Abstract
Aim: To compare maternal, and neonatal outcomes in IVF/ICSI and spontaneously conceived dichorionic twin pregnancy. Method: We collected data regarding dichorionic twin pregnancies following in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI, n=162) with the transfer of fresh embryos as well as data regarding spontaneously conceived pregnancies (n=213) delivered after 28 weeks of gestation at the Department of Obstetrics and Gynecology, Renmin Hospital in Wuhan in the years of 2010-2013. We then compared maternal and neonatal outcomes between IVF/ICSI and spontaneous dichorionic twin pregnancies, with a subgroup analysis separating traditional IVF from ICSI pregnancies. Odds ratios (OR) for associations between IVF/ICSI and pregnancy outcomes were adjusted for maternal factors. Results: The mean maternal age and the percentage of primiparous women were significantly higher in the IVF/ICSI group. Multivariate analysis revealed that maternal outcomes were comparable in both groups with/without adjustment for maternal age and parity. However, IVF/ICSI twins were less likely to have birth weight discordance than those spontaneously conceived (unadjusted OR=0.526, 95% CI 0.297-0.932; adjusted OR=0.486, 95% CI 0.255-0.856). In subgroup analyses, these associations were confirmed in the IVF (adjusted OR=0.496, 95% CI 0.265-0.926), but not in the ICSI group (adjusted OR=0.500, 95% CI 0.139-1.807). Conclusion: IVF/ICSI treatment was not a risk factor for adverse maternal neonatal outcomes, but the risk for birth weight discordance is lower among IVF/ICSI twins.
Keywords: In vitro fertilization/intracytoplasmic sperm injection, dichorionic twin pregnancy, maternal outcome, neonatal outcome
Introduction
Assisted reproductive techniques (ART) are a major breakthrough in the medical treatment for human subfertility. With the increasing use of ART the past three decades, the number of infants born from ART has reached an estimated 5 million since the first ART baby was born in 1978. Over 20% of all deliveries resulting from in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) include more than one fetus [1]. The main reason for the increased incidence of multiple fetuses is that multiple embryos are transferred. Due to the expensive nature of ART, couples employing IVF/ICSI may request that more than one embryo be transferred in order to optimize the chances of achieving pregnancy with a single treatment [1]. In addition, a multiple pregnancies is the preferred outcome for some Chinese women with infertility because of the national one-child policy. However, maternal complications are more frequent in twin (either monochorionic or dichorionic) than in singleton pregnancies [2]. Whether twin pregnancies after ART carry a higher obstetric risk than spontaneously conceived pregnancies is still under debate. Many cohort and case-control studies have addressed this issue with conflicting results. Some studies showed comparable maternal and perinatal outcomes [3,4], while others proved a high risk of adverse perinatal outcome for IVF twins [5,6] or an opposite association with IVF [7-9]. Meta-analyses of ART outcomes also have inconsistent conclusions [10-12]. In addition to the ART procedure, the conflicting results may stem from a variety of potentially confounding factors such as maternal age, parity, geographic residence, maternal education, socioeconomic status, obstetrical management, and pre-existing chronic diseases. A recently published Japanese study of 242,715 pregnancies demonstrated that maternal factors associated with infertility rather than ART procedures themselves may contribute to the adverse outcomes [13]. Therefore, studies to compare a range of obstetric complications and birth outcomes among twins conceived by ART and spontaneously with more comprehensive consideration of the potential confounding factors are necessary. In addition, monochorionicity, which has worse perinatal outcomes (14), could also be a confounding factor because it occurs less frequent among IVF/ICSI twin pregnancies (3.7-7%) compared with the spontaneous group (30%) [14-16]. To make our observations more homogeneous, we limited our analysis to dichorionic twin pregnancies.
Materials and method
From January 1, 2010 to March 31, 2013, we conducted a retrospective study of infants born from twin pregnancies after 28 weeks at the Obstetrics and Gynecology Department, Renmin Hospital, Wuhan University, China. Only dichorionic twin pregnancies were considered and distinguished by those conceived by conventional IVF/ICSI and those spontaneously conceived. Pregnancies resulting in singleton, triplet or monochorionic twins, or involving the use of ovulation stimulating drugs, or delivering before 28 weeks were excluded from this study. After selection, a total of 375 twin pregnancies were included in the analysis, of which 162 conceived by IFV/ICSI and 213 spontaneously.
The diagnosis of chorionicity was based on B-ultrasound before 14 weeks gestation. Pre-eclampsia (PE) was diagnosed after 20 weeks gestation persistent blood pressure was ≥140/90 with proteinuria ≥300 mg / 24 h. Gestational diabetes mellitus (GDM) was diagnosed according to IADPSG (International Association of Diabetic Pregnancy Study Group) criteria (fasting glucose <5.1 mmol; 1 hour glucose <10.0 mmol; 2 hour glucose <8.5 mmol) after 24 weeks gestation. The diagnosis of placenta praevia, premature rupture of membranes, antepartum anemia, and postpartum bleeding, were according to the matching standards in Obstetrics and Gynecology [17].
Preterm birth was defined as delivery before 34 weeks gestation. Birth weight discordance (BWD) between twins was defined as a birth weight difference greater than 20% between twins. Fetal mortality was calculated by dividing the sum of stillbirths and perinatal deaths by the total number of births. Data of neonatal outcomes on the 28th day after birth were collected by follow-up phone call and hospital records. The diagnosis of neonatal pneumonia, respiratory distress syndrome, hyperbilirubinemia, anemia and retinopathy were based on the corresponding criteria in Practical Pediatrics [18].
Differences in obstetric managements could produce potential bias; thus, these pregnancies were managed by the same group of obstetricians according to the same obstetric protocol.
Data are presented as means ± standard deviation of the mean, percentages and odds ratios. Statistical analysis was performed with Statistical Package for Social Science version 19.0 (SPSS). The chi-squared test or Fisher’s exact test was performed for categorical variables and the Student’s t-test for continuous variables. Multiple logistic regression analyses were used to calculate the odds ratios (OR) and 95% confidence intervals (CI) for the independent associations of IVF/ICSI with each outcome after adjustment for potentially confounding variables including maternal age, gravidity, parity and gestational age.
Some neonatal outcomes, such as respiratory distress syndrome (RDS), neonatal pneumonia, hyperbilirubinemia, and infection of unknown origin can occur in either one or both of the twins. The ordinal logistic regression was used to calculate adjusted cumulative ORs and 95% CIs for the association between the aforementioned outcomes and IVF/ICSI. This model calculates cumulative ORs that denote the probability of being in a higher category rather than a lower category. For very low birth weight (VLBW) and low Apgar score, two sets of analyses were performed. A value of p<0.05 was considered statistically significant.
Results
As presented in Table 1, the mean maternal age and the mean parity were significantly higher in the IVF/ICSI women than in the spontaneously conceived pregnancies (31.4 ± 3.9 v.s 29.1 ± 5.02; 1.10 ± 0.32 v.s. 1.29 ± 0.49, respectively). Distribution analysis showed that only 32.7% of women in the IVF/ICSI group were under age 30 compared with the women of spontaneously conceived (53.5%). Furthermore, 90.7% of IVF/ICSI conceived twin pregnancies were primiparous women compared with 72.8% in the spontaneously conceived group. The mean gestational age, gravidity and their distributions between the two groups were similar. Maternal and neonatal outcomes are summarized in Table 2. There was no significant difference between the two groups in maternal outcomes, which included GDM, PE, placenta abruption, antepartum anemia, postpartum bleeding, and premature rupture of membranes. The results were confirmed by multivariate regression with or without adjustment for maternal age and parity (Table 3).
Table 1.
Maternal characteristics of the IVF/ICSI and spontaneously conceived twin pregnancy
| Maternal characteristics | IVF/ICSI (n=162) | Spontaneously (n=213) | p value |
|---|---|---|---|
| Maternal age (year, mean ± SD)a | 31.4 ± 3.9 | 29.1 ± 5.02 | <;0.001 |
| Age distribution of womenb | |||
| ≤29 (n, %) | 53 (32.7) | 114 (53.5) | 0.000 |
| 30-34 (n, %) | 78 (48.1) | 64 (30.0) | 0.000 |
| ≥35 (n, %) | 31 (19.1) | 35 (16.5) | 0.498 |
| Gestational age (weeks, mean ± SD)a | 35.1 ± 2.63 | 35.3 ± 2.48 | 0.4663 |
| Gestational age distributionb | |||
| ≤34 (n, %) | 42 (25.9) | 64 (30.0) | 0.380 |
| 34-37 (n, %) | 65 (40.1) | 76 (35.7) | 0.379 |
| ≥37 (n, %) | 55 (34.0) | 73 (34.3) | 0.948 |
| Gravidity (frequency, mean ± SD)a | 1.76 ± 1.15 | 1.94 ± 1.19 | 0.1455 |
| Gravidity distributionb | |||
| 1 (n, %) | 92 (56.8) | 104 (48.8) | 0.126 |
| 2 (n, %) | 39 (24.1) | 52 (24.4) | 0.940 |
| ≥3 (n, %) | 31 (19.1) | 57 (26.8) | 0.084 |
| Parity (frequency, mean ± SD)a | 1.10 ± 0.32 | 1.29 ± 0.49 | <0.001 |
| Parity distributionb | |||
| 1 (n, %) | 147 (90.7) | 155 (72.8) | 0.000 |
| 2 (n, %) | 14 (8.6) | 54 (25.4) | 0.000 |
| 3 (n, %) | 1 (0.6) | 4 (1.9) | 0.549 |
IVF: in vitro fertilization, ICSI: intracytoplasmic sperm injection.
Student’s t-test.
Chi-square test or Fisher exact test.
Table 2.
Maternal, Fetal and Neonatal outcomes between IVF/CSI and spontaneously conceived Twins
| Maternal Outcomes, n (%) | IVF/ICSI (n=162) | Spontaneously (n=213) | p value |
|
| |||
| GDM | 6 (3.7) | 8 (3.8) | 0.979 |
| Preeclampsia | 32 (19.8) | 40 (18.8) | 0.813 |
| PROM | 36 (22.2) | 50 (23.5) | 0.775 |
| Placenta praevia | 6 (3.7) | 7 (3.3) | 0.827 |
| Antepartum anemia | 17 (10.5) | 21 (9.9) | 0.840 |
| Postpartum bleeding | 8 (4.9) | 10 (4.7) | 0.913 |
| Caesarean section | 134 (82.7) | 165 (77.5) | 0.210 |
|
| |||
| Fetal outcomes n (%) | IVF/ICSI (n=324) | Spontaneously (n=424) | |
| Preterm | 88 (27.2) | 122 (28.7) | 0.591 |
| BWD, ≥20% | 21 (13.0)* | 45 (21.2) | 0.046 |
| Neonatal mortality rate | 4 (1.2) | 9 (2.1) | 0.352 |
| Birth weight (g, mean ± SD)a | 2295.7 ± 513.5 | 2249.6 ± 499.7 | 0.382 |
| First twin-VLBW | 9 (5.5) | 20 (9.4) | 0.173 |
| Second twin-VLBW | 18 (11.0) | 25 (11.8) | 0.851 |
| Apgar score first-born <7 at 1 m | 12 (7.4) | 18 (8.6) | 0.708 |
| <7 at 5 m | 4 (2.5) | 6 (2.8) | 0.834 |
| Apgar score Second-born <7 at 1 m | 16 (9.8) | 24 (11.4) | 0.658 |
| <7 at 5 m | 13 (8.1) | 14 (6.7) | 0.596 |
|
| |||
| Neonatal outcomes, n (%) | IVF/ICSI (n=317) | Spontaneously (n=403) | |
| RDS | 8 (2.5) | 6 (1.5) | 0.318 |
| Neonatal pneumonia | 13 (4.1) | 9 (2.2) | 0.148 |
| Hyperlibirubinemia | 25 (7.9) | 43 (10.7) | 0.205 |
| Anemia | 3 (0.9) | 11 (2.7) | 0.085 |
| Retinopathy | 1 (0.3) | 5 (1.2) | 0.346 |
| IUO | 9 (2.8) | 16 (4.0) | 0.411 |
GDM: Gestational Diabetes Mellitus, PRoM: Premature Rupture of Membranes, BWD: Birth weight discordance, RDS: Respiratory Distress Syndrome, IUO: Infection of unknown origin.
Student’s t-test. Otherwise, Chi-square test was performed.
p<0.05, vs. spontaneously conceived twin pregnancies.
Table 3.
Multivariate Logistic regression analysis of Maternal, Fetal and Neonatal outcomes between IVF/CSI and spontaneously conceived Twins
| Maternal Outcomes, n (%) | Crude OR (95% CI) | Adjusted OR (95% CI)a | Adjusted OR (95% CI)b |
|
| |||
| GDM | 0.986 (0.335-2.899) | 1.013 (0.317-3.242) | |
| Preeclampsia | 1.065 (0.635-1.786) | 0.984 (0.568-1.703) | |
| PROM | 0.931 (0.572-1.516) | 0.854 (0.511-1.428) | |
| Placenta praevia | 1.132 (0.373-3.435) | 0.975 (0.306-3.109) | |
| Antepartum anemia | 1.072 (0.546-2.105) | 1.232 (0.602-2.517) | |
| Postpartum bleeding | 0.917 (0.341-2.463) | 0.824 (0.290-2.345) | |
| Caesarean section | 1.392 (0.829-2.339) | 1.189 (0.687-2.057) | |
|
| |||
| Fetal outcomes n (%) | |||
| Preterm | 0.921 (0.582-1.458) | 0.865 (0.532-1.405) | 0.898 (0.545-1.480) |
| BWD, ≥20% | 0.526 (0.297-0.932) | 0.468 (0.255-0.856) | 0.472 (0.257-0.869) |
| Fetal mortality rate | 0.745 (0.214-2.590) | 1.188 (1.315-4.488) | 1.205 (0.319-4.554) |
| First-born twin VLBW | 0.568 (0.251-1.282) | 0.772 (0.312-1.907) | 0.787 (0.301-2.060) |
| Second-born twin VLBW | 0.851 (0.494-1.789) | 1.302 (0.634-2.673) | 1.344 (0.633-2.853) |
| Apgar score first-born <7 at 1 m | 0.922 (0.428-1.990) | 1.088 (0.482-2.455) | 1.127 (0.495-2.569) |
| Apgar score second-born <7 at 1 m | 0.863 (0.442-1.684) | 1.906 (0.538-2.230) | 1.156 (0.563-2.371) |
|
| |||
| Neonatal outcomes, n (%) | |||
| RDS | 1.558 (0.513-4.728) | 2.270 (0.682-7.559) | 2.409 (0.715-8.118) |
| Neonatal pneumonia | 1.204 (0.373-2.809) | 1.351 (0.458-3.987) | 1.555 (0.515-4.700) |
| Hyperlibirubinemia | 0.537 (0.282-1.024) | 0.563 (0.286-1.107) | 0.564 (0.282-1.130) |
| Anemia | 0.346 (0.095-1.263) | 0.364 (0.094-1.407) | 0.326 (0.078-1.357) |
| Retinopathy | 0.214 (0.026-1.798) | 0.206 (0.023-1.851) | 0.170 (0.016-1.851) |
| IUO | 0.640 (0.267-1.534) | 0.725 (0.289-1.818) | 0.731 (0.289-1.851) |
Adjusted for maternal age and parity;
Adjusted for maternal age, parity, and maternal outcomes.
The fetal and neonatal outcomes in our study population are also shown in Tables 2 and 3. Significant differences were not observed between the two groups in preterm rate, fetal mortality rate, mean birth weight, proportion of twins with Apgar score <7 at 1 and 5 min, and the percentage of VLBW twins. However, the birth weight discordance between twins was more than 50% lower in the IVF/ICSI conceived group (OR=0.486, 95% CI 0.255-0.856) compared with spontaneous twins. No significant differences were observed between the two groups in the proportion of RDS, neonatal pneumonia, hyperbilirubinemia, anemia, retinopathy, and infection of unknown origins. After adjustment for maternal age and parity, the risk for adverse outcomes changed slightly (Table 3).
Maternal characteristics and complications may have profound influences on fetal and neonatal outcomes [19]. The multivariate regression analyses adjusted for obstetric complications such as GDM, pre-eclampsia, antepartum anemia, premature rupture of membranes and caesarean section (CS) that were performed. The association between fetal/neonatal outcomes and IVF/ICSI conception remained stable (Table 3).
ICSI was introduced in 1992 [20] for the treatment of severe male infertility. It was regarded as more risky than traditional IVF because a sperm was injected into the oocyte instead of mixing them together, which could pose additional harmful effects to the fetus. Maternal characteristics of the ICSI group were similar to IVF alone (Table 4). Subgroup regression revealed that maternal complications and fetal and neonatal outcomes between IVF alone and spontaneous twin pregnancies changed slightly with/without adjustment (Table 5).
Table 4.
Maternal characteristics of the IVF and ICSI twin pregnancy
| Maternal characteristics | IVF (n=140) | ICSI (n=22) | Spontaneously (n=213) |
|---|---|---|---|
| Maternal age (year, mean ± SD)a | 31.4 ± 3.97*** | 31.5 ± 3.39* | 29.1 ± 5.02 |
| Age distribution of womenb | |||
| ≤29 (n, %) | 47 (33.6)*** | 6 (27.3)* | 114 (53.5) |
| 30-34 (n, %) | 63 (45.0)** | 15 (68.2)*** | 64 (30.0) |
| ≥35 (n, %) | 30 (21.4) | 1 (4.5) | 35 (16.5) |
| Gestational age (weeks, mean ± SD)a | 35.0 ± 2.71 | 35.8 ± 2.06 | 35.34 ± 2.48 |
| Gestational age distributionb | |||
| ≤34 (n, %) | 38 (27.1) | 4 (18.2) | 64 (30.0) |
| 34-37 (n, %) | 56 (40.0) | 9 (40.9) | 76 (35.7) |
| ≥37 (n, %) | 46 (32.8) | 9 (40.9) | 73 (34.3) |
| Gravidity (frequency, mean ± SD)a | 1.84 ± 1.21 | 1.32 ± 0.48* | 1.94 ± 1.19 |
| Gravidity distributionb | |||
| 1 (n, %) | 77 (55.0) | 15 (68.2) | 104 (48.8) |
| 2 (n, %) | 32 (22.8) | 7 (31.8) | 52 (24.4) |
| ≥3 (n, %) | 31 (22.1) | 0 | 57 (26.8) |
| Parity (frequency, mean ± SD)a | 1.10 ± 0.32*** | 1.1 ± 0.29 | 1.29 ± 0.50 |
| Parity distributionb | |||
| 1 (n, %) | 127 (90.7)*** | 20 (90.9)* | 155 (72.8) |
| ≥2 (n, %) | 13 (9.3)*** | 2 (9.1) | 58 (27.2) |
Chi-square test.
Student’s t-test.
p<0.05;
p<0.01;
p<0.001, vs. dichorionic spontaneously conceived twin pregnancies.
Table 5.
Multivariate Logistic regression analyses* of Maternal, Fetal and Neonatal outcomes in IVF and CSI to spontaneously conceived group
| Maternal Outcomes, n (%) | IVF (n=140) | ICSI (n=22) | ||
|
| ||||
| n (%) | Adjusted OR (95% CI) | n (%) | Adjusted OR (95% CI) | |
|
| ||||
| GDM | 6 (4.3) | 0.784 (0.367-3.771) | N/A | |
| Preeclampsia | 29 (20.7) | 1.046 (0.594-1.840) | 3 (13.6) | 0.674 (0.185-2.447) |
| PROM | 28 (20.0) | 0.731 (0.423-1.264) | 8 (36.4) | 1.829 (0.705-4.745) |
| Placenta praevia | 6 (4.3) | 1.132 (0.356-3.603) | 0 | |
| Anemia | 16 (11.4) | 1.330 (0.643-2.752) | 1 (4.5) | 0.612 (0.218-4.843) |
| Postpartum bleeding | 7 (5.0) | 0.830 (0.279-2.475) | 1 (4.5) | 0.864 (0.101-7.378) |
| Caesarean section | 116 (82.8) | 1.190 (0.671-2.112) | 18 (81.8) | 1.088 (0.339-3.494) |
|
| ||||
| Fetal outcomes, n (%) | IVF (n=140) | ICSI (n=22) | ||
|
| ||||
| n (%) | Adjusted OR (95% CI) | n (%) | Adjusted OR (95% CI) | |
|
| ||||
| Preterm | 78 (27.8) | 0.900 (0.544-1.488) | 10 (22.7) | 0.669 (0.231-1.938) |
| BWD, ≥20% | 18 (12.8) | 0.496 (0.265-0.926) | 3 (13.6) | 0.500 (0.139-1.807) |
| Neonatal mortality rate | 4 (1.4) | 1.367 (0.360-5.192) | 0 | |
| Birth weight (g, mean ± SD)a | 2268.9 ± 520.4 | 2466.591 ± 439.4 | ||
| First twin-VLBW | 9 (6.4) | 0.857 (0.362-2.030) | 0 | |
| Second twin-VLBW | 17 (12.1) | 1.324 (0.657-2.672) | 1 (4.5) | 0.416 (0.052-3.312) |
| Apgar score first-born <7 at 1 m | 11 (7.8) | 1.171 (0.508-2.698) | 1 (4.5) | 0.687 (0.084-5.630) |
| Apgar score second-born <7 at 1 m | 14 (10.0) | 1.135 (0.542-2.378) | 2 (9.1) | 0.962 (0.204-4.550) |
|
| ||||
| Neonatal outcomes, n (%) | IVF (n=277) | ICSI (n=40) | ||
|
| ||||
| n (%) | Adjusted OR (95% CI) | n (%) | Adjusted OR (95% CI) | |
|
| ||||
| RDS | 8 (2.9) | 2.627 (0.787-8.775) | 0 | |
| Neonatal pneumonia | 13 (4.7) | 1.564 (0.529-4.622) | 0 | |
| Hyperlibirubinemia | 23 (8.3) | 0.616 (0.308-1.231) | 2 (5.0) | 0.307 (0.039-2.412) |
| Anemia | 3 (1.1) | 0.422 (0.109-1.632) | 0 | |
| Retinopathy | 1 (0.3) | 0.238 (0.026-2.142) | 0 | |
| IUO | 8 (2.9) | 0.745 (0.286-1.941) | 1 (2.5) | 0.487 (0.19-1.247) |
Adjusted for maternal age and parity.
Students t-test.
Discussion
Our findings suggest that twin pregnancies conceived through IVF/ICSI have comparable maternal outcomes to spontaneously conceived twin pregnancies regardless of maternal age and parity, which is consistent with previous studies [21,22]. We found that the CS rate was slightly higher in IVF/ICSI women (82.7% versus 77.5%), but did not reach a significant difference. However, in spontaneous pregnancies, 8.9% of CS were performed because of a previous CS, whereas there was only 2.5% with an IVF pregnancy. The increased incidence of CS may be due to patient anxiety and/or physician preference rather than an increased obstetric indication.
Available data, including meta-analysis indicated that twins conceived by IVF/ICSI are at a higher risk of lower gestational age, lower birth weight, preterm delivery, and fetal/infant mortality [23-27], while other studies showed no evidence of adverse outcomes [28,29], or even opposite results [30,31]. We observed no significant difference in fetal mortality rate between IVF/ICSI and spontaneously conceived twins (1.2% vs 2.1%). However, three of four fetal deaths in the IVF group occurred during preterm deliveries before 34 weeks gestation, and the birth weight of all four babies was below 1500 g (VLBW). Among 9 perinatal deaths of spontaneously conceived pregnancies, only two occurred during preterm deliveries, which also are VLBW infants. Thus, a larger sample study and stratified analyses of infant mortality by gestational age, birth weight, and preterm delivery would be of valuable to identify the underlying cause, and clarify the conflicting results.
Birth weight is an important determinant of childhood health because low birth weight infants usually experience severe developmental difficulties that could impose huge costs on both the family and society. In our study, despite no significant differences in mean birth weight between the two groups (2295.7 ± 513.5 vs 2249.6 ± 499.7), the proportion of VLBW in first born twins was lower (5.5%) in the IVF/ICSI group than that in the spontaneously conceived pregnancies (9.4%), although it did not reach statistical significance. Furthermore, IVF/ICSI conceived twins had lower risks of birth weight discordance between twins (adjusted OR= 0.486, 95% CI 0.255-0.856), and these associations were confirmed in the IVF by subgroup analysis (adjusted OR=0.496, 95% CI 0.265-0.926), but not in the ICSI group (OR=0.500, 95% CI 0.139-1.807). Twin pairs with birth weight discordance are not only at higher risk of prenatal complications, but also have less favorable growth and development compared to concordant gestation [32]. Ombelet et al [33] found ICSI twin pregnancies were at increased risk for perinatal mortality, prematurity and low birth weight compared with spontaneously conceived different-sex twin pairs. However, our ICSI sample is limited and not able to perform analysis after excluding like-sex twin pairs.
Since early reports in 1985, pregnancy complications, especially neonatal outcomes in ART pregnancies have been intensively investigated. However, whether it is the technology (hormonal stimulation, gamete manipulation, cryopreservation and in vitro culture) or the underlying infertility that plays a greater role in causing poor outcomes has not yet been clearly elucidated. Raatikainen K pointed out that maternal factors relating to subfertility and not only treatment are associated with adverse pregnancy outcome [34]. One recent Japanese study revealed that patients who conceived through the ART procedures have increased risk for adverse pregnancy outcomes regardless the type of ART procedure. These results demonstrate that maternal factors associated with infertility rather than the ART procedure themselves may contribute to the poor consequences [13]. An Australian study found that the increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors [35]. Therefore, well designed studies controlling for basic parental information should clarify these inconsistent results.
Strength and limitation
The major strength of our study is that we limited our analysis to dichorionic twins. Monochorionic pregnancies occur often with spontaneous conception and also carry a higher risk of adverse outcomes. Our retrospective study design and controlling for zygosity will rule out, at least in part, the potential bias on maternal and neonatal outcomes. In addition, the subgroup analysis, by separating ICSI from IVF, may reduce residual confounding. Furthermore, the only ART involved in our study is IVF or/and ICSI with fresh embryos transferred, which will further reduce the heterogeneity in our observations. Another strong point is that both IVF/ICSI and spontaneously conceived pregnancies were managed by the same obstetric group based on the same obstetric protocol.Different types of pregnancy managements are responsible, at least in part, for some of the observed maternal and neonatal outcomes, therefore, the homogenous management is expected to control for potential bias. Finally, our multivariate regression analysis, which included covariates such as maternal age, parity, gravidity and gestational age, would further reduce confounding effects.
The major limitation in this study is the lack of parental information regarding educational level, socio-economic status (SES), body mass index, and history of chronic disorders known to be associated with pregnancy outcomes. The majority of women who undertake IVF have higher SES. More women with low SES in the spontaneously conceived group may have exaggerated adverse outcomes and thus masked the differences between the two groups.
Moreover, Renmin Hospital, a Grade A tertiary general hospital, is the only setting from which we collected our data. As the first affiliated hospital of Wuhan University, Renmin has better management of obstetrics and better control for complications during the perinatal period. Therefore, our study may not be a representative sample for China.
In conclusion, our observations demonstrate that the obstetric and neonatal outcomes of IVF dichorionic twin pregnancies are comparable to that of spontaneously conceived twins, except that the rate of birth weight discordance is higher in the spontaneously conceived group. Well designed studies which take into account the effects of paternal infertility on IVF are needed to confirm these results.
Acknowledgements
The authors would like to thank Dr. Cara J Westmark for help with proofreading and critical suggestions.
Disclosure of conflict of interest
None.
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