066 ICSI .007 Age >40 y .009 Predictors for preterm delivery OI .103 IVF .914 ICSI .82 Predictors for delivery by cesarean section OI .442 IVF .005 ICSI .021 a
OR (95% CI) 1.4 (0.48–4.18) 2.5 (1.17–5.16) 1.8 (0.74–4.59) 1.76 (0.59–5.22) 1.96 (0.78–4.94) 2.48 (0.91–6.78) 3.07 (1.01–9.37) 3.89 (1.58–9.59) 2.82 (1.08–7.36) 3.87 (1.48–10.13) 0.48 (0.21–1.12) 0.50 (0.24–1.05) 0.19 (0.06–0.63) 6.16 (1.56–23.6) 0.41 (0.14–1.20) 1.04 (0.49–2.19) 0.89 (0.34–2.33) 1.25 (0.71–2.18) 2.12 (1.26–3.58) 2.07 (1.11–3.84)
Compared with spontaneous twin pregnancies adjusted for age and chorionicity.
Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
bleeding, gestational diabetes, and discordant growth. Firsttrimester bleeding is not described in other studies, and we found higher rates to be associated with monochorionicity, age >35 years, and IVF. The higher risk of gestational diabetes, also reported by Adler-Levy et al. (12) and Sim~ oes et al. (13), revealed no significant association with age, but a previous endocrine pathology was a predictor for its occurrence. The higher risk found for discordant growth was described also by Koudstaal et al. (8) and Bernasko et al. (20), whose hypothesis was to consider the birth weight discordance as an independent risk factor partly responsible for pregnancy complications and adverse perinatal outcomes. Hypertensive complications and intrauterine mortality were not observed differently between the two groups in our study, as described by some authors (5, 7, 8, 10, 13). Regarding the incidence of preterm birth, our study is not in agreement with others, such as Lambalk et al. (6), Moise et al. (7), Nassar et al. (9), McDonald et al. (10), Sim~ oes et al. (13), and Moini et al. (14), who found this complication to be more frequent in the group of pregnancies occurring after IVF. In agreement with the results of Adler-Levy et al. (12), we found a lower incidence of PPROM and PTD occurring in the induced group, which may result from the increased surveillance and enforcement of obstetrical prescription we use in the surveillance of these women. Regarding other obstetrical complications evaluated, no statistically significant differences between the two groups were observed. The largest percentage of cesarean sections in the induced group, as described by other studies (10, 11), 176
could be attributable to greater parental anxiety and obstetric stress surrounding these pregnancies. Regarding prevalence of very low birth weight, Apgar scores, need for hospitalization in NICU, fetal malformation, and perinatal mortality, we found no statistically significant differences between the two groups, confirming the results from McDonald et al. (10) and Dhont et al. (3) but not those from Moise et al. (7), d'Angelo et al. (17), and Morcel et al. (18), who described a higher incidence of low and very low birth weight. Except for first-trimester bleeding, which was strongly associated with older women and monochorionicity, all other results were independent from age or chorionicity. The other interesting result from our study is the similarity of obstetrical complication results independently from the induced method/technique used, in total contradiction to Morcel et al.'s results which found worse perinatal results in the induced group, especially in the OI subgroup (18). The exception to this similarity was the association of IVF in particular to first-trimester bleeding and the association of both IVF and ICSI to cesarean section deliveries. Our results do not corroborate the studies that argue that infertile couples have intrinsic factors responsible for adverse obstetrical outcomes, regardless of a spontaneous or induced conception (15, 22–24). It is noted that, of course, the present study has some limitations, particularly the fact of being carried out in a tertiary care center where all high-risk pregnancies are referred and with a rigorous protocol of surveillance in a specific twin consultation, which can influence the good outcomes. Our results are only similar to those found by Adler-Levy et al. (12), and the higher rates of first-trimester bleeding, gestational diabetes, and discordant growth found with induced twins do not contribute to different neonatal immediate outcomes and they do not contribute to higher rates of prematurity, low birth weight or other major perinatal complications.
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Masahiro M, Iwasa T, Kiyokawa M, Takahashi Y, Morine M. Investigation of the factors affectong the perinatal outcome of monochorionic diamniotic twins. Arch Gynecol Obstet 2011;283:1239–43. d'Angelo DV, Whitehead N, Helms K, Barfield W, Ahluwalia IB. Birth outcomes of intended pregnancies amog women who used assisted reproductive tecnhology, ovulation stimulation, or no treatment. Fertil Steril 2011;96: 314–20. Morcel K, Lavoue V, Beuchee A, Le Lannou D, Poulain P, Pladys P, et al. Perinatal morbidity and mortality in twin prregnancies with dichorionic placentas following assisted reproducitve techniques or ovarian induction alone: a comparative study. Eur J Obstet Gynecol Reprod Biol 2010;153: 138–42. Maman E, Lunenfeld E, Levy A, Vardi H, Potashnik G. Obstetric outcome of singleton pregnancies conceived by in vitro fertilization and ovulation induction compared wth those conceived spontaneously. Fertil Steril 1998;7: 240–5. Bernasko J, Lynch L, Lapinski R, Berkowitz R. Twin pregnancies conceived by assisted reproductive techniques: maternal and neonatal outcomes. Obstet Gynecol 1997;89:368–72. Allen VM, Wilson RD. Pregnancy outcome after assisted reproductive technology. J Obstet Gynaecol Can 2006;28:220–33. Joffe M, Li Z. Association of time to pregnancy and the outcome of pregnancy. Fertil Steril 1994;62:71–5. Thomson F, Shanbhag S, Templeton A, Bhattacharya S. Obstetric outcome in women with subfertility. Br J Obstet Gynecol 2005;112:632–7. Bosso O, Baird DD. Infertility and preterm delivery, birthweigh and caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18:2478–84.
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Impact of induced pregnancies in the obstetrical outcome of twin pregnancies Ana Patrícia Domingues, M.D., M.Sc.,a Sofia Raposo Dinis, M.D.,a Adriana Belo, M.Sc.,c Daniela Couto, M.D.,b Etelvina Fonseca, M.D.,a and Paulo Moura, M.D., Ph.D.a,d a c
Obstetrics-A Department and b Human Reproduction Department, Coimbra Hospital and University Center; Biostatistician; d Obstetrical Clinic, Faculty of Medicine, Coimbra University, Coimbra, Portugal
Objective: To compare obstetric outcomes of induced twins with those spontaneously conceived. Design: A prospective observational study was conducted in twin pregnancies delivered over 16 years. Setting: A tertiary obstetric center with differentiated perinatal support. Patient(s): A total of 180 induced twins and 698 spontaneously conceived were included. Intervention(s): None. Main Outcome Measure(s): Comparison of demographic factors, obstetrical complications, gestational age at delivery, mode of delivery, birth weight, and immediate newborn outcome. Result(s): First-trimester bleeding was higher in the induced group (6.0% vs. 12.2%), as were gestational diabetes (4.4% vs. 8.3%) and discordant intrauterine growth (4.3% vs. 11.1%). Preterm premature rupture of membranes was less frequent (23.9% vs. 12.8%) as was preterm delivery %32 weeks (22.5% vs. 14.0%). Cesarean section rate was higher (50.6% vs. 63.9%). Other obstetrical complications, newborn data, and puerperal complications were not statistically different. Except for first-trimester bleeding (significantly associated with monochorionicity), these results were independent from chorionicity. Regarding the induced method (ovulation induction, IVF, or ICSI), IVF is a predictor for first-trimester bleeding and IVF or ICSI a predictor for cesarean section. Conclusion(s): The higher rates found with induced twins of first-trimester bleeding, gestational diabetes, and discordant growth do not contribute to different neonatal immediate outcomes and do not contribute to higher rates Use your smartphone of prematurity, low birth weight, or other major perinatal complications. (Fertil SterilÒ to scan this QR code 2014;101:172–7. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: Twins, induced reproduction, obstetrical outcomes Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/dominguesap-induced-pregnancy-obstetric-outcome-twins/
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ince 1980 there has been a worldwide increase in multiple births. This seems to be due to an increase in the age of women at reproduction, the use of ovulation induction (OI), and the use of assisted reproduction techniques (ART), such as in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI). ART has become a widespread option for the treatment of human infertility,
and data show that 22% of all deliveries after ART occur in pregnancies with more than one fetus: 20.7% of twins and 1% of triplets (1). It is well known that maternal and obstetrical complications are more frequent in twin pregnancies than in singleton pregnancies. However, it is not yet clear if induced twin pregnancies must be considered to be at higher obstetrical risk than spontaneously
Received May 31, 2013; revised September 13, 2013; accepted September 18, 2013; published online October 17, 2013. A.P.D. has nothing to disclose. S.R.D. has nothing to disclose. A.B. has nothing to disclose. D.C. has nothing to disclose. E.F. has nothing to disclose. P.M. has nothing to disclose. Reprint requests: Ana Patrícia Domingues, M.D., M.Sc., Maternidade Dr Daniel de Matos, Servic¸o de rio de Coimbra, Rua Miguel Torga, 3030-165 Obstetrícia-A, Centro Hospitalar e Universita Coimbra, Portugal (E-mail: [email protected]). Fertility and Sterility® Vol. 101, No. 1, January 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2013.09.026 172
discussion forum for this article now.*
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conceived ones. Studies comparing the outcome of induced twin pregnancies and those of spontaneous conception report inconsistent findings; some report similar perinatal outcomes (2– 5), whereas others report a higher risk of adverse perinatal outcomes, such as gestational diabetes, hypertension, intrauterine growth discordance, preterm birth and cesarean section, low birth weight, and higher neonatal intensive care unit (NICU) admissions (6–14), and others find a better perinatal outcome after IVF/ICSI (15). In most studies, however, only IVF/ ICSI are evaluated, leaving out OI, and chorionicity, considered to be a confounding factor in predicting the perinatal outcomes of twin pregnancies, has not been determined or evaluated. VOL. 101 NO. 1 / JANUARY 2014
Fertility and Sterility® The aim of the present study was to compare obstetrical outcomes of induced twin pregnancies with those spontaneously conceived, and to evaluate the impact of chorionicity and the type of induction (OI, IVF, or ICSI) on the results.
MATERIALS AND METHODS Data from files of all twin pregnancies that were delivered in our tertiary obstetrics center with differentiated perinatal support over a period of 16 years (from January 1996 to December 2011) were prospectively collected and analyzed. No intervention was done besides the normal twin surveillance protocol in those with surveillance in our center. This study was included in an investigation project approved by the Ethics Committee of the University Hospitals of Coimbra. We excluded triplets, higher orders, and monoamniotic multiple gestations from the analysis. All twin pregnancies (dichorionic and monochorionic) that were spontaneously conceived and those obtained following an induction method/technique—OI, IVF, or ICSI—were included. In a first analysis, two groups were formed: one of all spontaneously conceived twin pregnancies and the other of all induced twin pregnancies. In both groups the following parameters were analyzed and compared: maternal age (categorized in the following classes <18, 18–25, 26–35, 36–40, and >40 years), parity, personal or family history of twins, personal disease history, and habits (current or earlier use of smoking, drugs, or alcohol). Obstetrical complications included were first-trimester bleeding; urinary, genital, or other infections; anemia; fetal malformations; hypertensive diseases of the pregnancy (gestational hypertension, preeclampsia, eclampsia, and HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome); gestational diabetes [GD]; preterm delivery [PTD], defined as delivery after 24 and before 37 weeks of gestation; preterm premature rupture of membranes (PPROM), defined as the occurrence of premature rupture of membranes after 24 and before 37 weeks of gestation; intrauterine growth restriction [IUGR], defined as fetal measure of abdominal perimeter <10th percentile; discordant growth, defined as 20% difference between fetal birthweights; and fetal death. Birth data analyzed included gestational age at delivery (categorized in the following classes: <28, 28–32, 33–34, 35–36, and >36 weeks), mode of delivery (categorized as vaginal, cesarean section during delivery, elective cesarean section, and cesarian section of the second twin), birthweights of both twins, Apgar (American Pediatric Gross Assessment Record) score at 1st and 5th minute of both twins, and admission of the neonates in the NICU. Puerperal complication occurrences were also analyzed: anemia, hemorrhage, hypertension complications, and endometritis. Gestational age was calculated from the date of embryo transfer for the induced pregnancies obtained from ART and from the date of the last menstrual period in the spontaneously conceived group, both confirmed and corrected by the time of the first-trimester ultrasound. Chorionicity was also determined in the first-trimester scan (by lambda and T signs). VOL. 101 NO. 1 / JANUARY 2014
In a second phase we went on to analyze the influence of chorionicity and of the type of induced technique (IO, IVF, or ICSI) in the above conditions. A global characterization of the sample (180 induced and 698 spontaneously conceived twin pregnancies) was performed considering the above listed parameters. Categoric variables were characterized by absolute frequencies and relative frequencies, and continuous variables were characterized with the use of mean, standard deviation, quartiles, minimum, and maximum. For categoric variables, differences in proportions between the two groups were evaluated with the use of the chi-square test or Fisher exact test. For continuous variables, the t test was used to compare means between the two groups and, when the assumptions for use of the t test were not satisfied, the Mann-Whitney test to compare the distribution of values. The normal distribution of values for continuous variables and the equality of their variances were tested with the use of the Kolmogorov-Smirnov and Levene tests, respectively. To analyze the stratification of risks according to age and chorionicity, the Breslow-Day test was used. A logistic regression model adjusted for age and chorionicity was made to look for predictors of the significantly different results found previously. The variables assumed as potential predictors were the type of pregnancy, induced method/ technique, and all other variables included in the personal history and obstetrical complications. The significance level used in this analysis was 5%. The statistical software SPSS v19.0.0.2 was used.
RESULTS During the period in study—January 1996 to December 2011— there were 878 deliveries of twin pregnancies in our center. Regarding the type of conception, 698 were spontaneous (79.5%) and 180 were induced (20.5%). Over the period studied we found a significant growing trend for induced twin pregnancies (P¼ .001), which represented 20.3% of twin deliveries in our center. This trend is no longer observed regarding the mode of conception individually over the years, which remained stable: OI accounting for 31.5% of the induced pregnancies, IVF 41%, and ICSI 27.5%. Maternal characteristics in both groups were analyzed (Table 1). As expected, women in the induced group were significantly older, had higher rates of infertility, and most were nulliparous. There were no significant differences regarding personal medical histories (hypertensive, endocrine, renal, or other systemic disease) or habits (tobacco, alcohol, drugs). The analysis of obstetrical complications (Table 2; anemia, infections, hypertensive disorders of pregnancy, fetal malformations, intrauterine fetal death, and IUGR) revealed no major statistically significant differences between the two groups. First-trimester bleeding was higher in the induced group [6.0% vs. 12.2%; P¼ .004; odds ratio [OR] 2.18 (95% confidence interval [CI] 1.26–3.75)], as were gestational diabetes [4.4% vs. 8.3%; P¼ .037; OR 1.96 (1.03–3.71)] and intrauterine discordant growth [4.3% vs. 11.1%, P< .001; OR 2.78 (1.54–5.03)]. 173
ORIGINAL ARTICLE: EARLY PREGNANCY
TABLE 1 Maternal characteristics of both groups, n (%).
Age >35 y <35 y Twins history Medical history Renal Hypertensive Endocrine Systemic Psychiatric STD Tobacco/alcohol Infertility history Nulliparity
Spontaneous pregnancy
Induced pregnancy
565 (81.1) 132 (18.9) 282 (41.4)
167 (92.8)a 13 (7.2)a 32 (18)
8 (1.1) 13 (1.9) 23 (3.3) 30 (4.3) 8 (1.1) 4 (0.6) 9 (1.3) 12 (1.7) 345 (49.9)
1 (0.6) 3 (1.7) 8 (4.4) 4 (2.2) 1 (0.6) 2 (1.1) 2 (1.1) 166 (92.2)a 159 (88.3)a
Note: Chi-square test used to compare categoric variables, t test for continuous variables. STD ¼ sexually transmitted disease. a P< .001. Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
PPROM was less frequent in the induced group [23.9% vs. 12.8%; P< .001; OR 0.47 (0.29–0.75)] as was preterm delivery at gestational age %32 weeks [22.5% vs. 14.0%; P¼ .012; OR 0.56 (0.35–0.88)].
TABLE 2 Obstetrical results of both groups, n (%).
Complications 1st-trimester bleeding Anemia Infections Hypertension induced by pregnancy Preeclampsia HELLP syndrome Gestational diabetes PPROM Preterm delivery %32 wk Preterm delivery <35 wk Fetal malformations IUFD TTTS IUGR Growth discordance 20% Cesarean section rate Puerperium complications NICU admission F1 and/or F2 Fetus data Birthweight F1 Birthweight F2 Apgar F1 1st min Apgar F1 5th min Apgar F2 1st min Apgar F2 5th min
Spontaneous pregnancy
Induced pregnancy
545 (78.1) 42 (6.0) 27 (3.9) 53 (7.6) 26 (3.7)
138 (76.7) 22 (12.2)a 9 (5.0) 16 (8.9) 6 (3.3)
32 (4.6) 6 (0.9) 31 (4.4) 166 (23.9) 157 (22.5) 283 (40.6) 11 (1.6) 17 (2.4) 15 (2.1) 89 (12.8) 30 (4.3) 353 (50.6) 131 (18.9) 173 (41.1)
6 (3.3) 1 (0.6) 15 (8.3)a 23 (12.8)b 25 (14)a 58 (32.4)a 3 (1.7) 6 (3.3) 2 (1.1) 25 (13.9) 20 (11.1)b 115 (63.9)b 36 (20.5) 54 (43.2)
2,176 611 g 2,136 620 g 8.3 3.4 9.7 7.8 7.9 9.7 9.6 6.9
2,211 187 g 2,187 738 g 8.3 3.2 9.6 6.9 7.8 8.6 9.6 6.7
Note: Chi-square test used to compare categoric variables, t test for continuous variables. F1, F2 ¼ fetuses 1 and 2; HELLP ¼ hemolysis, elevated liver enzymes, and low platelet count; IUFD ¼ intrauterine fetal death; IUGR ¼ intrauterine growth restriction; NICU ¼ neonatal intensive care unit; PPROM ¼ preterm premature rupture of membranes; TTTS ¼ twin-totwin transfusion syndrome. a P< .05. b P< .001. Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
174
Over the years, we found a significant decreasing trend for obstetrical complications in general (P¼ .001; 81.4% in 1996 to 58.9% in 2011 with an overall mean of 77.9%) and for PPROM and fetal death in particular (P¼ .001 [28.8% in 1996 to 16.1% in 2011 with an overall mean of 21.6%] and P¼ .011 [5.1% in 1996 to 0% in 2011 with an overall mean of 2.6%], respectively). A significantly growing tendency was observed in cases of first-trimester bleeding (P< .001; 1.7% in 1996 to 5.4% in 2011 with an overall mean of 7.2%), anemia (P¼ .009; 3.4% in 1996 to 5.4% in 2011 with an overall mean of 4%), IUGR (P¼ .001; 8.5% in 1996 to 14.3% in 2011 with an overall mean of 13%), and growth discordance (P< .001; 0% in 1996 to 8.9% in 2011 with an overall mean of 5.7%). All other parameters had a stable tendency over the years. Regarding delivery, the induced group had higher cesarean section rates (50.6% vs. 63.9%; P< .001; risk ratio [RR] 1.26 [95% CI 1.11–1.44]). Birth weight, Apgar scores at 1st and 5th minutes, admissions to NICU, and puerperal complications were not statistically different in both groups (Table 2). Analyzing the influence of the induction methods/techniques in pregnancy complications, we found that the results were also independent of the induced method (OI, IVF, or ICSI; Table 3). The only differences found were in maternal characteristics. As expected, we found that OI was significantly associated with younger maternal ages (<35 years; P¼ .047; 94.6% OI vs. 78% of IVF vs. 75.5% of ICSI). This subgroup of OI was also associated with lower rates of puerperal complications (P¼ .037), mainly due to postpartum anemia. When stratifying the risk of significantly obstetrical complications by chorionicity, we found that only first-trimester bleeding had a significantly association with monochorionicity (P¼ .006); this complication occurred in 5.7% of monochorionic spontaneous twin pregnancies vs. 35.7% of monochorionic induced pregnancies. Gestational diabetes occurred in 6.1% of monochorionic spontaneous twin pregnancies vs. none of the monochorionic induced pregnancies (P¼ .14); discordant growth restriction occurred in 4.7% of monochorionic spontaneous twin pregnancies vs. 28.6% of monochorionic induced pregnancies (P¼ .15); PPROM occurred in 26.4% of monochorionic spontaneous twin pregnancies vs. 28.6% in of monochorionic induced pregnancies (P¼ .21); and preterm delivery %32 weeks occurred in 27.8% of monochorionic spontaneous twin pregnancies vs. 23.1% of monochorionic induced pregnancies (P¼ .85). When stratifying the risk of obstetrical complications by age, we found that except for first-trimester bleeding, which had a significant association with age >35 years (P¼ .009), all other results were independent from the women's ages. Applying a logistic regression model adjusted for age and chorionicity, to look in the induced twin pregnancies group for predictors of the significant results obtained, we found that IVF was a predictor for first-trimester bleeding, endocrine pathology was a predictor for the occurrence of gestational diabetes, all types of induction methods/techniques were predictors risk factors for discordant growth, and both IVF and ICSI were predictors for cesarean section occurrence (Table 4). VOL. 101 NO. 1 / JANUARY 2014
Fertility and Sterility®
TABLE 3 Obstetrical results of both groups according to mode of conception. Spontaneous pregnancy
Ovulation induction
IVF
ICSI
565 (81.1) 132 (18.9)
49 (87.5) 7 (12.5)
68 (93.1) 5 (6.8)
48 (97.9)a 1 (2)a
13 (1.9) 23 (1.9) 30 (4.3) 4 (0.6) 12 (1.7) 345 (49.9) 545 (78.1) 42 (6.0) 27 (3.9) 53 (7.6) 26 (3.7) 32 (4.6) 6 (0.9) 31 (4.4) 166 (23.9) 157 (22.5) 11 (1.6) 17 (2.4) 15 (2.1) 89 (12.8) 30 (4.3) 353 (50.6) 131 (18.9) 173 (41.1)
2 (3.6) 2 (3.6) 0 1 (1.8) 48 (85.7) 48 (85.7) 42 (75) 5 (8.9) 2 (3.6) 4 (7.1) 1 (1.8) 2 (3.6) 0 48 (7.1) 9 (16.1) 6 (10.7) 1 (1.8) 1 (1.8) 1 (1.8) 10 (17.9) 7 (12.5) 32 (57.2) 5 (9.3) 15 (38.5)
0 4 (5.5) 2 (2.7) 1 (1.4) 70 (95.9) 63 (86.3) 58 (78.1) 11 (13.7) 4 (4.1) 8 (11) 2 (2.7) 1 (1.4) 0 6 (8.2) 11 (13.9) 12 (16.7) 0 5 (6.8) 0 10 (13.7) 6 (8.2) 49 (67.1) 21 (27.8) 23 (54.8)
1 (2) 2 (4.1) 2 (4.1) 0 46 (93.9) 47 (95.9) 38 (77.6) 6 (12.2) 3 (6.1) 4 (8.2) 3 (6.1) 3 (6.1) 1 (2) 5 (10.2) 3 (6.1) 7 (14.3) 2 (4.1) 0 1 (2) 5 (10.2) 7 (14.3) 34 (67.3) 10 (20.8)a 16 (38.1)
Age >35 y <35 y Medical history Hypertensive Endocrine Systemic STD Infertility history Nulliparity Complications 1st-trimester bleeding Anemia Infections Hypertension induced by pregnancy Preeclampsia HELLP syndrome Gestational diabetes PPROM Preterm delivery %32 wk Fetal malformations IUFD TTTS IUGR Growth discordance 20% Cesarean section rate Puerperium complications NICU admission, F1 and/or F2
Note: Fisher test used to compare categoric variables, Mann-Whitney test for continuous variables. Abbreviations as in Tables 1 and 2. a P< .05. Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
DISCUSSION/COMMENT The increasing use of ART has led to an increase in the incidence of multiple pregnancy. Currently in Europe, 21% of pregnancies resulting from these techniques are twins (1). A twin pregnancy is a high-risk situation that is generally associated with greater maternal morbidity (higher frequency of hypertension induced by pregnancy, anemia, thromboembolic phenomena, sepsis associated with premature rupture of membranes, and postpartum hemorrhage) and increased perinatal morbidity and mortality (higher frequency of preterm labor, premature rupture of membranes, and fetal growth restriction). Consequently, it has been suggested that the higher rates of prematurity, low birth weight, and perinatal complications in newborns resulting from pregnancy induction techniques may result from the higher prevalence of multiple pregnancy in this population. These facts support the need to increase the use of single-embryo transfer (SET) after IVF or ICSI, which among most European countries is still low—22% (1, 16). The impact of induced pregnancies on the adverse outcome of twin pregnancies is still unknown. Unlike studies of single-fetus pregnancies— a comparison that is well established—and its association with an increased risk of preterm delivery, low birth weight, need for induction of labor, cesarean section, and pregnancy-induced hypertension (3, 8, 17–19), studies comparing the obstetrical and neonatal results of twin pregnancies after induced methods or techniques with VOL. 101 NO. 1 / JANUARY 2014
those of spontaneous conception are quite contradictory. Some describe higher perinatal mortality rate, higher prematurity, and low birth weight (6, 7, 9, 20, 21). Others show no significant differences (3–5, 17). Fitzsimmons et al. (15) even showed a lower risk of adverse outcomes, including a lower rate of perinatal mortality, compared with spontaneous pregnancies. In most studies, however, only IVF and/or ICSI are evaluated (leaving out OI), and chorionicity, considered to be a confounding factor for predicting the perinatal outcomes of twin pregnancies, has not been determined or evaluated. The heterogeneous results reported can also depend on differences in studied populations and/or in the management approach to twin pregnancy. Unlike most of the studies published, we included all twin pregnancies, and we analyzed the impact or influence on the results of the usually considered confounding variables, namely, chorionicity and age. We also included all types of induced pregnancies—OI, IVF, and ICSI—and evaluated their influence in the global results. Our results showed, as expected, a more advanced maternal age and a higher proportion of nulliparity in the group of induced pregnancies over the years, which agrees with the literature, because women who need assisted procreation are usually older (4, 10, 18). We found this group to be at higher risk when pregnant from some obstetrical complications, namely, first-trimester 175
ORIGINAL ARTICLE: EARLY PREGNANCY
TABLE 4 Logistical regression for predictors of obstetric complications in induced twin pregnancies. P valuea Predictors for 1st-trimester bleeding OI .53 IVF .018 ICSI .19 Predictors for gestational diabetes OI .312 IVF .153 ICSI .076 Endocrine pathology .049 Predictors for discordant growth OI .003 IVF .034 ICSI .006 Predictors for preterm rupture of membranes Ovulation induction .091 IVF .066 ICSI .007 Age >40 y .009 Predictors for preterm delivery OI .103 IVF .914 ICSI .82 Predictors for delivery by cesarean section OI .442 IVF .005 ICSI .021 a
OR (95% CI) 1.4 (0.48–4.18) 2.5 (1.17–5.16) 1.8 (0.74–4.59) 1.76 (0.59–5.22) 1.96 (0.78–4.94) 2.48 (0.91–6.78) 3.07 (1.01–9.37) 3.89 (1.58–9.59) 2.82 (1.08–7.36) 3.87 (1.48–10.13) 0.48 (0.21–1.12) 0.50 (0.24–1.05) 0.19 (0.06–0.63) 6.16 (1.56–23.6) 0.41 (0.14–1.20) 1.04 (0.49–2.19) 0.89 (0.34–2.33) 1.25 (0.71–2.18) 2.12 (1.26–3.58) 2.07 (1.11–3.84)
Compared with spontaneous twin pregnancies adjusted for age and chorionicity.
Domingues. Obstetrical impact of induced twins. Fertil Steril 2014.
bleeding, gestational diabetes, and discordant growth. Firsttrimester bleeding is not described in other studies, and we found higher rates to be associated with monochorionicity, age >35 years, and IVF. The higher risk of gestational diabetes, also reported by Adler-Levy et al. (12) and Sim~ oes et al. (13), revealed no significant association with age, but a previous endocrine pathology was a predictor for its occurrence. The higher risk found for discordant growth was described also by Koudstaal et al. (8) and Bernasko et al. (20), whose hypothesis was to consider the birth weight discordance as an independent risk factor partly responsible for pregnancy complications and adverse perinatal outcomes. Hypertensive complications and intrauterine mortality were not observed differently between the two groups in our study, as described by some authors (5, 7, 8, 10, 13). Regarding the incidence of preterm birth, our study is not in agreement with others, such as Lambalk et al. (6), Moise et al. (7), Nassar et al. (9), McDonald et al. (10), Sim~ oes et al. (13), and Moini et al. (14), who found this complication to be more frequent in the group of pregnancies occurring after IVF. In agreement with the results of Adler-Levy et al. (12), we found a lower incidence of PPROM and PTD occurring in the induced group, which may result from the increased surveillance and enforcement of obstetrical prescription we use in the surveillance of these women. Regarding other obstetrical complications evaluated, no statistically significant differences between the two groups were observed. The largest percentage of cesarean sections in the induced group, as described by other studies (10, 11), 176
could be attributable to greater parental anxiety and obstetric stress surrounding these pregnancies. Regarding prevalence of very low birth weight, Apgar scores, need for hospitalization in NICU, fetal malformation, and perinatal mortality, we found no statistically significant differences between the two groups, confirming the results from McDonald et al. (10) and Dhont et al. (3) but not those from Moise et al. (7), d'Angelo et al. (17), and Morcel et al. (18), who described a higher incidence of low and very low birth weight. Except for first-trimester bleeding, which was strongly associated with older women and monochorionicity, all other results were independent from age or chorionicity. The other interesting result from our study is the similarity of obstetrical complication results independently from the induced method/technique used, in total contradiction to Morcel et al.'s results which found worse perinatal results in the induced group, especially in the OI subgroup (18). The exception to this similarity was the association of IVF in particular to first-trimester bleeding and the association of both IVF and ICSI to cesarean section deliveries. Our results do not corroborate the studies that argue that infertile couples have intrinsic factors responsible for adverse obstetrical outcomes, regardless of a spontaneous or induced conception (15, 22–24). It is noted that, of course, the present study has some limitations, particularly the fact of being carried out in a tertiary care center where all high-risk pregnancies are referred and with a rigorous protocol of surveillance in a specific twin consultation, which can influence the good outcomes. Our results are only similar to those found by Adler-Levy et al. (12), and the higher rates of first-trimester bleeding, gestational diabetes, and discordant growth found with induced twins do not contribute to different neonatal immediate outcomes and they do not contribute to higher rates of prematurity, low birth weight or other major perinatal complications.
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