INFLUENCE OF CHORIONICITY ON HEALTHY TWIN PREGNANCY OUTCOME UTICAJ HORIONICITETA NA ISHOD ZDRAVE BLIZANAĈKE TRUDNOĆE Authors

Background/Aim. It is still under debate in what sense and extent can chorionicity impact the pregnancy outcome of twins without gestational complications specific for monochorionicity. The study aimed to evaluate the effect of chorionicity on healthy twin pregnancy outcome. Methods. The study included patients with uncomplicated twin pregnancies after first trimester that were checked-up and delivered at the Clinic of Obstetrics and Gynecology Clinical Center of Serbia during three years (2010 – 2013). Data regarding mother’s age, comorbidities, parity, presence and type of gestational complications, chorionicity, mode and time of pregnancy ending, birth-weight and Apgar score of twins were determined. Obtained data were compared and statistically analyzed. Results. Study included 361 women with mean age of 33 years. Regardless of chorionicity twins were mostly born during the 36 th gestational week and received Apgar score ≥8. Only three monochorionic twins were stillborn, two preterm (29 and 32 gestational week) and one in term (35 gestational week) delivery. Contrary, no intrauterine fetal deaths were recorded. Monochorionicity negatively correlated with having live-born twins (OR=0.023; CI=[0.001–0.609]; p=0.024), but was not associated with twins condition at birth i.e. Apgar score (p=0.345), pregnancy ending time (p=0.578) or any other twins characteristic. However, premature preterm membrane rupture and earlier gestational week of pregnancy ending are important confounding factors for relationship between chorionicity and pregnancy outcome. Conclusion. Monochorionicity increases risk for adverse pregnancy outcomes even for uncomplicated healthy twins, but has no influence on the condition of twins who survive until term. If appropriate surveillance and therapy are applied both healthy twins can be delivered at term regardless of chorionicity.


Introduction
Careful monitoring and management of twin pregnancy is the basis of modern perinatology because multiple pregnancies carry an increased risk of perinatal morbidity and mortality compared with singleton pregnancies.This risk arises as a result of complications such as high incidence of preterm birth, fetal growth restriction, preeclampsia, etc. (1).Twin pregnancies are classified according to either zygosity or chorionicity, and chorionicity rather than zygosity determines the outcome.Twin pregnancies can be divided into monochorionic (MC) or dichorionic (DC) according to placentation, and MC twin are classified as monoamniotic or diamniotic (2).Apart from usual pregnancy complications, monochorionic twins develop unique type-specific perinatal complications, such as twin-twin transfusion syndrome, more often.Consequently, it is well determined by numerous studies that monochorionicity poses the highest risk for both morbidity and mortality of twins (3).However, it is still under debate in what sense and extent can chorionicity impact the pregnancy outcome of uncomplicated healthy twins.Therefore, increased detailed antenatal fetal surveillance with precise first-trimester diagnostics of chorionicity is suggested for twins (4).Determining chorionicity at early pregnancy can help the obstetricians to plan the care of these patients in managing twin pregnancies and in counseling according to the local perinatal outcome (5).
The study aim was to evaluate the effect of chorionicity on outcome of uncomplicated healthy twin pregnancy.

Methods
The study prospectively included all patients with twin pregnancies who were checkedup and delivered at the Clinic of Gynecology and Obstetrics, Clinical Center of Serbia in three years period (2010 -2013).The study was approved by Clinics Ethical Board and all women signed informed consent to participate in the study.After ultrasonographic confirmation of twin pregnancy and determination of chorionicity (single placental masses with T signmonochroionicity vs. separate placentas and lambda sign -dichorionicity) women were closely monitored throughout pregnancy.Exclusion criteria for this study were first trimester miscarriage, development of twin-to-twin transfusion syndrome, fetal growth restriction, placental pathologies and other complications specific for monochorionicity.
On the initial examination detailed history regarding age, number of previous pregnancies and chronic illnesses (cardiovascular, endocrinologic, etc.) were taken from each patient.If patients had chronic illnesses that were not adequately treated they were excluded from the study.
Obstetrical complications (presence and type) were registered throughout pregnancy such as presence of hypertension in pregnancy -HTA, gestational diabetes mellitus -GDM, placental problems (placental abruption, retro placental hematomas, placental insufficiency detected by small diameter and higher than expected grade of placenta on ultrasound and by pathological Doppler measures of placental vascularization), fetal growth restriction -IUGR (fetal weight at delivery below the 10 th percentile for gestational age), twin-to-twin transfusion syndrome -TTTS (presence of placental blood vessels anastomoses), perinatal asphyxia (assessed by cardiotocographic findings), other and combined comorbidities.In case of complications development patients were excluded from the study.
Twins delivery was either vaginal or Caesarean Section (urgent or elective CS).The time of membranes rupture was noted and classified as during delivery or premature (PPROM) while the characteristics of amniotic fluid were expressed as clear or meconial.According to the gestational week in which pregnancy ended (miscarriage/ delivery), twins' were considered as term or prematurely born (before 36 th week of gestation).After birth, sex (male or female), weight and Apgar score of both twins were determined.We also noted if both twins were live-born or if in one or both twins were stillborn.Moreover, all cases of intrauterine fetal death (IUFD) of one or both twins were registered.
Finally, as the primary outcome of this study we assessed the survival of twins throughout the whole pregnancy.Therefore, if both twins were live-born pregnancy outcome was good while as adverse outcome we regarded IUFD or stillbirth of one or both twins.Moreover, the condition at birth of twins was assessed through their Apgar scores and if both twins had Apgar scores ≥ 8 their condition was regarded as good.
For statistical analysis methods of descriptive (frequencies, mean value, standard deviation) and analytical ( pearman correlation, Kruscal Wallis χ 2 test, logistic regression) statistics were applied.All assessed data were correlated with chorionicity and pregnancy outcomes.Binary logistic regression was used to construct models of relationship between pregnancy outcome and chorionicity.Statistical significance was defined as p<0.05 and SPSS ver.15.0, Chicago IL, USA software was used for analysis.

Results
Initially study included 435 women with twin pregnancies who had 17 to 46 years of age at the time of birth (mean+/-sd=33.18+/-6.61years).Patients were mostly primiparous.Majority of women had no chronic illnesses, while women who reported comorbidities were regularly checked-up and on adequate therapy (Table 1).In our sample there were significantly more dichorionic twins (Table 2).
During examined pregnancy we registered hypertension in 51, diabetes in 24, placental pathologies in 8, TTTS in 8, IUGR in 15, malformations in 4, asphyxia in 13, chorioamnionits in 17 and other complications altogether in 43 cases.All of these gestational complications were more frequent in monochorionic than dichorionic twins (p=0.001).According to study criteria, due to complications we excluded 74 women from the study, while remaining 361 cases underwent further analysis.
In our sample of healthy twins without gestational complications only three twins were stillborn and all of them were from monochorionic pregnancies.These adverse outcomes occurred in two cases preterm (29 and 32 GW) and in one case in term (35 GW) delivery.Contrary, no IUFDs were recorded.First twins had the mean birth weight 2298.16+/-621.48grams and the mean Apgar score was 7.32 +/-1.85 (MC=7.86+/-0.99;DC=7.28+/-1.88).Second twins had the mean birth weight 2237.53 +/-651.49grams and the mean Apgar score was 7.28 +/-1.86 (M=7.86+/-0.99;DC=7.24+/-1.91).Nevertheless, majority of twins both monochorionic and dichorionic, were in good condition at birth and 59% of first and 55.7% of second twins received Apgar score ≥ 8 (Table 2).Therefore, the overall outcome of investigated twin pregnancies was good.
Chorionicity was correlated negatively with pregnancy outcome and positively with delivery mode (Table 3).Dichorionic twins had better survival rates.Monochorionic twins were at higher risk for adverse perinatal outcome (OR=0.023;95% CI = [0.001-0.609])and had a higher chance to be delivered by Cesarean Section (OR=1.88;95% CI = [1.05-3.38]).Pregnancy outcome was associated with amniotic fluid characteristics, delivery time and twins birth-weight, but not chorionicity.Moreover, there were no significant differences in mothers and twins characteristics or other assessed parameters regarding chorionicity.
Twin pregnancy outcome = -0.792+ 0.038 x PPROM -0.012 x gestational week of delivery -0.084 x chorionicity From the obtained equation it can be seen twin pregnancy outcome is significantly associated with chorionicity.Still, occurrence of PPROM and earlier gestational week of delivery are important confounding factors that can influence the relationship between chorionicity and pregnancy outcome.Therefore, prevention of gestational complications and preterm birth are crucial to minimize the potential negative impact of monochorionicity on twins' survival and condition.

Discussion
According to the results of our study chorionicity can influence survival of otherwise healthy twins placing MC twins at greater risk.However, chorionicity does not significantly impact the condition at birth of live-born twins as well as growth and development of twins who endure up to term.
Most literature data show that monochorionic twins have higher rate of very preterm birth (before 33 rd gestational week), very low birth weight (birth weight <1500g), first minute Apgar <7 and hospitalization (1,4).Perinatal mortality is usually also significantly higher as well as intrauterine fetal death (6).The prospective risk of IUFD is much higher for MC twins at all gestational ages but the highest risk is before 24 -28 gestational weeks (7).Monochorionic pregnancies carry an increased risk of both a single fetal demise and a double twin demise mostly occurring before the third trimester (8).MC twins were also two times more likely to be stillborn than DC twins.However, the prospective risks of stillbirth is found to be low for both MC and DC twins after 32 weeks of gestation and decreases even more at higher gestational weeks especially for MC twins (9,10).If both fetuses are alive at 24 -28 weeks, the chance of their survival until term is similar in MC and DC pregnancies (2).Some studies have shown that mortality of MC and DC twins did not differ in deliveries after 30 weeks of gestation, probably due to the fact that modern obstetrics is more effective in reducing mortality in both MC and DC twins (1,11).Still, after 38 gestational weeks MC twins have a higher risk for perinatal mortality compared to DC twins.Placental vascular malperfusion is the usually the main complication of dichorionic while IUGR, placental vascular abnormalities and TTTS, abnormal cord insertion and adverse neonatal outcomes are more common in monochorionic twins (12).In our study no IUFDs were registered in uncomplicated healthy twin pregnancies regardless of their chorionicity.On the other hand adverse perinatal outcomes occurred only in case of monochorionicity.All adverse outcomes happened during or close to delivery implying on the additional risk for monochorionic twins that might be caused by issues of the cord (entanglement in case of single amniotic sac, etc.) or some still unknown processes that needs further investigation.However, it should be mentioned that the rate of adverse outcomes was very low and that majority of investigated twins were live-born and in good condition with high Apgar scores.
The optimal time for delivery of monochorionic twins to prevent cord entanglement, growth discrepancies and intrauterine fetal death is still controversial (13).MC twins are mostly delivered preterm (4).As the highest morbidity for monochorionic twins is registered in 35 th and 36 th GW some authors support delivery of uncomplicated monochorionic twins at completed 34 gestational weeks (14,15).Conversely, others think that, with a strategy of close fetal surveillance, both monochorionic and dichorionic pregnancies can be continued to ninth lunar month (36 -37 gestational weeks) with minimal perinatal morbidity (16,17).Studies have shown that median gestational age is mostly one week longer in DC twins than in MC twins.In uncomplicated dichorionic twin pregnancies delivery should happen at 37 weeks of gestation and in monochorionic at 36 weeks (16,18).Although delivery closer to term was associated with better pregnancy outcome, chorionicity did not have any significant influence on time of delivery in our study.Investigated twins were successfully delivered mostly in the 36 th gestational week regardless of their chorionicity.Consequently, it can be said that if there are no gestational complications that might indicate induction of preterm delivery, both MC and DC healthy twins should not be delivered before ninth month of gestation.
Some studies indicate that there is usually no difference in the delivery mode of twins as a function of chorionicity and consequently intrapartum management should not vary due to chorionicity (19).Twins we followed were generally more often delivered by caesarean section.However, MC twins had a higher chance to be delivered by CS than DC twins.On the other hand, delivery mode did not influence pregnancy outcome, so the optima delivery mode of twins should be more thoroughly investigated in further studies.
Most literature data show that mean birth weight in DC twins is usually significantly higher than in MC and that MC twins are almost two times more likely to have fetal growth restriction or severe birth weight discordance (>20%) (4,16).Still, other studies show that severe birth weight discordance occurs equally in twins regardless of their chorionicity (1).There were no significant differences of birth weight between MC and DC twins in our sample.
In studies using multivariate analysis, lower gestational age at delivery, monochorionicity and growth restriction were independent predictors of adverse neonatal outcome (12).The model we constructed shows that chorionicity does impact pregnancy outcome even in healthy uncomplicated pregnancies.However, more attentions should be paid to prevention of PPROM and preterm birth as these two parameters were found to be significant confounding risk factors of adverse pregnancy outcome.
In conclusion, monochorionic twins, even if healthy and uncomplicated, are at high risk for perinatal mortality.Nevertheless, chorionicity does not significantly impact the condition at birth, growth and development of twins who manage to survive nine lunar months.Therefore, it can be said that if appropriate prenatal and peripartum surveillance and adequate therapy are applied both healthy twins can be delivered even in term regardless of their chorionicity.

Table 2 . Frequency of assessed parameters of twins
Legend: PPROM -
Legend: PPROMpremature preterm rupture of membranes; GW gestational week