Selective reduction of multifetal pregnancies to twins improves outcome over nonreduced triplet gestations

Selective reduction of multifetal pregnancies to twins improves outcome over nonreduced triplet gestations Michelle Smith-Levitin, MD," Ania Kowalik, MD, b Jason Birnholz, MD," Daniel W. Skupski, MD," J. Milton Hutson, M_D,~ Frank A. Chervenak, MD, ~ and Zev Rosenwaks, MD ~ New York, New York OBJECTIVE: Our purpose was to evaluate effects of multifetal pregnancy reduction on pregnancy complications and birth weights of remaining twin fetuses compared with expectantly managed triplets and nonreduced twins. STUDY DESIGN: Medical records of 54 triplet pregnancies, 59 twin pregnancies resulting from multifetal pregnancy reduction, and 88 sets of twins conceived with assisted reproductive techniques and delivered at New York Hospital after 24 weeks were retrospectively reviewed. Birth weights were corrected for gestational age at delivery by use of a formula derived from composite standardized growth curves. Statistical analysis was performed with ~2 analysis and Student t test. RESULTS: Twins remaining after reduction and nonreduced twins were less likely to have preeclampsia than were triplets (14% and 23% vs 30%) and to be delivered before 36 weeks (39% and 27% vs 72%). They had birth weights that were >100 gm larger than those of triplets even when corrected for gestational age. Reduced twins were similar to nonreduced twins in all parameters studied. CONCLUSIONS: Multifetal pregnancy reduction results in pregnancy complications, gestational age, and birth weights closer to those of nonreduced twins than to expectantly managed triplets. (Am J Obstet Gynecol 1996;175:878-82.)

Key words: Multifetal pregnancy reduction, multiple gestation, pregnancy outcome, fetal growth

The incidence of multiple gestations has increased dramatically over the past 20 years, largely because of more successful and widespread use of advanced reproductive techniques. There is substantial perinatal and maternal morbidity and mortality for multiple gestations, particularly for those of high-order multifetal pregnancies. 1-~ Multifetal pregnancy reduction was introduced in an effort to improve the overall pregnancy loss rate, gestational age at delivery, birth weight, neonatal morbidity and mortality, and incidence of pregnancy complications that are frequently associated with high-order gestations. 4' ~ It is clear that the procedure significantly improves outcomes for pregnancies with four or more fetuses.6, 7 Although several studies in the current literature suggest that multifetal pregnancy reduction improves outcomes for triplets a s w e l l , 7-9 it is less clear whether it reduces complication rates to those normally associated with twins. Furthermore, some suggest that twin pregnancies resulting from reduction of high-order multiple gesFrom the Divisions of Maternal-Fetal Medicinea and Reproductive Endocrinology, b Department of Obstetrics and Gynecology, New York Hospital-Cornell Medical Center. Presented at the Sixteenth Annual Meeting oJ the Society of Perinatal Obstetricians, Kamuela, Hawaii, February 4-10, 1996. Reprint requests: Michelle Smith-Levitin, MD, Division of MaternalFetal Medicine, Northshore University Hospital, 300 Community Dr., Manhasset, NY 11030. Copyright 9 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/6/74985

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tations still have earlier gestational ages at delivery and lower birth weights than do nonreduced t w i n s . 7' 10 A recent multicenter collaborative review demonstrated the safety of muldfetal pregnancy reduction in >1000 patients, with pregnancy loss rates after the procedure of approximately 10% and overall good outcomes for the remaining fetuses." The published studies that compare outcomes in expectantly managed multiple gestations to twin gestations resulting from embryo reduction, however, have relatively few patients, and they often compare birth weights of fetuses who are born at various gestational ages. We conducted this retrospective comparison of a large series of triplet gestations, twin gestations resulting from reduction of high-order multiples, and twin gestations to determine the effect of the procedure on the incidence of pregnancy-related complications, gestational age at delivery, and birth weight. We attempted to eliminate the effect of gestational age differences on birth weight by applying a novel way to correct birth weight to the weight expected at 36 weeks. Material and m e t h o d s

The birth weights and gestational age at delivery of all triplets and higher-order multiple gestations conceived with assisted reproductive techniques at New York Hospital from Jan. 1, 1990, to June 30, 1994, who had prenatal care and were delivered at this institution after 24 weeks' gestation were identified from delivery logs. A group of

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Table I. Study population

No. Age (wk) Race (No. and % white) Male fetuses (No. and %) Nulliparous (No. and %) IVF (No. and %)

Twins

Reductions

TTiplets

Spontaneous reductions to twzns

88 35.02 • 4.01" 80/84 (95.2%) 100/172 (58.1%) 67/81 (82.7%) 83/85 (97.6%)

59 (19: 4--42, 2: 5-92, I: 6--)2) 35.5 -+5.2* 54/57 (95%) 62/118 (53.4%) 44/58 (75.9%) 50/56 (89.3%)

54 32.75 _+4.36* 47/51 (94%) 88/156 (56.4%) 42/50 (84%) 40/46 (87%)

12 35.17 • 2.79 12 (100%) I6/24 (66.7%) 12 (100%) 12 (100%)

/VF,,In vitro fertilization. *Reductions versus triplets, p = 0.008; twins versus triplets, p = 0.003; twins versus reductions, not significant.

patients who conceived twins during the same stimulation cycles was also identified. The majority of the triplets (54%) were cared for by a private maternal-fetal medicine group. The remainder were cared for by a general faculty practice group using protocols similar to those of the maternal-fetal medicine group. Maternal age, race, parity, medical history, pregnancy complications, date of delivery, gestational age at delivery, birth weight, and gender of the fetuses was obtained from the medical records of these patients. Patients who were delivered of quadruplets, those who had undergone embryo reduction to a singleton, those who had undergone embryo reduction after 12 weeks, and those who were delivered of anomalous fetuses were excluded. All embryo reductions had been performed with transabdominal, intrathoracic potassium chloride injection by one operator between 10 and 12 weeks. A small subgroup of patients who were noted to spontaneously reduce to twins (between 9 and 11 weeks) after an initial finding of three distinct fetal hearts were identified but not included in the statistical analysis. The observed birth weights (BWobs) were then corrected to the weight expected at 36 weeks (BWcor36) along a cumulative growth curve displaying the fraction of 40-week weight achieved at each gestationa/age (GA) by use of the following equation: BWco~36 = (0.7856461798528)(gWobs) (-304.2292 + 47.780109 [GA] - 2.806143 [GA] ~ 0.073346301 [GA] "~- 0.0006683552 [GA] 4) The creation of the composite curve from several large population studies with certain gestational age at birth and the validity of the method were described by Birnholz et al. ~ Demographic data and the rates of preterm labor, preterm delivery, gestational diabetes, preeclampsia, intrauterine growth restriction (IUGR), gestational age at delivery, actuM birth weight, and corrected birth weight were compared by Z2 test and Student t test where appropriate.

Results The demographics of the study population are displayed in Table I. There were 54 sets of triplets, 59 sets of twins resulting from reduction of high-order multiples (1 sextuplet, 2 quintupiets, 19 quadruplets, and 37 triplets), and 88 sets of twins. In addition, there were 12 patients who had a spontaneous reduction from triplets to twins. The three study groups had similar race, parity, and fetal gender--factors that could influence pregnancy complications or birth weight. The incidence of pregnancy-related complications is displayed in Fig. 1. The patients who underwent embryo reduction were less likely to have preeclampsia than were the patients with triplets (p = 0.02). There was no significant difference in the rate of preeclampsia between the reduced and nonreduced twin groups. The rate of preterm labor (defined as contractions requiring oral or intravenous tocolytic therapy) was similar in the two twin groups but was significantly higher in the triplet group (p= 0.001). There was no significant difference in the rates of preterm premature rupture of membranes or gestational diabetes among the three study groups. The average gestational age at delivery was 2 weeks earlier in the triplet pregnancies than in the twin pregnancies (Table II). The risk of extreme prematurity, before 28 weeks, was low in all three groups, but the triplets were more likely to be delivered between 28 and 32 weeks compared with the other study groups (Fig. 2) (p = 0.001). Fig. 3 demonstrates that at each gestational age before 36 weeks the triplets were more likely to have been delivered. The rate of preterm delivery, at any gestational age, was similar between the reduced and nonreduced twins. The observed mean birth weight (Table lI) of the triplets was significantly smaller than that of the twins (r educed and nonreduced). This remained true even when the birth weights of all three groups were standardized to the weight that would have been expected at 36 weeks. After correction, the birth weights of the reduced twins were similar to the birth weights of the nonreduced twins. The correction decreased the standard SD of the mean birth weights.

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100

% 90 80 70

9

Triplets (n = 54)

[]

Multifetal Pregnancy Reductions (n = 59)

[]

Twins (n = 88)

60 50

44

40 30 20 10

0 Preeclampsia

Preterm Labor

Gestational Diabetes

Premature Rupture of Membranes

Fig. 1. Incidence of pregnancy-related complications.

loo|

9~f

% 80 70

9

Triplets (n = 54)

[]

Multifetal Pregnancy Reductions (n = 59)

[]

Twins (n = 88)

63 .Z/Z. 36 V//Z 4///.,

60

/ / / / - / / / ,

50 ---.-

40

,1//.

30 ////J

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////) ~///,

10 0

24 - 28 weeks

28 - 32 weeks

32 - 36 weeks

_>36 weeks

Fig. 2. Gestafional age at delivery. T h e incidence of I U G R (less than the California 10th percentile birth weight curve for singletons is) was n o t significantly different a m o n g the three groups. T h e triplet pregnancies, however, were complicated by discordant growth of the fetuses m o r e often than either of the twin pregnancy groups. Comment Couples who find themselves p r e g n a n t with a higho r d e r multifetal gestation, often after years of emotionally, physically, and financially exhaustive therapies, are faced with a dilemma: should they u n d e r g o expectant managem e n t with the high risk of pregnancy loss (up to 20% for triplets), 8 p r e m a t u r e delivery, neonatal morbidity, maternal morbidity) -~' ~4, ~ and e c o n o m i c and psychosocial cost I~18 or should they u n d e r g o multifetal p r e g n a n c y reduction, which will improve their chances of a successful

o u t c o m e but to an u n c e r t a i n degree? T h e d i l e m m a for couples with triplet gestations is particularly difficult because there have b e e n i m p r o v e m e n t s r e p o r t e d in the outc o m e of triplets recently, ~9 a l t h o u g h the data c o m p a r i n g o u t c o m e s in triplets to o u t c o m e s in twins remaining after multifetal pregnancy r e d u c t i o n are based on small patient n u m b e r s and have yielded conflicting answers. T h e results of the c u r r e n t study indicate that mulfifetal pregnancy r e d u c t i o n decreases the i n c i d e n c e of pregnancy complications, prolongs gestational age, and increases birth weight c o m p a r e d with expectantly m a n a g e d triplet pregnancies. This is in contrast to the findings of Porreco et al., 2~who did n o t find a significant difference in n e w b o r n or m a t e r n a l complications, m e a n birth weight, or gestational age at delivery in l I sets of triplets c o m p a r e d with 13 sets of triplets that u n d e r w e n t reduction to twins. O u r results are m o r e consistent with the

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100 " - ~ - - tw Yls

9 0 - - -

reductions 8 0 - - --,if--t rlplets 70 : i

/

6 0 . - -

/

/

40 30 2O 10

25

26

27

28

29

31

30

32

33

34

35

>.~36

gestational age

Fig. 3. Total percentage of pregnancies delivered at each gestational age. Table II. Actual and c o r r e c t e d birth weights !

Twins (n =88) EGA (wk, -+ SD) Actual BW (gin, _+SD Corrected BW (gin, + SD) IUGR (No. and %)+ Discordant pairs (No. and%)w

36.14+ 2.71" 2506.6 _+585.5 2488 + 348.25]43/176 (24%) 13/88 (15%)

Reductions (n = 59) 35.33 _+2.99* 2337.97 _+612 2468.33 _+396.96]31/118 (26%) 13/59 (22%)

[ I

Triplets (n = 54)

Spontaneous reductions (n = 12)

33.51 + 2.67* 1906.12 _+496.39 2374.17 _+379.53]40/162 (25%) 29/54 (54%)

36.05 -+ 1.73 2406.7 _+494.97 2399.2 -+ 339.03]6/24 (25%) 3/12 (25%)

EGA, Estimated gestational age; BW, birth weight. *Reductions versus triplets, p = 0.005; twins versus triplets, p < 0.0001; twins versus reductions, p = 0.14. ~-Reductions versus triplets, p < 0.004; twins versus triplets, p < 0.004; twins versus reductions, p = 0.64. +*IUGR (<10% on basis of California birth weight for singletonslS), p ~ 0.57. w weight difference ->20% of largest fetus, p < 0.002. three o t h e r published studies that c o m p a r e triplet pregnancies to twin pregnancies resulting f r o m r e d u c t i o n of triplets. 7-9 However, two o f these studies ~' 9 were small (20 triplets vs 5 reductions and 14 triplets vs 47 reductions, respectively, c o m p a r e d with 54 triplets vs 59 reductions in our study). The most r e c e n t publication, on the o t h e r hand, reports o u t c o m e s on a m o r e sizable g r o u p of expectantly m a n a g e d triplets (n = 106) but compares t h e m with only a small c o h o r t o f triplets that were r e d u c e d to twins (n = 34). 20 These studies f o u n d i m p r o v e d o u t c o m e s for the r e d u c e d g r o u p in p r e g n a n c y complications, n e o natal morbidity and mortality, gestational age at delivery, and birth weights. C o m p a r i n g twins r e m a i n i n g after muhifetal p r e g n a n c y reduction with n o n r e d u c e d twins provides i n f o r m a t i o n regarding the extent o f i m p r o v e m e n t in perinatal outc o m e that can be anticipated. This is particularly important because there has b e e n some evidence that there is " a price to be paid" for e m b r y o r e d u c t i o n with earlier gestational age at delivery and lower birth weight than e x p e c t e d for twins. 7' lo O u r results, which confirm those o f Macones et al.9 and D o n n e r et al., 2~ suggest that r e d u c e d

twins have the same incidence of complications, gestational age at delivery, and birth weight as a similar population o f n o n r e d u c e d twins. We did n o t find an increased incidence of I U G R a m o n g the reductions as the data of Macones et al. suggested. O f note, o u r reduction g r o u p included 22 pregnancies that u n d e r w e n t multifetal pregnancy r e d u c t i o n from h i g h e r - o r d e r (four or more) multiple gestations. This would have b e e n expected to have a detrimental effect on the o u t c o m e s for the reductions because an inverse relationship has b e e n d e m o n s t r a t e d between the starting n u m b e r of fetuses and the gestational age at delivery) 1 This adds f u r t h e r weight to the significance of our results. O u r study is the first to take variations in birth weight and variations in gestational age at delivery into a c c o u n t w h e n c o m p a r i n g m e a n birth weights of triplets, twins resulting from e m b r y o reduction, and twins. The m e t h o d that we used to correct the birth weights results in m e a n values that have smaller SDs than the actual birth weight values. As a result, comparison o f c o r r e c t e d m e a n birth weights yields statistically m o r e m e a n i n g f u l information. In addition, by correcting the birth weights of the three

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groups to the weight that would have b e e n e x p e c t e d had each fetus b e e n delivered at 36 weeks, we can better assess the effect of e m b r y o r e d u c t i o n on subsequent birth weight. T h e studies that r e p o r t lower m e a n birth weights for triplets than for reductions 7-9 or for reductions than for twins, 7' ~o for example, also r e p o r t m e a n gestational ages at delivery that are at least 2 weeks earlier for the i n d e x group. It is unclear w h e t h e r these results are merely due to earlier delivery, to an effect of the procedure, or to initial implantation and placentation of m o r e than two embryos. O u r results, however, suggest that the p r o c e d u r e does n o t have a detrimental effect and that factors such as uterine crowding or available decidual area for placental growth may be m o r e i m p o r t a n t determinants of fetal growth in these multiple gestations. T h e h i g h e r incidence of discordant growth a m o n g the triplets provides evidence for this theory. Some investigators have p r o p o s e d that there is residual effect f r o m a multifetal pregnancy r e d u c t i o n procedure. T M Further study c o m p a r i n g multiple gestations that u n d e r g o nmhifetal pregnancy r e d u c t i o n with multiple gestations that u n d e r g o spontaneous reductions m i g h t distinguish w h e t h e r an effect was due to the p r o c e d u r e itself or to the early implantation of m o r e than two fetuses. A l t h o u g h our group of spontaneous reductions was too small for statistical analysis, it is notable that their gestational age at delivery, birth weights, and incidence of I U G R and discordance were similar to the pregnancies that u n d e r w e n t e m b r y o reduction. This suggests that the p r o c e d u r e does n o t have serious adverse effects on the c o n t i n u i n g twin gestation. O u r study is the largest series to date c o m p a r i n g outcomes in twin pregnancies resulting f r o m multifetal pregnancy r e d u c t i o n with similar groups of b o t h triplets and twins. It provides further evidence that e m b r y o r e d u c t i o n of multiple gestations with three or m o r e fetuses can be of benefit. Until a large, multicenter, prospective study is acc o m p l i s h e d that compares early loss rates, all pregnancy and m a t e r n a l complications, n e o n a t a l morbidity and mortality, and l o n g - t e r m follow-up of the children and their families in all triplet pregnancies that elect e x p e c t a n t mana g e m e n t to all triplet and h i g h e r - o r d e r multiple gestations that elect multifetal pregnancy r e d u c t i o n relative to a m a t c h e d population of twin gestations, r e c o m m e n d a t i o n s c a n n o t be made. We conclude that multifetal p r e g n a n c y r e d u c t i o n should be offered to w o m e n carrying high-order multiple gestations including t r i p l e t s - - i n a n o n d i r e c rive way and with appropriate counseling. REFERENCES

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