Maternal and perinatal outcomes in twin pregnancies following assisted reproduction: a systematic review and meta-analysis involving 802 462 pregnancies.

BACKGROUND: ART is associated with higher rates of twin pregnancies than singleton pregnancies. Whether twin pregnancies conceived following ART have additional maternal and neonatal complications compared with non-ART twin pregnancies is not known. OBJECTIVE AND RATIONALE: The objective was to quantify the risk of adverse maternal and perinatal outcomes among twin pregnancies conceived following ART compared with non-ART and natural conception. Existing reviews vary in the reported outcomes, with many studies including triplet pregnancies in the study population. Therefore, we aimed to perform an up-to-date review with an in-depth analysis of maternal and perinatal outcomes limited to twin pregnancies. SEARCH METHODS: We searched electronic databases MEDLINE and EMBASE from January 1990 to May 2023 without language restrictions. All cohort studies reporting maternal and perinatal outcomes following ART compared with non-ART twin pregnancies and natural conception were included. Case-control studies, case reports, case series, animal studies, and in vitro studies were excluded. The Newcastle-Ottawa Scale was used to assess the methodological quality of the studies. Using random-effects meta-analysis, the estimates were pooled and the findings were reported as odds ratios (OR) with 95% CI. OUTCOMES: We included 111 studies (802 462 pregnancies). Twin pregnancies conceived following ART were at higher risk of preterm birth at <34 weeks (OR 1.33, 95% CI 1.14-1.56, 29 studies, I2 = 73%), <37 weeks (OR 1.26, 95% CI 1.19-1.33, 70 studies, I2 = 76%), hypertensive disorders in pregnancy (OR 1.29, 95% CI 1.14-1.46, 59 studies, I2 = 87%), gestational diabetes mellitus (OR 1.61, 95% CI 1.48-1.75, 51 studies, I2 = 65%), and caesarean delivery (OR 1.80, 95% CI 1.65-1.97, 70 studies, I2 = 89%) compared with non-ART twins. The risks for the above maternal outcomes were also increased in the ART group compared with natural conception. Of the perinatal outcomes, ART twins were at significantly increased risk of congenital malformations (OR 1.17, 95% CI 1.05-1.30, 39 studies, I2 = 59%), birthweight discordance (>25% (OR 1.31, 95% CI 1.05-1.63, 7 studies, I2 = 0%)), respiratory distress syndrome (OR 1.32, 95% CI 1.09-1.60, 16 studies, I2 = 61%), and neonatal intensive care unit admission (OR 1.24, 95% CI 1.14-1.35, 32 studies, I2 = 87%) compared with non-ART twins. When comparing ART with natural conception, the risk of respiratory distress syndrome, intensive care admissions, and birthweight discordance >25% was higher among the ART group. Perinatal complications, such as stillbirth (OR 0.83, 95% CI 0.70-0.99, 33 studies, I2 = 49%), small for gestational age <10th centile (OR 0.90, 95% CI 0.85-0.95, 26 studies, I2 = 36%), and twin-twin transfusion syndrome (OR 0.45, 95% CI 0.25-0.82, 9 studies, I2 = 25%), were reduced in twin pregnancies conceived with ART versus those without ART. The above perinatal complications were also fewer amongst the ART group than natural conception. WIDER IMPLICATIONS: ART twin pregnancies are associated with higher maternal complications than non-ART pregnancies and natural conception, with varied perinatal outcomes. Women seeking ART should be counselled about the increased risks of ART twin pregnancies and should be closely monitored in pregnancy for complications. We recommend exercising caution when interpreting the study findings owing to the study's limitations.

Biochemical predictors of preterm birth in twin pregnancies: A systematic review involving 6077 twin pregnancies.

In women with twin pregnancies biomarkers are not used to predict preterm birth in clinical practice. This systematic review assessed the risk of both spontaneous and iatrogenic preterm birth in twin pregnancies based on biochemical predictors. We searched the electronic databases from January 1990 to June 2019 without language restrictions. All studies on twin pregnancies where biochemical predictors and preterm birth were evaluated were included. We reported our findings as odds ratio (OR) with 95 % confidence intervals (CI) and pooled the estimates using random-effects meta-analysis for various predictor thresholds. From 12,623 citations, we included 33 studies involving 6077 pregnancies. The odds of preterm birth <28 weeks (OR 12.06, 95 % CI 4.90-29.70, I2 = 0%), <32 weeks (OR 10.03, 95 % CI 6.11-16.47, I2 = 0%), <34 weeks (OR 6.26, 95 % CI 3.85-10.17, I2 = 30 %), <37 weeks (OR 5.34, 95 % CI 3.68-7.76, I2 = 15 %) and delivery within 14 days of testing (OR 13.95, 95 % CI 4.33-44.98, I2 = 0%) was increased among women with a positive fetal Fibronectin (fFN) test who were either symptomatic or asymptomatic for preterm birth. Similarly, higher odds of preterm birth was also seen among twin pregnancies asymptomatic for preterm birth with a positive fFN test at gestations <32 weeks (OR 10.54, 95 % CI 5.66-19.64, I2 = 19 %), < 34 weeks (OR 8.07, 95 % CI 5.28-12.33, I2 = 0%) and < 37 weeks (OR 6.21, 95 % CI 4.34-8.87, I2 = 0%). As for other biomarkers, a significantly higher odds of preterm birth <37 weeks was seen among women with elevated maternal serum human Chorionic Gonadotrophin (mshCG) (OR 1.51, 95 % CI 1.07-2.13, I2 = 0%), 25 Hydroxy Vitamin D level <75 nmol/l (OR 2.59, 95 % CI 1.35-4.95, I2=NA), positive phosphorylated Insulin-like Growth Factor Binding Protein-1 (phIGFBP-1) (OR 4.23, 95 % CI 1.97-9.09, I2 = 0%) and in those with elevated Interleukin 8 (IL-8) (OR 3.13, 95 % CI 1.18-8.34, I2=NA). A higher odds of preterm birth at <34 weeks gestation was seen among women with maternal serum Alpha fetoprotein (AFP)>3.5 MoM (OR 2.35, 95 % CI 1.12-4.96, I2=NA) while higher odds of preterm birth at <32 weeks was seen among women with 25 Hydroxy Vitamin D level <75 nmol/l (OR 3.01, 95 % CI 1.26-7.19, I2=NA). Delivery within seven days of testing was significantly increased in women with a positive Matrix Metallo Protein-8 (MMP-8) test (OR 10.59, 95 % CI 3.70-30.29, I2=NA). Fetal Fibronectin is strongly associated with predicting preterm birth among women with twin pregnancies who are either asymptomatic or symptomatic for preterm birth as well as in those asymptomatic for preterm birth. Other biomarkers have shown a positive association in the prediction of preterm birth among women with twin pregnancies. Further studies are recommended to evaluate their role.

Maternal clinical predictors of preterm birth in twin pregnancies: A systematic review involving 2,930,958 twin pregnancies.

In twin pregnancies, which are at high risk of preterm birth, it is not known if maternal clinical characteristics pose additional risks. We undertook a systematic review to assess the risk of both spontaneous and iatrogenic early (<34 weeks) or late preterm birth (<37 weeks) in twin pregnancies based on maternal clinical predictors. We searched the electronic databases from January 1990 to November 2017 without language restrictions. We included studies on women with monochorionic or dichorionic twin pregnancies that evaluated clinical predictors and preterm births. We reported our findings as odds ratio (OR) with 95% confidence intervals (CI) and pooled the estimates using random-effects meta-analysis for various predictor thresholds. From 12, 473 citations, we included 59 studies (2,930,958 pregnancies). The risks of early preterm birth in twin pregnancies were significantly increased in women with a previous history of preterm birth (OR 2.67, 95% CI 2.16-3.29, I2 = 0%), teenagers (OR 1.81, 95% CI 1.68-1.95, I2 = 0%), BMI > 35 (OR 1.63, 95% CI 1.30-2.05, I2 = 52%), nulliparous (OR 1.51, 95% CI 1.38-1.65, I2 = 73%), non-white vs. white (OR 1.31, 95% CI 1.20-1.43, I2 = 0%), black vs. non-black (OR 1.38, 95% CI 1.07-1.77, I2 = 98%), diabetes (OR 1.73, 95% CI 1.29-2.33, I2 = 0%) and smokers (OR 1.30, 95% CI 1.23-1.37, I2 = 0%). The odds of late preterm birth were also increased in women with history of preterm birth (OR 3.08, 95% CI 2.10-4.51, I2 = 73%), teenagers (OR 1.36, 95% CI 1.18-1.57, I2 = 57%), BMI > 35 (OR 1.18, 95% CI 1.02-1.35, I2 = 46%), nulliparous (OR 1.41, 95% CI 1.23-1.62, I2 = 68%), diabetes (OR 1.44, 95% CI 1.05-1.98, I2 = 55%) and hypertension (OR 1.49, CI 1.20-1.86, I2 = 52%). The additional risks posed by maternal clinical characteristics for early and late preterm birth should be taken into account while counseling and managing women with twin pregnancies.