Assisted reproductive technology and risk of adverse obstetric outcomes in dichorionic twin pregnancies: a systematic review and meta-analysis

ORIGINAL ARTICLE: ASSISTED REPRODUCTION 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59

Assisted reproductive technology and risk of adverse obstetric outcomes in dichorionic twin pregnancies: a systematic review and meta-analysis Q4

Jiabi B. Qin, M.D., Ph.D.,a,b Hua Wang, M.D.,a Xiaoqi Sheng, M.D.,c Qiong Xie, M.D.,a and Shiyou Gao, M.D.d a Division of Medical Genetics, c Pediatric Rehabilitation, and d Reproductive Center, Maternal and Child Health Hospital of Hunan province; and b State Key Laboratory of Medical Genetics, Central South University, Hunan, People's Republic of China

Objective: To examine whether dichorionic twin pregnancies after assisted reproductive technology (ART) were at higher risk of adverse obstetric outcomes compared with those conceived naturally. Design: Meta-analysis. Setting: University-affiliated teaching hospital. Patient(s): Dichorionic twin pregnancies conceived with ART and naturally. Intervention(s): Studies comparing obstetric outcomes in dichorionic twin pregnancies conceived by ART and naturally were identified by searching PubMed, Google Scholar, Cochrane Libraries, and Chinese databases through July 2015 with no restrictions. Either a fixedeffects or a random-effects model was used to calculate the overall combined risk estimates. Subgroup analysis was performed to explore potential heterogeneity moderators. Main Outcome Measure(s): Maternal complications and adverse pregnancy outcomes. Result(s): Fifteen cohort studies involving 6,420 dichorionic twins after ART and 13,650 dichorionic twins conceived naturally were included. Most of maternal complications were similar in both groups, but placenta previa (relative risk [RR] ¼ 2.99, 95% confidence interval [CI] 1.51–5.92; I2 ¼ 0) was significantly more common in the ART group. For neonatal outcomes, the ART group experienced higher risk of preterm birth (RR ¼ 1.13, 95% CI 1.00–1.29; I2 ¼ 75%), very preterm birth (RR ¼ 1.39, 95% CI 1.07–1.82; I2 ¼ 71%), low birth weight (RR ¼ 1.11, 95% CI 1.00–1.23; I2 ¼ 61%), and congenital malformations (RR ¼ 1.26, 95% CI 1.09–1.46; I2 ¼ 26%). In addition, the ART group had a higher proportion of elective cesarean sections (RR ¼ 1.79, 95% CI 1.49–2.16; I2 ¼ 60%), but had a similar proportion for emergency cesarean sections. Relevant heterogeneity moderators have been identified by subgroup analysis. No evidence of publication bias was observed. Conclusion(s): The rates of placenta previa, elective cesarean section, preterm birth, very preterm birth, low birth weight, and congenital malformations were significantly higher in dichorionic twin pregnancies after ART. (Fertil Use your smartphone SterilÒ 2016;-:-–-. Ó2016 by American Society for Reproductive Medicine.) to scan this QR code Key Words: In vitro fertilization, intracytoplasmic sperm injection, neonatal outcomes, and connect to the obstetric outcomes, dichorionic twins Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/qinj-risks-assisted-twin-pregnancies-metaanalysis/

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Received October 15, 2015; revised December 15, 2015; accepted December 22, 2015. J.B.Q. has nothing to disclose. H.W. has nothing to disclose. X.S. has nothing to disclose. Q.X. has nothing to disclose. S.G. has nothing to disclose. J.B.Q. was supported by the Project Funded by China Postdoctoral Science Foundation (2015M572248) and Hunan Provincial Science and Technology Plan Project (2015RS4055). Reprint requests: Jiabi B. Qin, M.D., Ph.D., Division of Medical Genetics, Maternal and Child Health Hospital of Hunan province, 53 Xiangchun Road, Changsha, Hunan 410008, People's Republic of China (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2016 0015-0282/$36.00 Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.12.131 VOL. - NO. - / - 2016

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177

I

n the past 36 years, assisted reproductive technology (ART), such as IVF and/or intracytoplasmic sperm injection (ICSI), has become a widespread option for the treatment of human infertility. More than 200,000 babies are born worldwide each year by ART (1, 2), and at present, approximately 5 million babies are born as a result of all forms of conception (3). Twin pregnancies resulting from ART have increased worldwide in recent years because of increased requests for ART and the transfer of two or three embryos to achieve a higher pregnancy rate (PR) (4). This increase has occurred despite efforts aimed at limiting the incidence of multiple pregnancies after ART by using single ET (5). Pressure to achieve higher PRs with infertility treatment has resulted in an unacceptably high multiple pregnancy rate (6).The final effect is reflected by data showing that 21.8% of all deliveries after ART occur in pregnancies with more than one fetus (7). The increased rate of twins born as a result of ART is ‘‘the most serious complication’’ of ART treatment (8). It is well documented that twin pregnancies (either monochorionic or dichorionic) have a poorer maternal and neonatal outcomes than singleton pregnancies (9, 10), with higher rates of perinatal morbidity and mortality (11, 12). In addition, consistent evidence from meta-analyses (13–17) has shown that singleton pregnancies after ART are at greater risk of adverse obstetric outcomes than those conceived naturally. However, data are conflicting on the outcomes of ART twin pregnancies compared with spontaneously conceived (SC) twin pregnancies. Most studies comparing ART and SC twin pregnancies reported similar perinatal outcomes (5, 18–23). Some studies (4, 11, 24–26) reported a higher risk of poor perinatal outcomes for ART twins. Even other studies (27, 28) found better perinatal outcomes after ART. Differences in the study population and management methods of twin pregnancies, and especially whether or not monochorionicity was considered as a risk factor for adverse outcomes, are the main reasons for the inconsistent findings. It is well known that the occurrence of monochorionicity among twin pregnancies after ART is quite rare compared with SC twin pregnancies (about 2% vs. 22%, respectively), and monochorionic pregnancies have worse perinatal outcomes (21, 29, 30). Theoretically, the lower proportion of monochorionic twins in pregnancies from ART may somewhat offset the adverse effect of ART in twins. Therefore the chorionicity should be considered as an intermediate that modifies the relation between ART and adverse obstetric outcomes in twin pregnancies. Although several studies (4, 5, 11, 20, 21, 31–40) have been performed to address whether dichorionic twin pregnancies after ART have greater risk of adverse outcomes compared with those conceived naturally, their results are often inconsistent. Not long ago, we have performed a metaanalysis to compare obstetric risks of twin pregnancies from ART versus spontaneous conception (41). However, at that time, we did not take chorionicity into account when evaluating the relation between ART and poor outcomes. The present study aimed at examining whether dichorionic twin pregnancies after IVF and/or ICSI have a higher risk of

adverse obstetric outcomes compared with those conceived naturally by conducting a systematic review and metaanalysis.

MATERIALS AND METHODS Literature Search We performed a meta-analysis according to the MOOSE guidelines (42). The present study was approved by the Institutional Review Board of Maternal and Child Health Hospital of Hunan province. The studies that compared maternal and neonatal outcomes in dichorionic twin pregnancies conceived by ART and spontaneously were identified by searching PubMed, Google Scholar, Cochrane Libraries, China Biology Medicine disc (CBMdisc), Chinese Scientific Journals Fulltext Database (CQVIP), China National Knowledge Infrastructure (CNKI), and Wanfang Database through July 2015 with no restrictions. We used the following search terms: assisted reproductive technology/ART, assisted conception, assisted reproduction, in vitro fertilization/IVF, test tube baby, intracytoplasmic sperm injection/ICSI, artificial insemination, intrauterine insemination/IUI, cervical canal insemination, embryo transfer, frozen embryo transfer, pregnancy/birth outcome, complication, maternal/neonatal/perinatal/obstetric outcome, adverse/poor outcome, mortality/morbidity, preterm/low birth weight, congenital malformation/anomalies/ birth defect, and twin. In addition we reviewed references in seminal papers, review articles, and medical textbooks. We did not search gray literatures and conference abstracts, and did not contact authors of the primary studies for additional information.

Outcome Measures The main outcome measures for the present study were maternal complications and adverse pregnancy outcomes. The maternal complications involved were pregnancyinduced hypertension or preeclampsia, gestational diabetes mellitus, placenta previa, placental abruption, premature rupture of membranes, antepartum hemorrhage, postpartum hemorrhage, oligohydramnios, polyhydramnios, and cesarean sections. The adverse pregnancy outcomes involved were: preterm birth (PTB; defined as birth at <37 weeks of gestation); very PTB (VPTB; defined as birth at <32 weeks of gestation); low birth weight (LBW; defined as birth weight <2,500 g); very LBW (VLBW; defined as birth weight <1,500 g); small for gestational age (SGA; defined as birth weight <10%); perinatal mortality (defined as stillbirth, fetal death, or neonatal death); congenital malformations (CM; defined as abnormalities that were probably of prenatal origin, including structural, chromosomal, and genetic defects); intrauterine growth restriction (IUGR; defined as growth below the third percentile for gestational age); neonatal respiratory distress syndrome (NRDS); and admission to neonatal intensive care unit (NICU). Because variations in the definition of outcome measures exist across countries and cultures, it is extremely difficult to define uniform standards. The early literatures did not always define VOL. - NO. - / - 2016

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birth outcomes and in such cases we relied on the outcome terminology in the original articles.

Study Selection Two authors (J.B.Q. and H.W.) independently conducted the studies selection. We first performed an initial screening of titles or abstracts. A second screening was based on full-text review. Studies were considered eligible for inclusion if they: [1] were published in Chinese or English language; [2] had a prospective or retrospective cohort design; [3] compared maternal and neonatal outcomes in dichorionic twin pregnancies conceived by ART and spontaneously; [4] had use of IVF and/or ICSI as the exposure of interest; [5] had use of maternal complications and adverse pregnancy outcomes as outcomes of interest; and [6] reported relative risks (RRs), odd ratios (ORs), and the corresponding 95% confidence interval (CI) (or data to calculate them). In our study, only dichorionic twin pregnancies were considered and distinguished into those conceived by ART (either IVF or ICSI) and those conceived naturally. Singleton pregnancies, triplet pregnancies, multiple pregnancies, and monochorionic twin pregnancies were excluded. We excluded review articles, nonpeer-reviewed local/government reports, conference abstract, and presentation in the present study. Multiple articles from the same center and/or authors were analyzed to determine whether the most recent publication was an accumulation that included cases reported in earlier publications. If this was evident from our review, then we used only the most recent publication. We also assessed potential studies to ensure that there was no duplication of case series.

Data Extraction and Quality Assessment Two independent reviewers (J.B.Q. and H.W.) extracted data and assessed study quality. Any disagreements were resolved through discussion among the authors until consensus was reached. Data extraction was then performed using a standardized data collection form. We extracted any reported RRs or ORs of outcomes for ART dichorionic twin pregnancies compared with those conceived naturally. We also extracted study characteristics for each literature. Data were recorded as follows: first author's name; year of publication; study period; geographic region; sample source (population-based vs. clinic-based studies); study design (retrospective vs. prospective cohort design); sample size of ART and SC dichorionic twins; whether patients who achieved a pregnancy with ovulation induction (OI) and IUI were included in the SC group (yes, no, and not stated); type of ART; reported adverse outcomes; confounding factors matched or adjusted; and quality score. We adapted the principles of the Newcastle-Ottawa scale (NOS) to appraise the quality of included studies (43). In statistics, the scale is a tool used for assessing the quality of nonrandomized studies included in a systematic review and/or meta-analysis. Using the tool, each study is judged on eight items, categorized into three groups: the selection of the study groups; the comparability of the groups; and the ascertainment of outcome of interest for cohort studies. Stars awarded

for each quality item serve as a quick visual assessment. Stars are awarded such that the highest quality studies are awarded up to nine stars. When the study gains at least seven stars, it is considered of higher methodological quality.

Statistics Relative risk was used to measure the association between ART and adverse outcomes. Homogeneity of effect size across studies was tested by using the Q statistics at the P< .10 level of significance. The I2 statistic, which is a quantitative measure of inconsistency across studies, was also calculated (significance level at I2 >50%) (44, 45). The combined RR and the corresponding 95% CI were calculated using either fixedeffects models or, in the presence of heterogeneity, randomeffects models (46). Sensitivity analysis was conducted to explore possible explanations for heterogeneity and examine the influence of various exclusion criteria on the overall risk estimate. We performed a sensitivity analysis by omitting studies that had a prospective cohort design or with a sample size >2,000. Subgroup analyses according to whether the confounding factors were adjusted and/or matched, geographic region, sample source, quality score, whether patients who achieved a pregnancy with OI and IUI were included in the SC group, and type of ART were performed to assess the potential effect modification of these variables on outcomes. Potential publication bias was assessed by Begg's funnel plots and Egger's linear regression tests (47). The subgroup analysis and publication bias assessment were only performed for these outcomes with the number of included studies at seven or more. Statistical tests were declared significant for a two-sided P value not exceeding .05, except where otherwise specified. Egger's linear regression test was performed using the SAS statistical software, version 8.2 (SAS Institute). Other analyses were performed by Review Manager-version 5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration).

RESULTS Literature Search We initially searched 750 potentially eligible records from 7 databases. Of these, most were excluded after the first screening based on titles or abstracts, mainly because they were duplicates, reviews, or not relevant to our analysis. After full-text review of 96 studies, 15 studies were excluded because they only focused on singleton pregnancies. An additional 17 studies in which singletons, twins, and multiples data were not separated were excluded. Twenty-nine studies in which dichorionic twins data could not be extracted, 3 studies that only considered monochorionic twin pregnancies, 12 studies in which the exposure was inconsistent with our analysis, and 5 studies having limited information for outcome measures were also excluded. Finally, 15 studies including 2 prospective cohort studies (4, 5) and 13 retrospective cohort studies (11, 20, 21, 31–40) were included in our review (Fig. 1).

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413

FIGURE 1

Q3

Flow chart of study selection. Qin. Adverse outcomes in assisted twin pregnancies. Fertil Steril 2016.

Study Characteristics The characteristics of included studies involving 6,420 dichorionic twins conceived with ART and 13,650 dichorionic twins conceived naturally and published between 2003 and 2014 (Table 1). Seven studies (46.7%) were conducted in Europe, six (40%) in Asia, and two (13.3%) in Australia. For sample sources, 5 studies (33.3%) were population based, and 10 (66.7%) were clinic based. The size of ART infants ranged from 76 to 1,650 (total 6,420) and SC infants from 54 to 4,134 (total 13,650). The sample size in more than half studies (53.3%) was less than 500. Among the 15 studies included, those reporting complications and/or adverse outcomes were as follows: 7 pregnancy-induced hypertension or preeclampsia; 4 gestational diabetes mellitus; 4 placenta previa; 2 placental abruption; 5 premature rupture of membranes; only 1 antepartum hemorrhage; 3 postpartum hemorrhage; only 1 polyhydramnios; only 1 oligohydramnios; 5 cesarean sections; 12 PTB; 10 VPTB; 9 LBW; 7 VLBW; 3 SGA; 10 perinatal mortality; 14 CM; 3 IUGR; 5 NRDS; and 8 NICU admissions. Three studies (20%) (21, 31, 36) included patients who achieved a pregnancy with OI and IUI in the SC group, and the remaining studies did not include these patients in the SC group. Eleven studies (73.3%) were considered of higher

methodological quality, achieving a quality score R7 out of 9; these 11 studies contributed 89.8% of the ART infants and 94.1% of the SC infants. Four studies (26.7%) (20, 33, 34, 39) did not adjust and/or match any factors when estimating the effect of ART on obstetric outcomes, whereas other studies at least adjusted and/or matched for maternal age.

ART and Risk of Maternal Complications Pregnancy-induced hypertension or preeclampsia and gestational diabetes mellitus. Of the seven studies, three showed a positive association between ART and risk of pregnancy-induced hypertension or preeclampsia. For gestational diabetes mellitus, three studies (total 4) showed a positive association between ART and risk of gestational diabetes mellitus. Overall, there were no significant statistical differences between the two groups for developing pregnancyinduced hypertension or preeclampsia (RR ¼ 1.04, 95% CI 0.86–1.25; P¼ .70) and gestational diabetes mellitus (RR ¼ 1.13, 95% CI 0.78–1.65; P¼ .51), without the evidence of heterogeneity (all I2 ¼ 0) (Table 2). Placenta previa, placental abruption, and premature rupture of membranes. Four studies (total 4) showed a VOL. - NO. - / - 2016

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TABLE 1 Characteristics of 15 cohort studies of ART and risk of adverse obstetric outcomes in dichorionic twin pregnancies.

First author/ publication year(study period) Smithers/2003 (1991–1999)

Geographic region

Sample source

Study design

Whether patients who achieved a pregnancy with OI and IUI were ART SC twins included in the Type of twins (n) (n) SC group? ART

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Australia

Population Retrospective cohort

1,028

4,134

Yes

IVF

Denmark Pinborg/2004 (1995–2000)b

Population Retrospective cohort

1,650

3,546

Yes

IVF/ICSI

Kuwata/2004 (1990–2001) Ho/2005 (2002–2003)

Japan

Clinic

232

188

No

IVF; ICSI

Taiwan

Clinic

140

54

No

IVF

Belgium

Population Retrospective cohort

470

907

No

ICSI

76

170

No

IVF/ICSI

86

150

No

IVF

Ombelet/2005 (1997–2003)

UK Joy/2008 (2002–2003)b Zhang/2008 China (1998–2005)

Clinic Clinic

Retrospective cohort Retrospective cohort

Retrospective cohort Retrospective cohort

Pregnancy-related complications and adverse pregnancy outcomes

Adjusted or matched factors

Grouped by sample size (ART plus SC Quality group) scorea

Adjusted for maternal age and parity, except for CM

>2,000

1

Maternal age and parity

>2,000

1

Maternal age

<500

1

PTB; LBW; VLBW; CM; perinatal mortality; SGA; NICU admissions PTB; VPTB; LBW; VLBW; CM; perinatal mortality; NRDS; NICU admissions LBW; CM

None

<500

2

None

<500

2

Premature rupture of membrane; placenta previa; postpartum hemorrhage; preeclampsia or eclampsia; PTB; LBW; CM; perinatal mortality

None

<500

2

Placenta previa; antepartum hemorrhage; preeclampsia or eclampsia; premature rupture of membranes; cesarean sections; PTB; VPTB; CM PTB; VPTB; LBW; VLBW; CM; perinatal mortality; NICU admissions CM

Parity, maternal age, place of birth, date of birth, and fetal sex

500–2,000

1

5

Fertility and Sterility®

Qin. Adverse outcomes in assisted twin pregnancies. Fertil Steril 2016.

532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590

591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 Continued.

First author/ publication year(study period)

Geographic region

Sample source

Study design

Whether patients who achieved a pregnancy with OI and IUI were ART SC twins included in the Type of twins (n) (n) SC group? ART

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Vasario/2010 (2004–2008)

Italy

Clinic

Prospective cohort

168

278

No

IVF

Yang/2011 (1995–2008)

South Korea

Clinic

Retrospective cohort

134

286

No

IVF

Population Retrospective cohort

939

1,619

Yes

IVF/ICSI

Australia Hansen/2012 (1994–2002)b

Pregnancy-related complications and adverse pregnancy outcomes

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Pregnancy-induced hypertension; gestational diabetes mellitus; placenta previa; postpartum hemorrhage; premature rupture of membrane; PTB; VPTB; CM; perinatal mortality; NRDS; cesarean sections; IUGR; NICU admissions Preeclampsia or eclampsia; premature rupture of membrane; placenta previa; placental abruption; PTB; VPTB; LBW; VLBW; CM; SGA; perinatal mortality; NICU admissions Perinatal mortality; PTB; VPTB; LBW; VLBW; CM

Adjusted or matched factors

Grouped by sample size (ART plus SC Quality group) scorea

Maternal age and parity

<500

1

Maternal age and parity

<500

1

>2,000

1

Maternal age, parity, and date of fetal birth

Qin. Adverse outcomes in assisted twin pregnancies. Fertil Steril 2016.

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

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TABLE 1

650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708

709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 VOL. - NO. - / - 2016

TABLE 1 Continued.

First author/ publication year(study period)

Geographic region

Sample source

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Moini/2012 Iran (2008–2010)b

Clinic

Sagot/2012 (2000–2009)

France

Hu/2012 (2009–2011) Egic/2014 (2009–2012)

Study design Prospective cohort

Whether patients who achieved a pregnancy with OI and IUI were ART SC twins included in the Type of twins (n) (n) SC group? ART 460

340

No

IVF/ICSI

Population Retrospective cohort

168

550

No

IVF

China

Clinic

Retrospective cohort

175

262

No

IVF

Serbia

Clinic

Retrospective cohort

352

430

No

IVF

Ireland Geisler/2014 (2009–2012)b

Clinic

Retrospective cohort

342

736

No

IVF/ICSI

Pregnancy-related complications and adverse pregnancy outcomes Pregnancy-induced hypertension; gestational diabetes mellitus; placental abruption; oligohydramnion; polyhydramnion; postpartum hemorrhage; premature rupture of membranes; cesarean sections; PTB; VPTB; LBW; VLBW; CM; NRDS; IUGR; perinatal mortality; NICU admissions CM

Adjust for maternal 500–2,000 age and BMI for VPTB, VLBW, perinatal mortality, and NICU admissions

1

Maternal age and gestational diabetes Maternal age

1

None

Adjusting for maternal age, parity, type of antenatal care for pregnancyinduced hypertension, gestational diabetes mellitus, and cesarean sections

500–2,000 <500

1

<500

2

500–2,000

1

7

Note: ART ¼ assisted reproductive technology; BMI ¼ body mass index; CM ¼ congenital malformations; ICSI ¼ intracytoplasmic sperm injection; IUGR ¼ intrauterine growth restriction; LBW ¼ low birth weight; NICU ¼ neonatal intensive care unit; NRDS ¼ neonatal respiratory distress syndrome; OI ¼ ovulation induction; PTB ¼ preterm birth; SC ¼ spontaneously conceived; SGA ¼ small for gestational age; VLBW ¼ very low birth weight; VPTB ¼ very preterm birth. a Each study was assigned a score of 1–9; 1 ¼ higher quality studies with scores R7, 2 ¼ low quality with scores <7. b These articles did not estimate obstetric risks in IVF and ICSI dichorionic twin pregnancies separately. Qin. Adverse outcomes in assisted twin pregnancies. Fertil Steril 2016.

Fertility and Sterility®

PTB; VPTB; CM; NRDS; SGA; perinatal mortality Pregnancy-induced hypertension; gestational diabetes mellitus; PTB; VPTB; cesarean sections; NICU admissions Pregnancy-induced hypertension; gestational diabetes mellitus; cesarean sections; PTB; VPTB; LBW; VLBW; IUGR; CM; NRDS; perinatal mortality; NICU admissions

Adjusted or matched factors

Grouped by sample size (ART plus SC Quality group) scorea

768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826

0 96% 60% 90%

positive relation between ART and risk of placenta previa, only one of which had significant statistical differences. Only two studies (4, 35) reported placental abruption. For premature rupture of membranes, four studies (total 5) showed a positive association between ART and risk of premature rupture of membranes, only one of which had significant statistical differences. Overall, the risk of developing placental abruption (RR ¼ 1.33, 95% CI 0.30– 5.82; P¼ .71) and premature rupture of membranes (RR ¼ 1.20, 95% CI 0.97–1.49; P¼ .10) was similar in the ART group compared with the reference group, without the evidence of heterogeneity (all I2 ¼ 0). However, the ART group experienced a significantly increased risk of developing placenta previa (RR ¼ 2.99, 95% CI 1.51–5.92; P¼ .002), without the evidence of heterogeneity (I2 ¼ 0) (Table 2).

.88 < .00001 .11 .002

Antepartum and postpartum hemorrhage. Only one study (31) in which the RR in relation to ART was 1.73 (95% CI 1.05–2.86) reported antepartum hemorrhage. For postpartum hemorrhage, two studies (total 3) showed a positive association between ART and risk of postpartum hemorrhage. Overall, the risk of developing postpartum hemorrhage was similar between the two groups (RR ¼ 1.08, 95% CI 0.62–1.87; P¼ .79), without the evidence of heterogeneity (I2 ¼ 0) (Table 2). Cesarean sections. Three studies (total 5) showed a significantly positive association between ART and risk of cesarean section. Overall, the ART pregnancies were more likely to be delivered by cesarean sections than those conceived naturally (RR ¼ 1.58, 95% CI 1.15–2.16; P¼ .004), with substantial evidence of heterogeneity (I2 ¼ 96%). Of note, the ART group compared with the reference group had a higher proportion of elective cesarean sections (RR ¼ 1.79, 95% CI 1.49–2.16; P< .00001), but they had a similar proportion for emergency cesarean sections (RR ¼ 1.76, 95% CI 0.93–3.36; P¼ .08) (Table 2). Polyhydramnios and oligohydramnios. Only one study (4) reported polyhydramnios and oligohydramnios, and it did not show that the risk of developing polyhydramnios and oligohydramnios was significantly increased in the ART group compared with the reference group. Qin. Adverse outcomes in assisted twin pregnancies. Fertil Steril 2016.

Note: ART ¼ assisted reproductive technology; CI ¼ confidence interval; RR ¼ relative risk; SC ¼ spontaneously conceived.

0.25 98.54 2.50 9.58 1.08 (0.62–1.87) 1.58 (1.15–2.16) 1.87 (1.37–2.55) 1.76 (0.93–3.36) 1.08 (0.62–1.87) 1.24 (1.18–1.31) 1.79 (1.49–2.16) 1.64 (1.34–2.01) 3 5 2 2

714 2,350 1,370 1,370

768 5,918 4,870 4,870

.71 .74 .36 .58 1.40 1.25 0.85 2.89 1.13 (0.78–1.65) 2.99 (1.51–5.92) 1.33 (0.30–5.82) 1.20 (0.97–1.49) 1.13 (0.78–1.65) 2.99 (1.51–5.92) 1.33 (0.30–5.82) 1.20 (0.97–1.49) 4 4 2 5

1,322 1,416 594 1,876

1,784 4,848 626 5,188

.58 4.72 1.04 (0.86–1.25) 1.04 (0.86–1.25) 7

Pregnancy-induced hypertension or preeclampsia Gestational diabetes mellitus Placenta previa Placental abruption Premature rupture of membranes Postpartum hemorrhage Cesarean section Elective cesarean section Emergency cesarean section

Maternal complications

2,570

6,354

P value Q SC group ART group

RR (95% CI) from random-effects models RR (95% CI) from fixed-effects models The number of unlike sex twins

Number of studies (n)

Meta-analysis of association between ART and maternal complications in dichorionic twin pregnancies.

TABLE 2

Measure of heterogeneity

I2

0

827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885

0 0 0 0

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

ART and Risk of Adverse Pregnancy Outcomes Preterm birth and very preterm birth. For PTB, four studies (total 12) showed a significantly positive relation between ART and risk of PTB. For VPTB, three studies (total 10) indicated a significantly positive association with ART. Overall, the ART pregnancies had a higher risk of developing PTB (RR ¼ 1.13, 95% CI 1.00–1.29; P¼ .05) and VPTB (RR ¼ 1.39, 95% CI 1.07–1.82; P¼ .01) than those conceived spontaneously, with substantial evidence of heterogeneity (I2 ¼ 75% and 71% for PTB and VPTB, respectively) (Table 3). Low birth weight and very low birth weight. Of the nine studies reporting LBW, seven showed a positive association with ART, only two of which had significantly statistical differences. For VLBW, only two studies (total 7) hinted at a significantly positive relationship with ART. Overall, the VOL. - NO. - / - 2016

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886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944

ART group compared with the SC group experienced a significantly increased risk of developing LBW (RR ¼ 1.11, 95% CI 1.00–1.23; P¼ .05), but had a similar risk of developing VLBW (RR ¼ 1.36, 95% CI 0.96–1.94; P¼ .08), with substantial evidence of heterogeneity (I2 ¼ 61% and 71% for LBW and VLBW, respectively) (Table 3). Perinatal mortality. Six studies (total 10) showed a positive relationship with ART, only three of which had significantly statistical differences. Overall, there were no significantly statistical differences for risk of developing perinatal mortality (RR ¼ 1.38, 95% CI 0.83–2.30; P¼ .21) between the two groups. Substantial heterogeneity was observed (I2 ¼ 57%) (Table 3).

Note: ART ¼ assisted reproductive technology; CI ¼ confidence interval; NICU ¼ neonatal intensive care unit; RR ¼ relative risk; SC ¼ spontaneously conceived.

Congenital malformations. Of the 14 studies reporting CM, 3 showed a significantly positive association with ART. Overall, the ART group compared with the reference group experienced a significantly higher risk of developing CM (RR ¼ 1.26, 95% CI 1.09–1.46; P¼ .002), without the evidence of heterogeneity (I2 ¼ 26%) (Table 3). Small for gestational age, intrauterine growth restriction, and neonatal respiratory distress syndrome. For SGA, two studies (total 3) showed a positive relation between ART and risk of SGA. For IUGR, only one study (total 3) suggested a significantly positive association with ART. For NRDS, two studies (total 5) indicated a significantly positive association with ART. The overall combined RRs in relation to ART were 1.25 (95% CI 0.91–1.70; P¼ .17) for SGA, 1.08 (95% CI 0.88–1.34; P¼ .45) for IUGR, and 1.26 (95% CI 0.91–1.73; P¼ .16) for NRDS. There was no evidence of heterogeneity except for NRDS (I2 ¼ 51%) (Table 3). Admission to neonatal intensive care unit. Of the eight studies reporting NICU admission, only three showed a significantly positive association with ART. Overall, the ART group compared with the reference group was at a similar risk for NICU admission (RR ¼ 1.15, 95% CI 0.95–1.40; P¼ .14), with substantial evidence of heterogeneity (I2 ¼ 69%) (Table 3).

Subgroup Analysis Qin. Adverse outcomes in assisted twin pregnancies. Fertil Steril 2016.

69% 51% .002 .08 22.86 8.22 1.15 (0.95–1.40) 1.26 (0.91–1.73) 6,577 2,523 8 5

3,716 1,615

1.17 (1.07–1.27) 1.39 (1.14–1.69)

75% 71% 61% 71% 0 57% 26% 57% < .00001 .0002 .009 .002 .41 .01 .17 .10 43.50 31.44 20.34 20.71 1.76 20.93 17.63 4.67 1.13 (1.00–1.29) 1.39 (1.07–1.82) 1.11 (1.00–1.23) 1.36 (0.96–1.94) 1.25 (0.91–1.70) 1.38 (0.83–2.30) 1.32 (1.07–1.62) 1.05 (0.74–1.50) 12,742 12,538 7,808 7,488 602 8,178 13,220 1,354

Preterm birth Very preterm birth Low birth weight Very low birth weight Small for gestational age Perinatal mortality Congenital malformations Intrauterine growth restriction NICU admissions Neonatal respiratory distress syndrome

12 10 9 7 3 10 14 3

5,944 5,718 4,297 4,135 449 4,564 6,068 970

1.08 (1.02–1.13) 1.39 (1.24–1.57) 1.09 (1.03–1.16) 1.28 (1.10–1.50) 1.25 (0.91–1.70) 1.60 (1.20–2.13) 1.26 (1.09–1.46) 1.08 (0.88–1.34)

I2 P value Q SC group ART group

RR (95% CI) from random-effects models RR (95% CI) from fixed-effects models The number of unlike sex twins

Number of studies (n) Adverse pregnancy outcomes

Meta-analysis of association between ART and adverse pregnancy outcomes in dichorionic twin pregnancies.

TABLE 3

945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003

Measure of heterogeneity

Fertility and Sterility®

Subgroup analysis for adverse obstetric outcomes was summarized in Supplemental Table 1. After subgroup analysis, geographic region, whether the confounding factors were adjusted and/or matched, type of ART, sample sources, and whether patients who achieved a pregnancy with OI and IUI were included in the SC group as the first five of the most relevant heterogeneity moderators have been identified. These differences for risks of developing LBW (test for subgroup differences: c2 ¼ 13.39, P¼ .001; I2 ¼ 85.1%) and VLBW (test for subgroup differences: c2 ¼ 18.48, P< .0001; I2 ¼ 89.2%) in the ART pregnancies were statistically significant between different geographic regions. There was statistically significant difference for the risk of developing CM (test for subgroup differences: c2 ¼ 3.94, P¼ .05; I2 ¼ 74.6%) in the ART pregnancies for whether the confounding factors were adjusted and/or matched. Also, there was statistically significant difference for the risk of developing perinatal mortality

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1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062

ORIGINAL ARTICLE: ASSISTED REPRODUCTION 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121

(test for subgroup differences: c2 ¼ 5.05, P¼ .02; I2 ¼ 80.2%) in the ART pregnancies for type of ART.

Sensitivity Analyses Sensitivity analyses were conducted to explore potential sources of heterogeneity in the association between ART and adverse obstetric outcomes and to examine the influence of various exclusion criteria on the overall risk estimate. Exclusion of two studies (4, 5) that had a prospective cohort design yielded similar results, and the new combined RRs in relation to ART were 1.02 (95% CI 0.83–1.25; I2 ¼ 6%) for pregnancy-induced hypertension or preeclampsia; 1.11 (95% CI 0.66–1.87; I2 ¼ 0) for gestational diabetes mellitus; 3.19 (95% CI 1.57–6.48; I2 ¼ 0) for placenta previa; 1.28 (95% CI 0.97–1.68; I2 ¼ 16%) for premature rupture of membranes; 2.04 (95% CI 1.44–2.89; I2 ¼ 89%) for cesarean sections; 1.16 (95% CI 1.03–1.30; I2 ¼ 65%) for PTB; 1.32 (95% CI 1.03–1.69; I2 ¼ 69%) for VPTB; 1.14 (95% CI 1.02– 1.28; I2 ¼ 53%) for LBW; 1.28 (95% CI 0.88–1.87; I2 ¼ 73%) for VLBW; 1.32 (95% CI 0.71–2.44; I2 ¼ 61%) for perinatal mortality; 1.25 (95% CI 1.08–1.45; I2 ¼ 37%) for CM; 1.09 (95% CI 0.89–1.34; I2 ¼ 73%) for NICU admission; and 1.14 (95% CI 0.63–2.07; I2 ¼ 67%) for NRDS. Further exclusion of 3 studies (21, 31, 36) with a sample size of >2,000 showed a somewhat greater risk of CM (RR ¼ 1.50, 95% CI 1.12–2.01; I2 ¼ 34%), but showed a somewhat lower risk of pregnancy-induced hypertension or preeclampsia (RR ¼ 0.92, 95% CI 0.72–1.17; I2 ¼ 0), placenta previa (RR ¼ 2.86, 95% CI 0.98–8.36; I2 ¼ 0), premature rupture of membranes (RR ¼ 1.20, 95% CI 0.88–1.65; I2 ¼ 0), cesarean sections (RR ¼ 1.40, 95% CI 1.07–1.84; I2 ¼ 94%), PTB (RR ¼ 1.09, 95% CI 0.93–1.28; I2 ¼ 71%), VPTB (RR ¼ 1.35, 95% CI 0.92–2.03; I2 ¼ 60%), LBW (RR ¼ 1.05, 95% CI 0.97–1.13; I2 ¼ 29%), VLBW (RR ¼ 1.17, 95% CI 0.88–1.54; I2 ¼ 41%), perinatal mortality (RR ¼ 1.18, 95% CI 0.58–2.40; I2 ¼ 58%), and NICU admission (RR ¼ 1.12, 95% CI 0.88–1.42; I2 ¼ 69%).

Publication Bias Visual inspection of Begg's funnel plots did not identify substantial asymmetry. The Egger's linear regression test also indicated no evidence of publication bias among studies of ART and adverse obstetric outcomes (P¼ .283 for pregnancyinduced hypertension or preeclampsia; .507 for PTB, .229 for VPTB; .260 for LBW; .411 for VLBW; .124 for perinatal mortality; .293 for CM; and .658 for NICU admissions).

DISCUSSION During the past decades, ART has been transformed from a miracle to a standard and common part of medical practice. Although the initial skepticism surrounding ART has greatly waned, the perinatal outcome remains the focus of continuing critical scrutiny from the medical world and the public at large. We have observed the inconsistent findings from published studies on twin pregnancy outcomes obtained by ART and spontaneous conception. In most studies, however, the

concrete chorionicity, regarded as an intermediate that modifies the relation between ART and pregnancy outcomes in twin pregnancies, has not been determined. Our metaanalysis, which included 15 cohort studies and involved 6,420 dichorionic twins resulting from ART and 13,650 dichorionic twins conceived naturally, is to verify whether dichorionic twin pregnancies after ART have a higher risk of adverse obstetric outcomes compared with those conceived naturally by complete and systematic literature search. To get homogeneous observations, monochorionic twin pregnancies and triplet pregnancies were excluded. It was possible to identify potential heterogeneity moderators by subgroup and sensitivity analyses. Our findings may have important clinical implications given the possibility that the clear results might be useful for counseling ART patients and properly designing the consent forms. Findings from the present study suggested that most maternal complications, such as pregnancy-induced hypertension or preeclampsia, gestational diabetes mellitus, placental abruption, premature rupture of membranes, and postpartum hemorrhage, were similar in the two groups, but placenta previa was significantly more common in the ART group. For neonatal outcomes, our study indicated that the risk of PTB, VPTB, LBW, and CM in the ART group was markedly increased by 15%, 39%, 11%, and 26%, respectively. The ART pregnancies were more likely to be delivered by cesarean sections than those conceived naturally. Of note, the ART group compared with the reference group had a higher proportion of elective cesarean sections, but had a similar proportion for emergency cesarean sections. When data were restricted to matched and/or adjusted studies, the risk of PTB, perinatal mortality, and CM increased further. In addition, the risk of PTB, LBW, perinatal mortality, and CM increased further when data were restricted to populationbased studies or those with high quality. However, these results have to be viewed with caution because of some evidence of heterogeneity (I2 range, 0–96%). These findings require confirmation when more data from larger multiple studies become available, because 53% of the studies included in this subgroup analysis had a small sample size (<500). Following the worldwide introduction of ART, critical concern about the incidence of adverse obstetric outcomes prompted studies addressing this issue. At present, a public belief still holds that maternal and neonatal outcome of ART pregnancies is substantially worse compared with those created naturally (16, 41). This belief can be explained partly by the higher rate multiple pregnancies, which in turn is associated with a higher rate of perinatal mortality and morbidity (11, 12). It is already very clear that compared with SC pregnancies, ART leads to more multiple pregnancies, most of which are twin pregnancies (8, 12). It is worth noting that previous studies generally considered ART singleton pregnancies as having a higher risk of poor obstetric outcomes, such as antepartum hemorrhage, pregnancy-induced hypertension, premature rupture of membranes, gestational diabetes mellitus, PTB, LBW, CM, perinatal mortality, and SGA, than SC singleton pregnancies, which has been confirmed by several meta-analysis (13–17). VOL. - NO. - / - 2016

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Fertility and Sterility® 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239

It is not yet clear, however, whether twin pregnancies resulting from ART must be considered at higher obstetric risk than those conceived naturally. Although the past few years have seen a rapidly growing interest in testing this hypothesis, studies comparing maternal and neonatal outcomes of ART and SC twin pregnancies have reported conflicting results. Most of studies reported comparable maternal outcomes for ART and SC twin pregnancies (4, 5, 19, 48, 49), whereas some (50–52) reported that maternal complications, such as gestational diabetes mellitus, pregnancy-induced hypertension, placenta previa, premature rupture of membranes, and anemia during pregnancy, were significantly more common in ART twin pregnancies. In terms of neonatal outcomes, some studies (21, 30, 36, 53, 54) have showed that ART twin pregnancies were at greater risk of LBW, PTB, CM, NRDS, and perinatal mortality; some other studies (5, 18, 19, 50, 55) did not accept these findings and reported that ART twin pregnancies compared with those conceived naturally had similar neonatal outcomes. Even some reports (4, 27, 56) have suggested better neonatal outcomes after ART. Accordingly, there had been contradictory results for twin pregnancies according to the conception methods, which may be due to differences in the study population, management methods of twin pregnancies, and especially whether or not monochorionicity was considered as a risk factor for adverse outcomes. Monochorionic twins constitute up to one-third of all twin gestations (57). With the expansion of ART, there has been an increase in the incidence of monozygotic twinning (58, 59). Nevertheless, it has been reported that the occurrence of monozygotic twinning among ART pregnancies is still rare compare with among SC pregnancies (4, 5). Compared with dichorionic twins, monochorionic twins are at an increased risk for perinatal morbidity, because of their shared placenta, including growth discordance, twin-to-twin transfusion syndrome, fetal loss before 24 weeks of gestation, prematurity, neurological deficits, and perinatal death (21, 29, 30). Therefore, the chorionicity should be regarded as an intermediate for predicting the perinatal outcomes of twin pregnancies. The importance of the present study was that we only analyzed dichorionic twin pregnancies to avoid possible adverse effects of monochorionicity itself. Although several studies (4, 5, 11, 20, 21,31–40) have been performed to address whether dichorionic twin pregnancies after ART have greater risk of adverse outcomes compared with those conceived naturally, their results are often inconsistent. For maternal complications, most studies (4, 5, 35, 39, 40) obtained similar outcomes for ART and SC dichorionic twin pregnancies. In contrast, some studies reported a higher risk of placenta previa (31), premature rupture of membranes (34), and antepartum hemorrhage (31) in dichorionic twin pregnancies after ART. Regarding neonatal outcomes, some studies reported PTB (11, 31, 34, 36), VPTB (4, 36, 40), LBW (11, 36), VLBW (4, 36, 40), perinatal mortality (4, 11, 36), CM (32, 37, 38), IUGR (4), NRDS (4, 40), and NICU admission (4, 21, 39) were significantly more common in dichorionic twin pregnancies resulting from ART. Other studies (5, 20, 33, 35) reported

similar neonatal outcomes between the two groups. Considering that most of these studies had a small sample size, the present study was able to increase the sample size by collecting published cohort studies to enhance statistical power, which will help to find a statistically significant difference, especially for risk of rare outcomes. Recently we have published a meta-analysis (41) to compare obstetric risks of twin pregnancies from ART versus spontaneous conception and found that ART twin pregnancies were associated with a higher risk of premature rupture of membranes, pregnancyinduced hypertension, gestational diabetes mellitus, PTB, VPTB, LBW, VLBW, and CM. However, at that time, we did not analyze the impact of chorionicity on adverse outcomes. Up to now, to our knowledge, there is only one meta-analysis (60) that has took the effect of chorionicity on adverse outcomes into account when assessing obstetric risks of twin pregnancies after ART. Of note, that review (60) did not focus on other adverse outcomes except for CM, and it did not find statistically significant difference for risk of CM. Different from that review (60), the present study had a stronger statistical power and indicated that dichorionic twin pregnancies after ART had a significantly increased risk of CM compared with those conceived naturally. Substantial heterogeneity was observed among studies of ART and obstetric risks in dichorionic twin pregnancies, which was not surprising given the differences in study population and management methods of twin pregnancies. In our review, subgroup analysis was used to explore heterogeneity sources. Our subgroup analyses have identified main heterogeneity moderators including geographic region, whether the confounding factors were adjusted and/or matched, type of ART, sample sources, and whether patients who achieved a pregnancy with OI and IUI were included in the SC group. Previous studies (4, 5, 27, 54) showed that differences in the obstetric management of twin pregnancies, diagnosis of adverse outcomes, length of follow-up, ethnic background, socioeconomic situation, maternal education, food and life habits, ART procedures, and prenatal care services exist in different geographic region, which may lead to substantial heterogeneity. In addition, the pregnancies occurring after OI and IUI have been reported to more frequently have poorer outcomes (37, 55, 61). Therefore, if the SC category included patients who achieved a pregnancy with OI and IUI, the SC pregnancies had an increased incidence of adverse outcomes. Our study has confirmed that hypothesis. When data were restricted to studies that did not include these patients in the SC group, the risk of CM was increased further. There are several limitations in our study. First, more than half of the studies included in the present review had a small sample size, which implies that our findings require confirmation when more data from larger multiple studies become available. Second, most of included studies belonged to retrospective cohort design. Thereby, the retrospective nature of data collection and incomplete data on the specific reason for the iatrogenic deliveries should be considered as a limitation. Third, there was substantial heterogeneity among studies for association between ART and obstetric risks in dichorionic twin pregnancies. Nevertheless, we were able to detect the major source of heterogeneity through the

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357

subgroup analysis and the sensitivity analysis. The sensitivity analysis yielded consistent results. After subgroup analysis, the heterogeneity was decreased. However, our estimates have to be viewed with caution because of heterogeneity. Fourth, a number of the outcomes, especially for maternal complications, relied on between 2 and 7 of the 15 total studies, therefore more studies should be included in future reviews to provide further support for our results. Fifth, residual confounding is of concern. Uncontrolled or unmeasured risk factors potentially produce biases. In our review, four studies (26.7%) did not adjust and/or match any factors when estimating the effect of ART on obstetric outcomes in dichorionic twin pregnancies, whereas other studies at least adjusted and/or matched for maternal age. Although restricting analysis to matched and/or adjusted data did not materially alter the combined risk estimate, we still cannot rule out the possibility that residual confounding, such as obstetric management of twin pregnancies, smoking during pregnancy, obesity, and pregnancy intention, could affect the results, because these factors do not explain all of the obstetric risk. Finally, because the present review only included studies published in Chinese or English language, additional research in other populations is warranted to generalize the findings. In conclusion, the present study represents, to our knowledge, the first meta-analysis that comprehensively assessed obstetric outcomes of dichorionic twin pregnancies after ART. Our study aimed at addressing whether dichorionic twin pregnancies after ART have higher risk of adverse outcomes compared with those conceived naturally by complete and systematic literature search. Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, finding from our study indicated that the risks of placenta previa, PTB, VPTB, LBW, and CM were significantly higher in dichorionic twin pregnancies after ART. In addition, the ART group was more likely to be delivered by cesarean section, especially by elective cesarean sections. A priority in the management of twin pregnancy should be accurate prediction and early detection of these complications, which may offer the opportunity for timely intervention and improved outcomes. Further well-designed and large population studies on ART and SC dichorionic twin pregnancies are needed to confirm these results. Acknowledgments: The authors thank the editors and reviewers for their suggestions.

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