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The outcome of the multifetal pregnancy reduction procedures in a single centre: A report of 202 completed cases
European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 22–27
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
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The outcome of the multifetal pregnancy reduction procedures in a single centre: A report of 202 completed cases Necip Cihangir Yılanlıoglua , Altug Semiza , Resul Arisoya,* , Semra Kahramanb , Ali Arslan Gürkanc a b c
Sisli Memorial Hospital, Department of Obsteric and Gynecology, Istanbul, Turkey Sisli Memorial Hospital, Assisted Reproductive Technologies and Genetics Centre, Istanbul, Turkey Middle East Technical University, Ankara, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 June 2018 Accepted 10 September 2018 Available online xxx
Objective: To review the results of fetal reduction procedures in our institution, evaluate its effects on the pregnancy outcome in terms of miscarriage, preterm delivery, taking home healthy babies and discuss the factors that may have contributed to the outcome. Study design: This is a retrospective study performed at the Fetal Medicine Unit of the Sisli Memorial Hospital in Istanbul after ART therapies in our unit from 2000 to 2011. Results: The sample comprised 151 triplets, 35 quadruplets, 11 quintuplets, 3 twins, 1 sextuplet and 1 septuplet. The average maternal age was 30 4.4 and the average week of interventions was 11.7 1.3 weeks. In 40 cases two or more needle insertions were necessary. The two-week post-procedure loss rate, defined as ‘the procedure related loss rate’, was 0.7%; however, for the whole sample, the losses were 6.9% when they occured before 24 completed weeks and was defined as ‘the total loss rate’. 184 of the remaining 188 cases had at least one baby to take home (91.1% of 202 patients). The average birth week for those healthy babies discharged home was 35.5 2.4. The rate of early preterm birth before gestational weeks of 32 was 9%. The mean birthweight of this “take-home” group was 2302 525 g. Conclusion: Fetal reduction in multifetal pregnancy is associated with low miscarriage rate and preterm delivery rates. Fetal reduction in multifetal pregnancy should be considered for better pregnancy outcomes and the results of this study can be used in prenatal counseling. © 2018 Elsevier B.V. All rights reserved.
Keywords: Multifetal pregnancyy Miscarriage Preterm delivery Fetal reduction
Introduction Reducing the number of fetuses in triplet and higher order multiple pregnacies has been a widely employed procedure since assisted reproduction technologies (ART) became almost explosively common all over the world in the past few decades. As the number of embryos tranferred were kept high to ensure “success”, the number of triplet and higher-order multiple pregnancies rose accordingly [1,2]. The rapid increase of the rate of twins and higher-order multiple births has been shown to be largely attributable to ART in the past three decades [1–3]. Older childbearing age accounts for only one-third of this increase with infertility treatments account for the remainder [1,3]. The incidence of loss, prematurity and related sequelae rise along with the fetal number [4–7]. The two obvious prevention modalities of such
problems stand out as achieving a singleton or twin pregnancy to start with, or failing that, performing fetal reduction procedures. It is generally accepted that elective fetal reduction of high order multiple pregnancy with 4 or more fetuses substantially improves maternal and perinatal outcomes. On the other hand, studies comparing triplet pregnancies reduced to twins and triplet pregnancies managed conservatively have reported conflicting results: some have shown no difference in gestational age at delivery or in neonatal outcomes [8,9], whereas others have reported substantial improvements in perinatal outcomes, such as, preterm birth and low birth weight [10–12]. The aim of this study was to evaluate the outcome of multiple pregnancies that were reduced to a single fetus or twins or triplets with regard to the risks of miscarriage, rate of preterm delivery, birthweight and the rate of taking home healthy babies. Materials and methods
* Corresponding author at: Kaptan Paşa Mh, Halit Ziya Türkkan Sok No: 14 _ Middleist Sitesi D Blok Daire 7 Şişli, Istanbul, Turkey. E-mail address: [email protected] (R. Arisoy). https://doi.org/10.1016/j.ejogrb.2018.09.008 0301-2115/© 2018 Elsevier B.V. All rights reserved.
This is a retrospective study performed at the Fetal Medicine Unit of the Şişli Memorial Hospital in Istanbul after ART therapies
N. Cihangir Yılanlıoglu et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 22–27
in the unit from 2000 to 2011. We looked into a wide range of factors to elucidate their effectiveness on influencing the outcomes of 206 multifetal pregnancy reduction procedures performed during this period. The patients were scanned a week to a few days prior to the intended fetal reduction procedure to take place around 10–11 weeks of the pregnancy, and again a few days later if required. Triplets were counseled, giving information on the possible success rate of the procedures and those related prematurity, handicap risks and intensive care unit probabilities. Higher order multiples (quadruplets and higher) were counseled on the basis that their risks warrant a recommendation of reduction procedure from a medical point of view, but in every case the decision was left with the couple after making sure the known facts were fully understood. On the same scan visit, chorionicity, growth (Crownrump length; CRL), nuchal translucency, gestational sac size, proximity to the internal cervical os, and other anatomical criteria for fetal normality were noted for each fetus. No information on the sex of the fetuses was revealed. If the couple expressed preference for undergoing reduction, the final decision to proceed with the process was made through considering the above parameters and the location of the fetuses in the uterus. The lowermost sac/fetus on the internal os was avoided whenever possible, except in cases where a probable anomaly or a monochorionic pair in that position was assessed. All procedures were performed by the same operator (the first author), the same trained nurse and an assisting nurse. Only one observer in the team was present. The spouse was allowed in only if the couple requested it. The skin was prepared with swabs of 70% alcohol first and povidone-iodine afterwards, the colored antiseptic especially used to avoid any mistakes about the prepared portion of the skin. A final touch with a dry swab delineated the area of entry. A twostage local anesthetic (Xylocaine 2%) infiltration was followed by the introduction of a #21 gauge, 12 or 15 cm needle. Other fetuses’ sacs were strictly avoided during insertion. An injection of 15% potassium chloride, 0.5 ml when intracardiac or 1–1.5 ml when intrathoracic, was sufficient to achieve asystole. After two to three minutes of observation in this state, the needle was withdrawn. The patient was taken to a quiet room to rest for an hour and then allowed home with an advice to stay home for the rest of the day and the day after. When a monochorionic pair was to be reduced (28 cases in the present sample, 13 triplets and 15 higher-order multiples), only one of the fetuses was injected. A control-scan was perform after 3 to 5 days after the procedure, and in all instances, the other fetus was found to have followed suit. A maximum number of two fetuses were reduced in one session. For instance, we took three sessions (2 - 2 -1) to reduce the one septuplet to twin. Data were obtained from written and computer databases. The majority of the patients were delivered in other hospitals in different provinces of the country, information from them was obtained by correspondence over mail and phone. The study sample of 202 cases were included in the study. A wide range of parameters including age, initial number of fetuses, remaining Table 1 Breakdown of 202 reduction cases in terms of multiplicity and chorionicity.
Triplets Quadruplets Quintuplets Sextuplets Septuplets Twins TOTAL
Total Number of Patients
Dichorionic
With monochorionic combination(s)
151 35 11 1 1 3 202
138 26 8 – 1 3 176
13 9 3 1 – – 26
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number of fetuses, chorionicity, loss within two weeks of the procedure, loss before 24 weeks, birth week, birth weight and neonatal outcome were saved. Four cases, one triplet, one quadruplet and two quintuplets were excluded from the study for reasons of uncertain data and termination (of the quadruplet) for anomaly. Data analysis was performed by using Statistical Package for Social Sciences (SPSS) version 11.5 software (SPSS Inc., Chicago, IL, United States).Descriptive statistical methods (mean, standard deviation and range) were used to evaluate the data. Kolmogorov– Smirnov test was performed to determine whether or not parameters are normally distributed. Student’s t-test and MannWhitney U to compare parameters among the groups. Results were evaluated with 95% confidence intervals, and p < 0.05 was considered to indicate significance. Results Of the total study sample of 202 patients: 151 triplets, 35 quadruplets, 11 quintuplets, 3 twins, 1 sextuplet and 1 septuplet (Table 1), the average maternal age was 30 4.4 (20–49) and the mean number of fetuses was 3.3 0.6 (2–7). Out of this total, 175 pregnancies were reduced to twins, 24 were reduced to singletons and 3 were reduced to triplets (Table 2). The average week of interventions was 117 1.3 weeks, the mean of the number of remaining fetuses were 1.9 0.3 (1–3) and the mean of the number of interventions were 1.2 0.5 (1–5). The procedure-related loss rate was 0.7% (one case, a triplet), the total loss rate (miscarriage before 24 completed weeks) was 6.9% (with 9 triplets, 2 quadruplets, 1 quintuplet and 1 sextuplet) (Table 3). The total loss rate for the triplets and the quadruplets were very close each other (6.6% and 5.7% respectively) to and to the whole sample. 11 (3.1%) neonatal deaths occured in total: 7 (2.7%) of the fetuses who started as triplets, 3 (4.4%) of the quadruplets and 1 (5.2%) of the quintuplets (Table 4). As seen in Table 5, a total of 184 patients out of 202 (91.1%) were able to take home at least one baby (the “take home baby” rate). Of these 154 mothers embraced twins, 27 mothers a single baby, and 1 mother took home triplets: an average of 187 baby per mother. The birth weight in each group of reduction cases, determined according to their starting and finishing number is shown in Table 6. When the whole study sample is considered, the average birth weight of the healthy babies discharged home is 2302 525 g. The average rate of weight difference of all twins born in this group with any starting number was 115 percent. Twins reduced from quadruplets displayed significant discordance rate from those reduced from triplets (233% and 11.9% respectively) (Table 7). The gestational ages at delivery (birth week) of all infants according to their starting and finishing numbe r are given in Table 8. The average birth week of the whole sample (344 infants) was 355 2.4. The rate of early preterm birth before gestational weeks of 32 was 9%. Comment Multifetal pregnancy reduction (MFPR) clearly promises better neonatal outcomes in terms of reducing the rate of moderate and severe prematurity, morbidity and neuropsychomotor disability [4–7]. The most common practice is to reduce the total number of fetuses to two [13,14], but there is also published data that reducing to singleton as opposed to a twin results in a later gestational age at birth, without significant differences in fetal loss rate or “take-home baby rate” : defined as the number of mothers taking at least one baby home [14,15]. The fetal loss rate of 9.1% when reduced to singleton versus 5.1% when reduced to twins is a difference not found to be significant in the study by Kuhn-Beck
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Table 2 Breakdown of number of remaining fetuses after reduction procedure in each group.
Triplets Quadruplets Quintuplets Sextuplets Septuplets Twins TOTAL
Number Of Patients (# fetus)
Patients left with Singleton (# fetus)
Patients left with Twins (# fetus)
Parients left with Triplets (# fetus)
151 (453) 35 (140) 11 (55) 1 (6) 1 (7) 3 (6) 202 (667)
19 (19) – 2 (2) – – 3 (3) 24 (24)
132 (264) 33 (66) 8 (16) 1 (2) 1 (2) – 175 (350)
– 2 (6) 1 (3) – – – 3 (9)
Table 3 Procedure related loss, total Loss, live delivery and severe prematurity rates of all reduction cases.
Triplets Quadruplets Quintuplets Sextuplets Septuplets Twins TOTAL * **
No. of Patients
Procedure related loss* (%)
Total loss** (%)
Remaining Patients
Live delivery*** of at least 1 baby (%)
151 35 11 1 1 3 202
1 (0.7%) – – – – – 1 (0.5%)
10 (6.6%) 2 (5.7%) 1 (9.1%) 1 (100%) – – 14 (6.9%)
141 33 10
138 (91.4%) 32 (91.4%) 10 (91%) – 1 (100%) 3 (100%) 184 (91.1%)
1 3 188
Procedure related loss: Miscarriage within two weeks of reduction procedure. Total Loss: All losses before 24 completed weeks. Live Delivery: Babies delivered live after 24 completed weeks.
***
Table 4 Neonatal death numbers in each multiple pregnancy combination, number of patients losing one or both babies and neonatal loss rate of all reduced pregnancy fetuses. After reduction Total No. Of fetuses remaining
Remaining cases (<24 w Total loss**)
Remaining fetuses (<24 w Total loss**)
NNDa of 1 fetus (# Patient) # Fetus
NNDa of 2 fetuses (# Patient) # Fetus
Total No. Of Neonatal Deaths
Neonatal Death Rate (% lost as neonate out of the remaining fetuses)
Triplets 151 Quadruplets 35
283 72
141 33
264 68
(3) 3 (1) 1
(2) 4 (1) 2
7 3
2.7% 4.4%
11 1 1 3 202
21 2 2 3 383
10 – 1 3 188
19
(1) 1 – – – (5) 5
1 – – – (3) 6
5.2% 0% 0% 0% 3.1%
No. of Patients undergoing reduction
Quintuplets Sextuplets Septuplets Twins TOTAL a
2 3 356
– – 11
NND: Neonatal Death - death within six weeks of delivery.
et al. [15], just as the difference between 86.4% and 91.9% take home baby rates was not, respectively. In this study, the benefit is stated as higher rate of birth beyond 37 weeks and loss rate of moderate prematurity. This is a controversial subject to say the least and as there is ample data that triplets reduced to twins perform as well as non-reduced twins [16] and reduction to singleton does not do as well [13,14] but then there is the “quality of life” issue as well as the trend towards a more advanced maternal age and further societal aspects [2,14]. In our series the highest birth weights seem to be on the side of the singletons, whether they are reduced from triplets or twins. Those twins reduced from quintuplets however, weigh less than their counterparts. The average birthweight of all reduced twins is 2294 g, and their average birth weight in each starting number group including quintuplets is also over 2000 g. The reduced triplets scored the lowest birth weight, an average of 1589 g. We feel that reducing to twins and no further, constitutes the best balance between all conceivable options in our society. Hence
we did not and still do not, offer reducing a twin pregnancy to singleton unless a medical indication exists, such as a monochorionic pair as a party or some medical condition of the patient, while observing the established principles of non-directive counseling and respect for autonomy [13,17]. If a monochorionic pair exists in a higher order multiple, the best result is obtained by reducing that pair, be it a singleton to remain [14]. The two major risks in triplet and higher–order pregnancies are total pregnancy loss before 24 weeks and severe prematurity. In series where triplets are reduced to twins with control groups of non-reduced triplets, the risk of severe prematurity drops from 28% to 10% as reported by Papageorghiou et al. [18] and from 37.5% to 7% as reported by Drugan et al [19], with a trade-off of an increase in total loss rate of 4% and a low 1% respectively, though in the latter study the number of reduced cases was relatively small (46 versus 180 in the former). Only in our study, the sample sizes 151 for triplets and 35 for quadruplets were large enough to conduct meaningful statistical analysis: relatively small sample sizes of 3 twins, 11
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Table 5 Take-home babya rates (Percentage of patients with at least one baby to take home), with baby numbers and total number of babies salvaged in each group. No. of Patients undergoing Reduction (# Fetuses)
One Baby Taken home (# Baby)
Two Babies Taken home (# Baby)
Three Babies Taken Home (# Baby)
The “Take Home Baby” mothers & Rate (Tot.# Baby)
Triplets
151 (453)
21 (21)
117 (234)
–
Quadruplets
35 (140)
0 (0)
32 (64)
–
Quintuplets
11 (55)
3 (3)
6 (12)
1 (3)
Sextuplets Septuplets
1 (6) 1 (7)
– –
– 1 (2)
– –
Twins
3 (6)
3 (3)
–
–
TOTAL
202 (667)
27 (27)
154 (308)
1 (3)
138 patients 91.4% (255 babies) 32 patients 91.4% (64 babies) 10 patients 90.9% (18 babies) 0% 1 patient (2 babies) 3 patients (3 babies) 184 patients 91.1% (344 babies)
a Take-home baby: The number (and percentage) of patients who have at least one baby discharged home in health from the hospital, after all pregnancy losses and neonatal deaths.
Table 6 The average birthweighta of the babies of 188 cases. N
Reduced to singletons Birth weight (SD) (Range)
Reduced to twins Birth weight (SD) (Range)
Reduced to triplets Birth weight (SD) (Range)
Total Birth weight (SD) (Range)
All babies in the reduction cohortb discharged home in health Birth weight (SD) (Range)
Triplets (n = 141)c
(n = 18) 18 babies 2726gr 774 (2250–3500gr) –
(n = 123) 241 babies 2270gr 488 (710–4000gr) (n = 31) 61 babies 2422gr 462 (1205–3800gr) (n = 7) 14 babies 2191gr 413 (1300–2749gr) –
–
(n = 141) 259 babies 2301gr 524 (710–4000gr) (n = 33) 67 babies 2361gr 504 (1180–3800gr) (n = 10) 19 babies 2039gr 525 (1030–2749gr) –
(n = 141) 255 babies 2309gr 520 (710–4000gr) (n = 33) 64 babies 2381gr 485 (1180–3800gr) (n = 10) 18 babies 2052gr 536 (1030–2749gr) –
(n = 1) 2 babies 2100gr 141 (2000–2200gr) (n = 3) 3 babies 2900gr 627 (2250–3500gr) n = 188 350 babies 2303gr 525 (710–4000gr)
(n = 1) 2 babies 2100gr 141 (2000–2200gr) (n = 3) 3 babies 2900gr 627 (2250–3500gr) n = 184 342 babies 2313gr 519 (710–4000gr)
Quadruplets (n = 33)
Quintuplets (n = 10)
Sextuplets (n = 0) Septuplets (n = 1)
Twins (n = 2)
TOTAL Sample (n = 188)
a b c
(n = 2) 2 babies 2115gr 728 (1600–2630gr) – –
(n = 3) 3 babies 2900gr 627 (2250–3500gr) n = 23 2696 gr 748 (910–3700gr)
(n = 2) 6 babies 1743gr 528 (1180–2600gr) (n = 1) 3 babies 1280gr 269 (1030–1565gr)
(n = 1) 2 babies 2100gr 141 (2000–2200gr) –
n = 162 318 babies 2294gr 482 (710–4000gr)
n=3 9 babies 1589gr 496 (1030–2600gr)
Only of those who were discharged home in health. Reduction cohort : With reference to starting and finishing number. (n =) : Number of patients.
Table 7 The average intertwin weight difference and the percentage of infants discordant in weighta between take home twins with regard to the starting number of fetuses at reduction.
% Weight difference % Range Twins (%) with <20% weight discordance a
Triplets (Started with 3 - took home 2)
Quadruplets (Started with 4 - took home 2)
Quintuplets (Started with 5 - took home 2)
Septuplet (Started with 7 - took home 2)
All patients with any starting number and took home 2
11.1% 0%–47% 14/119 11.8%
13.9% 0%-%33.2 7/30 23.3%
6.8% 20.4% 1/7 14.3%
9.1% – 0/1
11.5% 0%–46.8% 22/157 13.9 %*
A weight difference of more than % 20 of the heavier twin is accepted as” discordant in weight”.
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N. Cihangir Yılanlıoglu et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 22–27
Table 8 Average gestational age at delivery of those infants after 24 completed weeks.
Triplets (n = 141) Quadruplets (n = 33) Quintuplets (n = 10) Sextuplets (n = 1) Septuplets (n = 1) Twins (n = 3) TOTAL (n = 188)
Reduced singletons (wk) (Range)
Reduced twins (wk) (Range)
Reduced triplets (wk) (Range)
Total wk
Early Preterm <32 + 0 w Deliveries
All babies in the whole sample discharged home in health (wk) (Range)
(n = 18) 37 3.1 (28–40 w) –
(n = 123) 35.2 2,4 (27–41 w) (n = 31) 35.3 1.6 (31–37 w) (n = 7) 34.6 2.6 (31–38 w) –
–
35.4 2.6
(n = 13)
35.5 2.4
(n = 2) 32 2.8 (30–34 w) (n = 1) 30 w
35.1 1.8
(n = 2)
35.2 1.8
34.5 2.8
(n = 2)
34.5 2.8
(n = 2) 36.5 2,1 (35–38 w) – – (n = 3) 38.7 1,5 (37–40 w) n = 23 37.2 2.9 (28–40 w)
–
–
(n = 1) 36 w –
–
36 w
36 w
–
38.7 1.5
38.7 1.5
n = 162 35.2 2.3 (27–41 w)
n=3 37 3.1 (28–40 w)
35.4 2.5
17 (9 %)
35.5 2.4
(n =): Number of patients*.
quintuplets, 1 sextuplet and 1 septuplet pregnancies meant that statistical analysis could not be carried out, these were nevertheless presented to provide a general picture for evaluation. The procedure-related losses, at a low 0.7% for the whole sample, were only encountered in the triplets group and none were recorded in the quaduplets or higher-order multiples (Table 3). Total loss rate, as can be seen on the same table, stood at 7% for triplets, 6% for quadruplets, and at 7% when all cases were included. These results compare favorably with the literature and somewhat better than some, regarding inclusion in our study sample of all higher order multiples along with triplets. It is also worth noting that the timing of the interventions and the number of needle insertions did not affect the loss rate or birth week. The result for triplets in our series were similar to those of other studies [14,15,18,20]. As far as quadruplets and quintuplets are concerned, the loss rates as well as prematurity and fetal growth figures for triplet and quadruplet pregnancies who have undergone reduction procedure in our sample come out as quite similar to the “improved outcome” figures reported in the extensive analysis by Evans M. I. et al. of 3513 cases fom 11 centres in 5 countries [20]. The early preterm-severe prematurity rate for our reduced cases were 11% for those reduced from triplets, 6% for quadruplets and 36% for quintuplets. The rates for triplets were very similar to those reported [14,18] and better for quadruplets then those reported in (6% vs 12.2%) [20]. The association of weight discordance and intrauterine growth restriction with fetal reduction is found to be nonexistent in some reports [21,22], but there are other well designed studies which stress its association with morbidity and mortality of the twin neonates. Embryo reduction was found to be the only independent risk factor for birth weight discordance in a study by Audibert F, et al., who reported a four-fold increase in neonatal mortality of weight discordant twins [23]. In our study, the average rate of weight difference of all twins born in the group with any starting number was 11.5%. Whereas, in specific terms, the rate of ‘weight discordance was 13.9%. In further detail, the rate of weight discordance was 11.8% when the starting number was 3, 23.3% when the starting number was 4, and 14.3% when the starting number was 5. The average rate of discordance for twins reduced from quadruplets was twice as large as that
reduced from triplets (23.3% and 11.8% respectively). The average discordance rate of twins reduced from quintuplets was lower at 14.3%, but the sample size of 11 was too small to draw any conclusion. Despite the need for more reliable data on discordance rates for natural twins, the results from various studies seem to be similar. The low birth weight and discordance rates in our study appear to be somewhat better, as the initial number of embryos does not seem to effect the growth restriction rate and weight discordance of twins reduced from triplets up to quintuplets - a favorable result compared to other series [20], but the number of cases here are admittedly smaller in comparison. Torok O., et al. [21] reported that fetal reduction was not found to be associated with an increased risk of intrauterine growth restriction, unless the initial fetal number was 5 or greater in their series, which comprised 156 quadruplets and 52 quintuplets (these numbers were 35 and 11 in our sample respectively). The results of the procedures compare favorably with the literature and somewhat better than some, regarding inclusion in our study sample of all higher order multiples along with triplets. The limitation of our study: We have not included a control group of nonreduced triplet pregnancies which can be considered a shortcoming of this study, but the data presented enables, in our opinion, to make a meaningful comparison and conclusion with respect to association between intial and final number of embryos and the already established outcome measures of multifetal reduction procedures, namely: loss rates, prematurity, birthweight, rate of mothers with a high order multiple pregnancy who took home a healthy baby. Acknowledgment None. References [1] Martin J.A., Hamilton BE, Osterman MJ. Three decades of twin births in the United States, 1980–2009. NCHS Data Brief 2012;(80):1–8. [2] Evans MI, Andriole S, Britt DW. Fetal reduction: 25 years’ experience. Fetal Diagn Ther 2014;35:69–82. [3] Kulkarni AD, Jamieson DJ, Jones Jr. HW, Kissin DM, Gallo MF, Macaluso M, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013;369(23):2218–25.
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The outcome of the multifetal pregnancy reduction procedures in a single centre: A report of 202 completed cases Necip Cihangir Yılanlıoglua , Altug Semiza , Resul Arisoya,* , Semra Kahramanb , Ali Arslan Gürkanc a b c
Sisli Memorial Hospital, Department of Obsteric and Gynecology, Istanbul, Turkey Sisli Memorial Hospital, Assisted Reproductive Technologies and Genetics Centre, Istanbul, Turkey Middle East Technical University, Ankara, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 June 2018 Accepted 10 September 2018 Available online xxx
Objective: To review the results of fetal reduction procedures in our institution, evaluate its effects on the pregnancy outcome in terms of miscarriage, preterm delivery, taking home healthy babies and discuss the factors that may have contributed to the outcome. Study design: This is a retrospective study performed at the Fetal Medicine Unit of the Sisli Memorial Hospital in Istanbul after ART therapies in our unit from 2000 to 2011. Results: The sample comprised 151 triplets, 35 quadruplets, 11 quintuplets, 3 twins, 1 sextuplet and 1 septuplet. The average maternal age was 30 4.4 and the average week of interventions was 11.7 1.3 weeks. In 40 cases two or more needle insertions were necessary. The two-week post-procedure loss rate, defined as ‘the procedure related loss rate’, was 0.7%; however, for the whole sample, the losses were 6.9% when they occured before 24 completed weeks and was defined as ‘the total loss rate’. 184 of the remaining 188 cases had at least one baby to take home (91.1% of 202 patients). The average birth week for those healthy babies discharged home was 35.5 2.4. The rate of early preterm birth before gestational weeks of 32 was 9%. The mean birthweight of this “take-home” group was 2302 525 g. Conclusion: Fetal reduction in multifetal pregnancy is associated with low miscarriage rate and preterm delivery rates. Fetal reduction in multifetal pregnancy should be considered for better pregnancy outcomes and the results of this study can be used in prenatal counseling. © 2018 Elsevier B.V. All rights reserved.
Keywords: Multifetal pregnancyy Miscarriage Preterm delivery Fetal reduction
Introduction Reducing the number of fetuses in triplet and higher order multiple pregnacies has been a widely employed procedure since assisted reproduction technologies (ART) became almost explosively common all over the world in the past few decades. As the number of embryos tranferred were kept high to ensure “success”, the number of triplet and higher-order multiple pregnancies rose accordingly [1,2]. The rapid increase of the rate of twins and higher-order multiple births has been shown to be largely attributable to ART in the past three decades [1–3]. Older childbearing age accounts for only one-third of this increase with infertility treatments account for the remainder [1,3]. The incidence of loss, prematurity and related sequelae rise along with the fetal number [4–7]. The two obvious prevention modalities of such
problems stand out as achieving a singleton or twin pregnancy to start with, or failing that, performing fetal reduction procedures. It is generally accepted that elective fetal reduction of high order multiple pregnancy with 4 or more fetuses substantially improves maternal and perinatal outcomes. On the other hand, studies comparing triplet pregnancies reduced to twins and triplet pregnancies managed conservatively have reported conflicting results: some have shown no difference in gestational age at delivery or in neonatal outcomes [8,9], whereas others have reported substantial improvements in perinatal outcomes, such as, preterm birth and low birth weight [10–12]. The aim of this study was to evaluate the outcome of multiple pregnancies that were reduced to a single fetus or twins or triplets with regard to the risks of miscarriage, rate of preterm delivery, birthweight and the rate of taking home healthy babies. Materials and methods
* Corresponding author at: Kaptan Paşa Mh, Halit Ziya Türkkan Sok No: 14 _ Middleist Sitesi D Blok Daire 7 Şişli, Istanbul, Turkey. E-mail address: [email protected] (R. Arisoy). https://doi.org/10.1016/j.ejogrb.2018.09.008 0301-2115/© 2018 Elsevier B.V. All rights reserved.
This is a retrospective study performed at the Fetal Medicine Unit of the Şişli Memorial Hospital in Istanbul after ART therapies
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in the unit from 2000 to 2011. We looked into a wide range of factors to elucidate their effectiveness on influencing the outcomes of 206 multifetal pregnancy reduction procedures performed during this period. The patients were scanned a week to a few days prior to the intended fetal reduction procedure to take place around 10–11 weeks of the pregnancy, and again a few days later if required. Triplets were counseled, giving information on the possible success rate of the procedures and those related prematurity, handicap risks and intensive care unit probabilities. Higher order multiples (quadruplets and higher) were counseled on the basis that their risks warrant a recommendation of reduction procedure from a medical point of view, but in every case the decision was left with the couple after making sure the known facts were fully understood. On the same scan visit, chorionicity, growth (Crownrump length; CRL), nuchal translucency, gestational sac size, proximity to the internal cervical os, and other anatomical criteria for fetal normality were noted for each fetus. No information on the sex of the fetuses was revealed. If the couple expressed preference for undergoing reduction, the final decision to proceed with the process was made through considering the above parameters and the location of the fetuses in the uterus. The lowermost sac/fetus on the internal os was avoided whenever possible, except in cases where a probable anomaly or a monochorionic pair in that position was assessed. All procedures were performed by the same operator (the first author), the same trained nurse and an assisting nurse. Only one observer in the team was present. The spouse was allowed in only if the couple requested it. The skin was prepared with swabs of 70% alcohol first and povidone-iodine afterwards, the colored antiseptic especially used to avoid any mistakes about the prepared portion of the skin. A final touch with a dry swab delineated the area of entry. A twostage local anesthetic (Xylocaine 2%) infiltration was followed by the introduction of a #21 gauge, 12 or 15 cm needle. Other fetuses’ sacs were strictly avoided during insertion. An injection of 15% potassium chloride, 0.5 ml when intracardiac or 1–1.5 ml when intrathoracic, was sufficient to achieve asystole. After two to three minutes of observation in this state, the needle was withdrawn. The patient was taken to a quiet room to rest for an hour and then allowed home with an advice to stay home for the rest of the day and the day after. When a monochorionic pair was to be reduced (28 cases in the present sample, 13 triplets and 15 higher-order multiples), only one of the fetuses was injected. A control-scan was perform after 3 to 5 days after the procedure, and in all instances, the other fetus was found to have followed suit. A maximum number of two fetuses were reduced in one session. For instance, we took three sessions (2 - 2 -1) to reduce the one septuplet to twin. Data were obtained from written and computer databases. The majority of the patients were delivered in other hospitals in different provinces of the country, information from them was obtained by correspondence over mail and phone. The study sample of 202 cases were included in the study. A wide range of parameters including age, initial number of fetuses, remaining Table 1 Breakdown of 202 reduction cases in terms of multiplicity and chorionicity.
Triplets Quadruplets Quintuplets Sextuplets Septuplets Twins TOTAL
Total Number of Patients
Dichorionic
With monochorionic combination(s)
151 35 11 1 1 3 202
138 26 8 – 1 3 176
13 9 3 1 – – 26
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number of fetuses, chorionicity, loss within two weeks of the procedure, loss before 24 weeks, birth week, birth weight and neonatal outcome were saved. Four cases, one triplet, one quadruplet and two quintuplets were excluded from the study for reasons of uncertain data and termination (of the quadruplet) for anomaly. Data analysis was performed by using Statistical Package for Social Sciences (SPSS) version 11.5 software (SPSS Inc., Chicago, IL, United States).Descriptive statistical methods (mean, standard deviation and range) were used to evaluate the data. Kolmogorov– Smirnov test was performed to determine whether or not parameters are normally distributed. Student’s t-test and MannWhitney U to compare parameters among the groups. Results were evaluated with 95% confidence intervals, and p < 0.05 was considered to indicate significance. Results Of the total study sample of 202 patients: 151 triplets, 35 quadruplets, 11 quintuplets, 3 twins, 1 sextuplet and 1 septuplet (Table 1), the average maternal age was 30 4.4 (20–49) and the mean number of fetuses was 3.3 0.6 (2–7). Out of this total, 175 pregnancies were reduced to twins, 24 were reduced to singletons and 3 were reduced to triplets (Table 2). The average week of interventions was 117 1.3 weeks, the mean of the number of remaining fetuses were 1.9 0.3 (1–3) and the mean of the number of interventions were 1.2 0.5 (1–5). The procedure-related loss rate was 0.7% (one case, a triplet), the total loss rate (miscarriage before 24 completed weeks) was 6.9% (with 9 triplets, 2 quadruplets, 1 quintuplet and 1 sextuplet) (Table 3). The total loss rate for the triplets and the quadruplets were very close each other (6.6% and 5.7% respectively) to and to the whole sample. 11 (3.1%) neonatal deaths occured in total: 7 (2.7%) of the fetuses who started as triplets, 3 (4.4%) of the quadruplets and 1 (5.2%) of the quintuplets (Table 4). As seen in Table 5, a total of 184 patients out of 202 (91.1%) were able to take home at least one baby (the “take home baby” rate). Of these 154 mothers embraced twins, 27 mothers a single baby, and 1 mother took home triplets: an average of 187 baby per mother. The birth weight in each group of reduction cases, determined according to their starting and finishing number is shown in Table 6. When the whole study sample is considered, the average birth weight of the healthy babies discharged home is 2302 525 g. The average rate of weight difference of all twins born in this group with any starting number was 115 percent. Twins reduced from quadruplets displayed significant discordance rate from those reduced from triplets (233% and 11.9% respectively) (Table 7). The gestational ages at delivery (birth week) of all infants according to their starting and finishing numbe r are given in Table 8. The average birth week of the whole sample (344 infants) was 355 2.4. The rate of early preterm birth before gestational weeks of 32 was 9%. Comment Multifetal pregnancy reduction (MFPR) clearly promises better neonatal outcomes in terms of reducing the rate of moderate and severe prematurity, morbidity and neuropsychomotor disability [4–7]. The most common practice is to reduce the total number of fetuses to two [13,14], but there is also published data that reducing to singleton as opposed to a twin results in a later gestational age at birth, without significant differences in fetal loss rate or “take-home baby rate” : defined as the number of mothers taking at least one baby home [14,15]. The fetal loss rate of 9.1% when reduced to singleton versus 5.1% when reduced to twins is a difference not found to be significant in the study by Kuhn-Beck
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Table 2 Breakdown of number of remaining fetuses after reduction procedure in each group.
Triplets Quadruplets Quintuplets Sextuplets Septuplets Twins TOTAL
Number Of Patients (# fetus)
Patients left with Singleton (# fetus)
Patients left with Twins (# fetus)
Parients left with Triplets (# fetus)
151 (453) 35 (140) 11 (55) 1 (6) 1 (7) 3 (6) 202 (667)
19 (19) – 2 (2) – – 3 (3) 24 (24)
132 (264) 33 (66) 8 (16) 1 (2) 1 (2) – 175 (350)
– 2 (6) 1 (3) – – – 3 (9)
Table 3 Procedure related loss, total Loss, live delivery and severe prematurity rates of all reduction cases.
Triplets Quadruplets Quintuplets Sextuplets Septuplets Twins TOTAL * **
No. of Patients
Procedure related loss* (%)
Total loss** (%)
Remaining Patients
Live delivery*** of at least 1 baby (%)
151 35 11 1 1 3 202
1 (0.7%) – – – – – 1 (0.5%)
10 (6.6%) 2 (5.7%) 1 (9.1%) 1 (100%) – – 14 (6.9%)
141 33 10
138 (91.4%) 32 (91.4%) 10 (91%) – 1 (100%) 3 (100%) 184 (91.1%)
1 3 188
Procedure related loss: Miscarriage within two weeks of reduction procedure. Total Loss: All losses before 24 completed weeks. Live Delivery: Babies delivered live after 24 completed weeks.
***
Table 4 Neonatal death numbers in each multiple pregnancy combination, number of patients losing one or both babies and neonatal loss rate of all reduced pregnancy fetuses. After reduction Total No. Of fetuses remaining
Remaining cases (<24 w Total loss**)
Remaining fetuses (<24 w Total loss**)
NNDa of 1 fetus (# Patient) # Fetus
NNDa of 2 fetuses (# Patient) # Fetus
Total No. Of Neonatal Deaths
Neonatal Death Rate (% lost as neonate out of the remaining fetuses)
Triplets 151 Quadruplets 35
283 72
141 33
264 68
(3) 3 (1) 1
(2) 4 (1) 2
7 3
2.7% 4.4%
11 1 1 3 202
21 2 2 3 383
10 – 1 3 188
19
(1) 1 – – – (5) 5
1 – – – (3) 6
5.2% 0% 0% 0% 3.1%
No. of Patients undergoing reduction
Quintuplets Sextuplets Septuplets Twins TOTAL a
2 3 356
– – 11
NND: Neonatal Death - death within six weeks of delivery.
et al. [15], just as the difference between 86.4% and 91.9% take home baby rates was not, respectively. In this study, the benefit is stated as higher rate of birth beyond 37 weeks and loss rate of moderate prematurity. This is a controversial subject to say the least and as there is ample data that triplets reduced to twins perform as well as non-reduced twins [16] and reduction to singleton does not do as well [13,14] but then there is the “quality of life” issue as well as the trend towards a more advanced maternal age and further societal aspects [2,14]. In our series the highest birth weights seem to be on the side of the singletons, whether they are reduced from triplets or twins. Those twins reduced from quintuplets however, weigh less than their counterparts. The average birthweight of all reduced twins is 2294 g, and their average birth weight in each starting number group including quintuplets is also over 2000 g. The reduced triplets scored the lowest birth weight, an average of 1589 g. We feel that reducing to twins and no further, constitutes the best balance between all conceivable options in our society. Hence
we did not and still do not, offer reducing a twin pregnancy to singleton unless a medical indication exists, such as a monochorionic pair as a party or some medical condition of the patient, while observing the established principles of non-directive counseling and respect for autonomy [13,17]. If a monochorionic pair exists in a higher order multiple, the best result is obtained by reducing that pair, be it a singleton to remain [14]. The two major risks in triplet and higher–order pregnancies are total pregnancy loss before 24 weeks and severe prematurity. In series where triplets are reduced to twins with control groups of non-reduced triplets, the risk of severe prematurity drops from 28% to 10% as reported by Papageorghiou et al. [18] and from 37.5% to 7% as reported by Drugan et al [19], with a trade-off of an increase in total loss rate of 4% and a low 1% respectively, though in the latter study the number of reduced cases was relatively small (46 versus 180 in the former). Only in our study, the sample sizes 151 for triplets and 35 for quadruplets were large enough to conduct meaningful statistical analysis: relatively small sample sizes of 3 twins, 11
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Table 5 Take-home babya rates (Percentage of patients with at least one baby to take home), with baby numbers and total number of babies salvaged in each group. No. of Patients undergoing Reduction (# Fetuses)
One Baby Taken home (# Baby)
Two Babies Taken home (# Baby)
Three Babies Taken Home (# Baby)
The “Take Home Baby” mothers & Rate (Tot.# Baby)
Triplets
151 (453)
21 (21)
117 (234)
–
Quadruplets
35 (140)
0 (0)
32 (64)
–
Quintuplets
11 (55)
3 (3)
6 (12)
1 (3)
Sextuplets Septuplets
1 (6) 1 (7)
– –
– 1 (2)
– –
Twins
3 (6)
3 (3)
–
–
TOTAL
202 (667)
27 (27)
154 (308)
1 (3)
138 patients 91.4% (255 babies) 32 patients 91.4% (64 babies) 10 patients 90.9% (18 babies) 0% 1 patient (2 babies) 3 patients (3 babies) 184 patients 91.1% (344 babies)
a Take-home baby: The number (and percentage) of patients who have at least one baby discharged home in health from the hospital, after all pregnancy losses and neonatal deaths.
Table 6 The average birthweighta of the babies of 188 cases. N
Reduced to singletons Birth weight (SD) (Range)
Reduced to twins Birth weight (SD) (Range)
Reduced to triplets Birth weight (SD) (Range)
Total Birth weight (SD) (Range)
All babies in the reduction cohortb discharged home in health Birth weight (SD) (Range)
Triplets (n = 141)c
(n = 18) 18 babies 2726gr 774 (2250–3500gr) –
(n = 123) 241 babies 2270gr 488 (710–4000gr) (n = 31) 61 babies 2422gr 462 (1205–3800gr) (n = 7) 14 babies 2191gr 413 (1300–2749gr) –
–
(n = 141) 259 babies 2301gr 524 (710–4000gr) (n = 33) 67 babies 2361gr 504 (1180–3800gr) (n = 10) 19 babies 2039gr 525 (1030–2749gr) –
(n = 141) 255 babies 2309gr 520 (710–4000gr) (n = 33) 64 babies 2381gr 485 (1180–3800gr) (n = 10) 18 babies 2052gr 536 (1030–2749gr) –
(n = 1) 2 babies 2100gr 141 (2000–2200gr) (n = 3) 3 babies 2900gr 627 (2250–3500gr) n = 188 350 babies 2303gr 525 (710–4000gr)
(n = 1) 2 babies 2100gr 141 (2000–2200gr) (n = 3) 3 babies 2900gr 627 (2250–3500gr) n = 184 342 babies 2313gr 519 (710–4000gr)
Quadruplets (n = 33)
Quintuplets (n = 10)
Sextuplets (n = 0) Septuplets (n = 1)
Twins (n = 2)
TOTAL Sample (n = 188)
a b c
(n = 2) 2 babies 2115gr 728 (1600–2630gr) – –
(n = 3) 3 babies 2900gr 627 (2250–3500gr) n = 23 2696 gr 748 (910–3700gr)
(n = 2) 6 babies 1743gr 528 (1180–2600gr) (n = 1) 3 babies 1280gr 269 (1030–1565gr)
(n = 1) 2 babies 2100gr 141 (2000–2200gr) –
n = 162 318 babies 2294gr 482 (710–4000gr)
n=3 9 babies 1589gr 496 (1030–2600gr)
Only of those who were discharged home in health. Reduction cohort : With reference to starting and finishing number. (n =) : Number of patients.
Table 7 The average intertwin weight difference and the percentage of infants discordant in weighta between take home twins with regard to the starting number of fetuses at reduction.
% Weight difference % Range Twins (%) with <20% weight discordance a
Triplets (Started with 3 - took home 2)
Quadruplets (Started with 4 - took home 2)
Quintuplets (Started with 5 - took home 2)
Septuplet (Started with 7 - took home 2)
All patients with any starting number and took home 2
11.1% 0%–47% 14/119 11.8%
13.9% 0%-%33.2 7/30 23.3%
6.8% 20.4% 1/7 14.3%
9.1% – 0/1
11.5% 0%–46.8% 22/157 13.9 %*
A weight difference of more than % 20 of the heavier twin is accepted as” discordant in weight”.
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Table 8 Average gestational age at delivery of those infants after 24 completed weeks.
Triplets (n = 141) Quadruplets (n = 33) Quintuplets (n = 10) Sextuplets (n = 1) Septuplets (n = 1) Twins (n = 3) TOTAL (n = 188)
Reduced singletons (wk) (Range)
Reduced twins (wk) (Range)
Reduced triplets (wk) (Range)
Total wk
Early Preterm <32 + 0 w Deliveries
All babies in the whole sample discharged home in health (wk) (Range)
(n = 18) 37 3.1 (28–40 w) –
(n = 123) 35.2 2,4 (27–41 w) (n = 31) 35.3 1.6 (31–37 w) (n = 7) 34.6 2.6 (31–38 w) –
–
35.4 2.6
(n = 13)
35.5 2.4
(n = 2) 32 2.8 (30–34 w) (n = 1) 30 w
35.1 1.8
(n = 2)
35.2 1.8
34.5 2.8
(n = 2)
34.5 2.8
(n = 2) 36.5 2,1 (35–38 w) – – (n = 3) 38.7 1,5 (37–40 w) n = 23 37.2 2.9 (28–40 w)
–
–
(n = 1) 36 w –
–
36 w
36 w
–
38.7 1.5
38.7 1.5
n = 162 35.2 2.3 (27–41 w)
n=3 37 3.1 (28–40 w)
35.4 2.5
17 (9 %)
35.5 2.4
(n =): Number of patients*.
quintuplets, 1 sextuplet and 1 septuplet pregnancies meant that statistical analysis could not be carried out, these were nevertheless presented to provide a general picture for evaluation. The procedure-related losses, at a low 0.7% for the whole sample, were only encountered in the triplets group and none were recorded in the quaduplets or higher-order multiples (Table 3). Total loss rate, as can be seen on the same table, stood at 7% for triplets, 6% for quadruplets, and at 7% when all cases were included. These results compare favorably with the literature and somewhat better than some, regarding inclusion in our study sample of all higher order multiples along with triplets. It is also worth noting that the timing of the interventions and the number of needle insertions did not affect the loss rate or birth week. The result for triplets in our series were similar to those of other studies [14,15,18,20]. As far as quadruplets and quintuplets are concerned, the loss rates as well as prematurity and fetal growth figures for triplet and quadruplet pregnancies who have undergone reduction procedure in our sample come out as quite similar to the “improved outcome” figures reported in the extensive analysis by Evans M. I. et al. of 3513 cases fom 11 centres in 5 countries [20]. The early preterm-severe prematurity rate for our reduced cases were 11% for those reduced from triplets, 6% for quadruplets and 36% for quintuplets. The rates for triplets were very similar to those reported [14,18] and better for quadruplets then those reported in (6% vs 12.2%) [20]. The association of weight discordance and intrauterine growth restriction with fetal reduction is found to be nonexistent in some reports [21,22], but there are other well designed studies which stress its association with morbidity and mortality of the twin neonates. Embryo reduction was found to be the only independent risk factor for birth weight discordance in a study by Audibert F, et al., who reported a four-fold increase in neonatal mortality of weight discordant twins [23]. In our study, the average rate of weight difference of all twins born in the group with any starting number was 11.5%. Whereas, in specific terms, the rate of ‘weight discordance was 13.9%. In further detail, the rate of weight discordance was 11.8% when the starting number was 3, 23.3% when the starting number was 4, and 14.3% when the starting number was 5. The average rate of discordance for twins reduced from quadruplets was twice as large as that
reduced from triplets (23.3% and 11.8% respectively). The average discordance rate of twins reduced from quintuplets was lower at 14.3%, but the sample size of 11 was too small to draw any conclusion. Despite the need for more reliable data on discordance rates for natural twins, the results from various studies seem to be similar. The low birth weight and discordance rates in our study appear to be somewhat better, as the initial number of embryos does not seem to effect the growth restriction rate and weight discordance of twins reduced from triplets up to quintuplets - a favorable result compared to other series [20], but the number of cases here are admittedly smaller in comparison. Torok O., et al. [21] reported that fetal reduction was not found to be associated with an increased risk of intrauterine growth restriction, unless the initial fetal number was 5 or greater in their series, which comprised 156 quadruplets and 52 quintuplets (these numbers were 35 and 11 in our sample respectively). The results of the procedures compare favorably with the literature and somewhat better than some, regarding inclusion in our study sample of all higher order multiples along with triplets. The limitation of our study: We have not included a control group of nonreduced triplet pregnancies which can be considered a shortcoming of this study, but the data presented enables, in our opinion, to make a meaningful comparison and conclusion with respect to association between intial and final number of embryos and the already established outcome measures of multifetal reduction procedures, namely: loss rates, prematurity, birthweight, rate of mothers with a high order multiple pregnancy who took home a healthy baby. Acknowledgment None. References [1] Martin J.A., Hamilton BE, Osterman MJ. Three decades of twin births in the United States, 1980–2009. NCHS Data Brief 2012;(80):1–8. [2] Evans MI, Andriole S, Britt DW. Fetal reduction: 25 years’ experience. Fetal Diagn Ther 2014;35:69–82. [3] Kulkarni AD, Jamieson DJ, Jones Jr. HW, Kissin DM, Gallo MF, Macaluso M, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013;369(23):2218–25.
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