- Email: [email protected]
Perinatal and neonatal outcomes in multiple gestations: Assisted reproduction versus spontaneous conception
Perinatal and neonatal outcomes in multiple gestations: Assisted reproduction versus spontaneous conception Brian P. Fitzsimmons, MD,a Michael W. Bebbington, MD, MHSc,a and Margo R. Fluker, MDb Vancouver, British Columbia, Canada OBJECTIVE: Our purpose was to test the hypothesis that multiple pregnancies resulting from assisted reproductive therapy have a better outcome than those resulting from spontaneous conception. STUDY DESIGN: This was a retrospective cohort study. Cases came from pregnancies from assisted reproductive techniques. Controls were identified from spontaneous multiple pregnancies delivered in the same time period. Matching was done for maternal age, parity, fetal number, and presence of maternal medical problems. A total of 72 cases (56 twins and 16 triplets) and 124 controls (108 twins and 16 triplets) were studied. The primary outcome was perinatal mortality. Secondary outcomes were preterm delivery, birth weight, maternal complications, neonatal morbidity, and length of hospitalization. RESULTS: Perinatal mortality is significantly increased in spontaneous twin gestations compared with twins resulting from assisted reproductive techniques (24 vs 2, P = .003). No difference is seen in the perinatal mortality in triplets. Mean gestational age at diagnosis was lower for twins and triplets resulting from assisted reproductive techniques (9.4 vs 13.3; P < .001 and 8.8 vs 15.8; P < .001, respectively). Rate of cerclage and number of prenatal visits was higher for triplets in the assisted reproductive techniques group (P = .05 and .02, respectively). Mean gestational age at delivery, birth weight, rate of preterm labor, preterm premature rupture of membranes, pregnancy-induced hypertension, and incidence of gestational diabetes were not significantly different between the groups. No significant differences in neonatal morbidity were detected. CONCLUSIONS: Assisted reproductive techniques–associated twins have lower perinatal mortality than spontaneously conceived twins. Perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by assisted reproductive techniques, even with closer surveillance and earlier gestational age at diagnosis in this group. Differences may be due to a higher frequency of monochorionic placentation in the spontaneously conceived group. (Am J Obstet Gynecol 1998;179:1162-7.)
Key words: Multiple pregnancy, assisted reproduction, perinatal outcomes
With increasing rates of infertility and a delay in childbearing until later in life, the demand for assisted reproductive technologies has grown. Rates of multiple pregnancies associated with assisted reproductive techniques have been quoted as high as 15% to 30%.1-3 In 1993, within Canada and the United States, 41,209 cycles of assisted reproductive techniques and 6869 embryo transfer procedures resulted in 8741 deliveries with almost 20% of these being twin gestations.4 This is in contrast to spontaneous rates of 1.05% to 1.35% for twins and 0.01% to 0.017% for triplets.1 The increased rates for multiple gestations associated with assisted reproductive techniques also results in an increased incidence of both neonatal and maternal morbidity and mortality.5, 6 Prematurity, low birth weight, From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of British Columbia,a and the Department of Obstetrics and Gynecology, University of British Columbia, Genesis Fertility Center.b Presented at the Eighteenth Annual Meeting of the Society of Perinatal Obstetricians, Miami Beach, Florida, February 2-7, 1998. Reprints not available from the authors. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/6/93538
1162
pregnancy-induced hypertension, gestational diabetes, postpartum hemorrhage, and cesarean section are all seen more frequently with multiple pregnancies.7 Obstetricians caring for pregnancies resulting from assisted reproductive techniques are called on to counsel patients about the risks and outcomes of multiple pregnancies. The information provided may have implications for decisions surrounding selective fetal reduction and pregnancy termination.8 Few data exist for perinatal outcome in spontaneous versus assisted reproductive techniques–associated twins or triplets.4, 9-11 Patients who undergo assisted reproductive techniques may constitute a different population than those who conceive spontaneously. They are often of a higher socioeconomic status, may benefit from increased nutrition, earlier prenatal diagnosis and care, and may have a greater potential for rest during pregnancy. These may represent factors that would positively influence pregnancy outcomes. Assisted reproductive techniques are associated with higher rates of multiple gestations arising from the fertilization of more than one egg, thus increasing the incidence of dichorionic, diamniotic multiples.
Fitzsimmons, Bebbington, and Fluker 1163
Volume 179, Number 5 Am J Obstet Gynecol
Table I. Demographics
Category
Assisted reproductive techniques twins (n = 56)
Non–assisted reproductive techniques twins (n = 108)
32.8
Maternal age (y, mean) Parity Primiparous Multiparous Gestational age at diagnosis (wk) Gestational age at first prenatal visit (wk, mean) No. of prenatal visits
Statistical significance
Assisted reproductive techniques triplets (n = 16)
Non–assisted reproductive techniques triplets (n = 16)
Statistical significance
32.2
NS
32.8
31.2
NS
41 15 9.4 ± 4.7
80 28 13.3 ± 5.2
NS
8 8 15.8 ± 4.2
NS
P = .001
12 4 8.8 ± 2.8
P = .001
10.3 ± 3.4
11.5 ± 6.3
NS
9.5 ± 2.4
12.7 ± 4.2
P = .02
10.7 ± 4.7
9.9 ± 4.1
NS
9.6 ± 3.3
6.8 ± 2.6
P = .02
Statistical significance
Assisted reproductive techniques triplets (n = 16)
Non–assisted reproductive techniques triplets (n = 16)
Statistical significance NS
Table II. Perinatal outcomes
Category Preterm premature rupture of membranes Gestational age at preterm premature rupture of membranes (wk) Preterm labor Gestational age at onset of preterm labor (wk) Pregnancy-induced hypertension Gestational age at onset of pregnancy-induced hypertension (wk) Gestational diabetes Gestational age at diagnosis of gestational diabetes (wk) Cerclage Prophylactic Emergency
Assisted reproductive techniques twins (n = 56)
Non–assisted reproductive techniques twins (n = 108)
8
21
NS
5
6
31.4 ± 4.7
27.8 ± 8
NS
25.4 ± 8.5
29.6 ± 3.7
20 29.8 ± 3.3
29 29 ± 4.6
NS NS
3 25.4 ± 1.2
10 28.7 ± 4.7
NS NS
9 33.6 ± 3
20 33.9 ± 2.8
NS
3 25 ± 5
2 35.3 ± 0.4
NS
8 26 ± 6
16 27.5 ± 5.1
NS NS
1 24
3 25 ± 5.3
NS NS
3 1 2
5 2 3
NS
5 2 3
0 —
P = .05
The purpose of this study was to compare perinatal and neonatal outcome of twins and triplets conceived by means of assisted reproductive techniques (clomiphene citrate [Clomid], in vitro fertilization, gamete intrafallopian transfer) with spontaneously conceived multiples. Our objective was to test the hypothesis that multiple pregnancies resulting from assisted reproductive techniques have a better outcome than those resulting from spontaneous conception. Methods This study followed a retrospective cohort design. Cases and controls were taken from all patients delivered of twins and triplets at the British Columbia Women’s Hospital between 1985 and 1996. Study patients were derived from a list of all twin and triplet deliveries during the specified time period. Patients were excluded if they delivered before 20 weeks’ gestation, underwent selective reduction, or had underlying maternal disease that would likely increase their risks
of pregnancy complications (ie, preexisting hypertension, type 1 or 2 diabetes, renal disease, or collagen vascular disease). The assisted reproductive techniques cases were identified by cross-referencing the patient list generated by the hospital health records department with 1 from the local assisted reproductive techniques program. The non– assisted reproductive techniques cases were assembled from the remaining patient list. They were matched with the assisted reproductive techniques cases according to the number of fetuses (twins or triplets), maternal age, and parity (primiparous vs multiparous). Matching was done sequentially with assisted reproductive techniques cases being matched to the next multiple pregnancy that was delivered. All matching could be done within the same calendar year. Matching was done 2:1 for twins and 1:1 for triplets. The decision to match the members of the 2 cohorts was an effort to make the 2 groups as comparable as possible for factors other than the method of conception.
1164 Fitzsimmons, Bebbington, and Fluker
November 1998 Am J Obstet Gynecol
Table IV. Triplet birth weights (mean ± SD)
Table III. Twin birth weights (mean ± SD)
Infant A B
Assisted reproductive techniques twins (g) (n = 56)
Non–assisted reproductive techniques twins (g) (n = 108)
Statistical significance
2423 ± 615 2324 ± 655
2204 ± 786 2128 ± 839
NS NS
A standard data sheet was used to collect the data. The primary outcome was perinatal mortality. Secondary outcomes that were assessed included degree of antenatal care, perinatal morbidity, neonatal morbidity, placentation, birth weight, and gestational age at delivery. Gestational dating was confirmed by last menstrual period, early ultrasonography, or date of embryo replacement. When a discrepancy occurred, ultrasonographic data were used. Standard definitions of perinatal and neonatal events were used. Standardized recording and coding systems for both neonates and mothers were helpful in obtaining complete data. Analysis was done with either χ2 and Fisher exact test for categoric variables or t tests for continuous variables. Approval for the study was obtained from the Ethics Committee at the University of British Columbia and the Research Coordinating Committee at B.C. Women’s Hospital. Results Seventy-nine cases of multiple pregnancies arising from assisted reproductive techniques were identified. Seven of these were excluded because they underwent fetal reduction. The remaining 72 cases were used in the study. These consisted of 56 twin sets and 16 triplet sets. The methods of assisted reproductive techniques consisted of 2 from clomiphene, 6 from superovulation, 3 from gamete intrafallopian transfer, and 61 from in vitro fertilization. The non–assisted reproductive techniques group consisted of 124 multiple pregnancies with 108 twin sets and 16 triplet sets. Demographics are shown in Table I. No significant difference was found in maternal age at delivery, parity, or presence of medical problems predating the pregnancy. This was done as a check on the matching process. Table I also shows that the mean gestational age at diagnosis was significantly different between the groups (P < .001). As expected, twins and triplets in the assisted reproductive techniques group were diagnosed at an earlier gestational age than in the spontaneous group. Mean gestational age at the first prenatal visit showed no significant difference for the twin sets, but a significant difference was found between the triplet set (P = .02), with ear-
Infant A B C
Assisted reproductive techniques triplets (g) (n = 16)
Non–assisted reproductive techniques triplets (g) (n = 16)
Statistical significance
1754 ± 593 1781 ± 735 1551 ± 639
1703 ± 592 1683 ± 642 1664 ± 623
NS NS NS
lier first prenatal visits for the assisted reproductive techniques triplets. Hospitalization during pregnancy was more common for the assisted reproductive techniques twin sets (P = .01), mostly for maternal reasons. No difference was seen in hospitalization rates for the triplets, but the numbers were comparatively small. When complications of pregnancy were assessed, no significant differences were found between the groups for rate of preterm premature rupture of membranes, preterm labor, pregnancy-induced hypertension, or gestational diabetes. Cervical cerclage rates were not significantly different between twin groups, but between the triplet groups cerclage was significantly different between the groups, with no cerclages performed for the spontaneous triplets but 5 performed for the assisted reproductive techniques triplets (P = .05). This information is shown in Table II. No significant differences were found in gestational age at delivery, with the mean gestational ages for twins being 35.4 ± 3.3 versus 34.6 ± 4.5 weeks for the assisted reproductive techniques and nonassisted reproductive techniques twins, respectively. Similarly for the assisted reproductive techniques versus non–assisted reproductive techniques triplets, the mean gestational ages at delivery were 32.4 ± 3.3 and 32.6 ± 3.8, respectively. The gestational ages at delivery date were also analyzed after they were stratified into groups <24 weeks, 24 to 28 weeks, 28 to 32 weeks, 32 to 36 weeks, and >36 weeks. Again, no differences were seen. Birth weight data are shown in Tables III and IV. No differences in mean birth weight were seen. Again data were stratified into weight groupings with no effect on the result of the analysis. Similarly no difference was seen in the method of delivery between either the twin or triplet sets. Assessment of fetal outcomes revealed no differences in Apgar scores <7 at 5 minutes. Admission rates to the neonatal intensive care unit and mean number of days in the neonatal intensive care unit were not significantly different. Overall morbidity was not different between the groups. Specifically, no significant differences were found between the groups for days of ventilation, inci-
Fitzsimmons, Bebbington, and Fluker 1165
Volume 179, Number 5 Am J Obstet Gynecol
Table V. Perinatal mortality Stillbirth
Neonatal death
Perinatal mortality
0
2
2
13
11
24
Assisted reproductive techniques triplets
2
1
3
Non–assisted reproductive techniques triplets
0
3
3
Assisted reproductive techniques twins Non–assisted reproductive techniques twins
Comments From same pregnancy; monochorionic: A, Potter’s syndrome; B, renal failure 12 caused by twin-to-twin transfusion syndrome in monochorionic pregnancy; 10 deaths in dichorionic pregnancies: Preterm premature rupture of membranes, abruptio placentae, prematurity; 1 monoamniotic pregnancy had no death 1 at 34 wk: A and B >2000 g, healthy; C only 365 g, inconclusive autopsy; 1 at 25 wk 3 d: 680 g, meningitis and cardiomyopathy, died on day 192; 1 stillborn at 27 wk 3 d All 3 caused by extreme prematurity; delivered at 23 wk 3 d; 8 monochorionic had no deaths
Comment dence of hyaline membrane disease, intracranial hemorrhage, neonatal seizures, sepsis, or necrotizing enterocolitis. No significant difference was noted in the number of infants who died in the neonatal intensive care unit. No difference was found in the numbers of babies who were discharged from the hospital <7 days after delivery or in the number of babies who were discharged with their mother. Type of placentation was significantly different between the two groups. Two cases of monochorionic twinning were among the twin assisted reproductive techniques group, whereas 34 sets of twins were monochorionic in the non–assisted reproductive techniques group. Eight sets of triplets had at least 1 monochorionic placentation in the non–assisted reproductive techniques group, whereas all the assisted reproductive techniques triplets resulted from implantation of 3 embryos. Table V shows that overall perinatal mortality was significantly increased in spontaneous twin gestations compared with twins resulting from assisted reproductive techniques (24 vs 2; P = .003). In the control group 10 cases of twin-to-twin transfusion syndrome were documented. These all met the clinical criteria for the diagnosis and had anastomoses proved by pathologic assessment of the placenta. In 5 twin pairs both twins died as a direct result of twin-to-twin transfusion syndrome. One case occurred in which 1 twin was delivered alive and the second died. Among the causes of death for the other twins, preterm labor, preterm premature rupture of membranes, and abruptio placentae were cited as causes of prematurity. One case of a monoamniotic twin pregnancy was uncomplicated. When the data for perinatal mortality were controlled for the presence of monochorionic placentation, a statistically significant difference was still present in the perinatal mortality between the twin groups (0 vs 12; P = .01). No difference was seen in the perinatal mortality in triplets between the two groups.
The outcome of multiple gestation resulting from assisted reproductive techniques has been a subject of controversy. Patients want to know the safety and quality of the outcome that they will have when they undergo medical intervention to achieve pregnancy. Some believe that because of advanced maternal age and factors related to the cause of the patient’s infertility that the resulting pregnancy may be more complicated than that originating from spontaneous conception. Patients often ask about the effects of the medication needed for in vitro fertilization on the quality of the pregnancy. To date, information specifically addressing the perinatal and neonatal outcome of multiple gestations arising from assisted reproductive techniques compared with those resulting from spontaneous conceptions is still limited. In 1995 Petersen et al10 prospectively compared 90 in vitro fertilization with 90 non–in vitro fertilization pregnancies. The study population consisted of singletons, twins, and triplets. Rates of toxemia, preterm labor, intrauterine growth restriction, and abruptio placentae were similar when overall in vitro fertilization and control pregnancies were compared regardless of fetal number. Their study concluded that the birth weights of twins and triplets were not significantly different between in vitro fertilization and control groups. No other perinatal or neonatal morbidity/mortality outcomes were reported. The focus of this paper was clearly singletons because only 16 twin and 4 triplet gestations were included, making conclusions about this subgroup difficult. In 1993 Lipitz et al9 did a prospective study comparing the outcome of 106 triplet pregnancies arising from assisted reproductive techniques and spontaneous pregnancies. Their results suggest no difference with respect to perinatal morbidity and mortality. They concluded that no significant difference occurred in rates of premature rupture of membranes, premature contractions, pregnancy-induced hypertension, or gestational diabetes
1166 Fitzsimmons, Bebbington, and Fluker
between the groups. They also concluded that no significant difference was present in neonatal complications. This study included 99 assisted reproductive techniques pregnancies and only 7 spontaneous triplet conceptions. Although this may provide information on assisted reproductive techniques pregnancies, it is difficult to draw comparisons with spontaneously conceived pregnancies with such a small comparison group. More recently, Bernasko et al4 observed 105 assisted reproductive techniques and 279 non–assisted reproductive techniques twin pregnancies and compared maternal and neonatal outcomes. In a study with size and design similar to ours they concluded that the incidence of discordant birth weight was higher for assisted reproductive techniques but overall perinatal outcome was similar for the 2 groups. In their study elective cesarean sections were 4 times more likely to occur in twins resulting from assisted reproductive techniques, but no statistically significant difference was found in the frequency of antepartum or intrapartum complications. The non– assisted reproductive techniques group was assembled from all the remaining twins in their perinatal database once the assisted reproductive techniques twins had been removed. Their groups were significantly different, with the assisted reproductive techniques group containing more nulliparous patients and a greater percentage of women aged 35 or older. These factors were controlled for in the matching process for our study. Olivennes et al11 also compared perinatal outcome of 154 twins from in vitro fertilization with 164 spontaneously conceived twins and found that no associated increase in adverse perinatal outcomes was present. In general, the findings of this study are supported by the previous literature, except that our spontaneously conceived twin pregnancies had higher mortality rates than did twins in the assisted reproductive techniques group. This seems to be due mostly to an increase in monochorionicity in spontaneous twins and the subsequent development of twin-to-twin transfusion syndrome that occurred in 10 cases and resulted in 12 deaths. However, even when the mortality resulting from monochorionic placentation is removed, an excess perinatal mortality is still seen in the dichorionic placentation group that results from spontaneous conception. The reason for this is a higher rate of complications resulting in prematurity. This difference may be real or may be due to bias introduced by the study of patients delivered in a tertiary care center. Our triplet data did not show a significant difference between the groups for perinatal mortality, but our sample size for this group may be too small to detect a difference. When controlled for age, parity, and the absence of medical problems, mean gestational age at delivery, birth weight, rate of preterm labor, preterm premature rupture of membranes, pregnancy-induced hypertension,
November 1998 Am J Obstet Gynecol
neonatal morbidity, and incidence of gestational diabetes were not significantly different between the groups. This has important counseling and management implications for antenatal care. Pregnancies from assisted reproduction are likely to undergo greater scrutiny, and this could serve as a confounding variable. In this study we attempted to track this and to quantify it by totaling the number of prenatal visits. Mean gestational age at diagnosis was significantly earlier in the assisted reproductive techniques group as would be expected. The number of prenatal visits, however, was not different for the twin groups. For triplets, assisted reproductive techniques pregnancies had, on average, 9.6 prenatal visits compared with 6.8 in spontaneous triplets (P = .02). As well, assisted reproductive techniques triplets had significantly more use of cervical cerclage. This difference in attention and intervention did not confer a better outcome on this group. Many limitations can be associated with the use of retrospective studies that can influence outcomes. Changing standards of perinatal care over the course of the period of observation can influence outcomes, but no such change occurred. Any minor deviations would equally affect both groups of multiple gestations and is controlled for by our ability to match within calendar years. Matching of assisted reproductive techniques to non–assisted reproductive techniques for maternal age, absence of underlying medical problems, and parity was an attempt to control for other factors that may influence outcome. A risk of selection bias is associated with the study of patients at a tertiary care maternity hospital because one would expect that more of the multiple gestations with complications would be delivered there. The frequency of monochorionic placentation in the spontaneous conception group is no different than that expected in the general twin population. The completeness of charting is also often a factor, but the use of standardized recording and coding resulted in complete data being available on all cases. Bias in the collection of data was minimized by the use of a standardized data collection form. Small numbers of patients may allow for type II error, especially in regard to the outcome of the triplet pregnancies. Callahan et al1 argued that the higher rate of multiples arising from assisted reproductive techniques adds a considerable burden to the costs of health care. Multiple gestations are associated with more preterm deliveries and perinatal complications. However, our study does not suggest that outcomes of assisted reproductive techniques multiple pregnancies would likely be more of an economic burden than those from spontaneous conceptions. Any additional burden would appear to be a direct effect of the increased numbers of multiples because of assisted reproductive techniques.
Fitzsimmons, Bebbington, and Fluker 1167
Volume 179, Number 5 Am J Obstet Gynecol
Our study did not address long-term outcomes of the infants from these multiple pregnancies. Brandes et al,12 however, followed multiples from in vitro fertilization and matched them with control infants. They found no significant difference in mental developmental indexes between the two groups. When patients with multiple gestations from assisted reproductive techniques are counseled, the data from this study do not suggest the need to advise selective reduction for twin pregnancies. In triplet pregnancies, we cannot conclude that more intensive care is advised or is of benefit. In this study assisted reproductive techniques twins had a lower perinatal mortality than spontaneously conceived twins, but triplets did not appear to show any difference in mortality between the groups. Perinatal and neonatal morbidity may be affected favorably by assisted reproductive techniques, but this finding requires further confirmation. In twin gestations closer follow-up of assisted reproductive techniques conceptions than with those conceived spontaneously does not seem to be needed.
3.
4.
5.
6.
7.
8. 9.
10.
11. REFERENCES
1. Callahan T, Hall J, Ettner S, Christiansen C, Greene M, Crowley W. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med 1994;331:244-9. 2. Friedler S, Mashiach S, Laufer N. Births in Israel resulting from
12.
in-vitro fertilization/embryo transfer, 1982-1989: National Registry for the Israeli Association for Fertility Research. Hum Reprod 1992;7:1159-63. Medical Research Council Party on Children Conceived by In Vitro Fertilisation. Births in Great Britain resulting from assisted conception, 1978-87. BMJ 1990;300:1229-33. Bernasko J, Lynch L, Lapinski R, Berkowitz R. Twin pregnancies conceived by assisted reproductive techniques: maternal and neonatal outcomes. Obstet Gynecol 1997;89:368-72. Cunningham FG, MacDonald PC, Leveno KJ, Gant NF, Gilstrap LC. Williams’ obstetrics. 19th ed. Norwalk (CT): Appleton & Lange; 1993. Rizk B, Doyle P, Tan SL, Rainsbury P, Betts J, Brinsden P, et al. Perinatal outcome and congenital malformations in in-vitro fertilization babies from the Bourn-Hallam group. Hum Reprod 1991;6:1259-64. Tan SL, Doyle P, Campbell S, Beral V, Rizk B, Brinsden P, et al. Obstetric outcome of in vitro fertilization pregnancies compared with normally conceived pregnancies. Am J Obstet Gynecol 1992;167:778-84. Thorp J, Turney L, Bowes W. Outcome of multifetal gestations: a case-control study. J Matern Fetal Med 1994;3:23-6. Lipitz S, Seidman D, Alcalay M, Achiron R, Mashiach S, Reichman B. The effect of fertility drugs and in vitro methods on the outcome of 106 triplet pregnancies. Fertil Steril 1993;60:1031-4. Petersen K, Hornnes PJ, Ellingsen S, Jensen F, Brocks V, Starup J, et al. Perinatal outcome after in vitro fertilization. Acta Obstet Gynecol Scand 1995;74:129-31. Olivennes F, Kadhel P, Rufat P, Fanchin R, Fernandez H, Frydman R. Perinatal outcome of twin pregnancies obtained after in vitro fertilization: comparison with twin pregnancies obtained spontaneously or after ovarian stimulation. Fertil Steril 1996;66:105-9. Brandes J, Scher A, Itzkovits J, Thaler I, Sarid M, GershoniBaruch R. Growth and development of children conceived by in vitro fertilization. Pediatrics 1992;90:424-9.
Key words: Multiple pregnancy, assisted reproduction, perinatal outcomes
With increasing rates of infertility and a delay in childbearing until later in life, the demand for assisted reproductive technologies has grown. Rates of multiple pregnancies associated with assisted reproductive techniques have been quoted as high as 15% to 30%.1-3 In 1993, within Canada and the United States, 41,209 cycles of assisted reproductive techniques and 6869 embryo transfer procedures resulted in 8741 deliveries with almost 20% of these being twin gestations.4 This is in contrast to spontaneous rates of 1.05% to 1.35% for twins and 0.01% to 0.017% for triplets.1 The increased rates for multiple gestations associated with assisted reproductive techniques also results in an increased incidence of both neonatal and maternal morbidity and mortality.5, 6 Prematurity, low birth weight, From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of British Columbia,a and the Department of Obstetrics and Gynecology, University of British Columbia, Genesis Fertility Center.b Presented at the Eighteenth Annual Meeting of the Society of Perinatal Obstetricians, Miami Beach, Florida, February 2-7, 1998. Reprints not available from the authors. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/6/93538
1162
pregnancy-induced hypertension, gestational diabetes, postpartum hemorrhage, and cesarean section are all seen more frequently with multiple pregnancies.7 Obstetricians caring for pregnancies resulting from assisted reproductive techniques are called on to counsel patients about the risks and outcomes of multiple pregnancies. The information provided may have implications for decisions surrounding selective fetal reduction and pregnancy termination.8 Few data exist for perinatal outcome in spontaneous versus assisted reproductive techniques–associated twins or triplets.4, 9-11 Patients who undergo assisted reproductive techniques may constitute a different population than those who conceive spontaneously. They are often of a higher socioeconomic status, may benefit from increased nutrition, earlier prenatal diagnosis and care, and may have a greater potential for rest during pregnancy. These may represent factors that would positively influence pregnancy outcomes. Assisted reproductive techniques are associated with higher rates of multiple gestations arising from the fertilization of more than one egg, thus increasing the incidence of dichorionic, diamniotic multiples.
Fitzsimmons, Bebbington, and Fluker 1163
Volume 179, Number 5 Am J Obstet Gynecol
Table I. Demographics
Category
Assisted reproductive techniques twins (n = 56)
Non–assisted reproductive techniques twins (n = 108)
32.8
Maternal age (y, mean) Parity Primiparous Multiparous Gestational age at diagnosis (wk) Gestational age at first prenatal visit (wk, mean) No. of prenatal visits
Statistical significance
Assisted reproductive techniques triplets (n = 16)
Non–assisted reproductive techniques triplets (n = 16)
Statistical significance
32.2
NS
32.8
31.2
NS
41 15 9.4 ± 4.7
80 28 13.3 ± 5.2
NS
8 8 15.8 ± 4.2
NS
P = .001
12 4 8.8 ± 2.8
P = .001
10.3 ± 3.4
11.5 ± 6.3
NS
9.5 ± 2.4
12.7 ± 4.2
P = .02
10.7 ± 4.7
9.9 ± 4.1
NS
9.6 ± 3.3
6.8 ± 2.6
P = .02
Statistical significance
Assisted reproductive techniques triplets (n = 16)
Non–assisted reproductive techniques triplets (n = 16)
Statistical significance NS
Table II. Perinatal outcomes
Category Preterm premature rupture of membranes Gestational age at preterm premature rupture of membranes (wk) Preterm labor Gestational age at onset of preterm labor (wk) Pregnancy-induced hypertension Gestational age at onset of pregnancy-induced hypertension (wk) Gestational diabetes Gestational age at diagnosis of gestational diabetes (wk) Cerclage Prophylactic Emergency
Assisted reproductive techniques twins (n = 56)
Non–assisted reproductive techniques twins (n = 108)
8
21
NS
5
6
31.4 ± 4.7
27.8 ± 8
NS
25.4 ± 8.5
29.6 ± 3.7
20 29.8 ± 3.3
29 29 ± 4.6
NS NS
3 25.4 ± 1.2
10 28.7 ± 4.7
NS NS
9 33.6 ± 3
20 33.9 ± 2.8
NS
3 25 ± 5
2 35.3 ± 0.4
NS
8 26 ± 6
16 27.5 ± 5.1
NS NS
1 24
3 25 ± 5.3
NS NS
3 1 2
5 2 3
NS
5 2 3
0 —
P = .05
The purpose of this study was to compare perinatal and neonatal outcome of twins and triplets conceived by means of assisted reproductive techniques (clomiphene citrate [Clomid], in vitro fertilization, gamete intrafallopian transfer) with spontaneously conceived multiples. Our objective was to test the hypothesis that multiple pregnancies resulting from assisted reproductive techniques have a better outcome than those resulting from spontaneous conception. Methods This study followed a retrospective cohort design. Cases and controls were taken from all patients delivered of twins and triplets at the British Columbia Women’s Hospital between 1985 and 1996. Study patients were derived from a list of all twin and triplet deliveries during the specified time period. Patients were excluded if they delivered before 20 weeks’ gestation, underwent selective reduction, or had underlying maternal disease that would likely increase their risks
of pregnancy complications (ie, preexisting hypertension, type 1 or 2 diabetes, renal disease, or collagen vascular disease). The assisted reproductive techniques cases were identified by cross-referencing the patient list generated by the hospital health records department with 1 from the local assisted reproductive techniques program. The non– assisted reproductive techniques cases were assembled from the remaining patient list. They were matched with the assisted reproductive techniques cases according to the number of fetuses (twins or triplets), maternal age, and parity (primiparous vs multiparous). Matching was done sequentially with assisted reproductive techniques cases being matched to the next multiple pregnancy that was delivered. All matching could be done within the same calendar year. Matching was done 2:1 for twins and 1:1 for triplets. The decision to match the members of the 2 cohorts was an effort to make the 2 groups as comparable as possible for factors other than the method of conception.
1164 Fitzsimmons, Bebbington, and Fluker
November 1998 Am J Obstet Gynecol
Table IV. Triplet birth weights (mean ± SD)
Table III. Twin birth weights (mean ± SD)
Infant A B
Assisted reproductive techniques twins (g) (n = 56)
Non–assisted reproductive techniques twins (g) (n = 108)
Statistical significance
2423 ± 615 2324 ± 655
2204 ± 786 2128 ± 839
NS NS
A standard data sheet was used to collect the data. The primary outcome was perinatal mortality. Secondary outcomes that were assessed included degree of antenatal care, perinatal morbidity, neonatal morbidity, placentation, birth weight, and gestational age at delivery. Gestational dating was confirmed by last menstrual period, early ultrasonography, or date of embryo replacement. When a discrepancy occurred, ultrasonographic data were used. Standard definitions of perinatal and neonatal events were used. Standardized recording and coding systems for both neonates and mothers were helpful in obtaining complete data. Analysis was done with either χ2 and Fisher exact test for categoric variables or t tests for continuous variables. Approval for the study was obtained from the Ethics Committee at the University of British Columbia and the Research Coordinating Committee at B.C. Women’s Hospital. Results Seventy-nine cases of multiple pregnancies arising from assisted reproductive techniques were identified. Seven of these were excluded because they underwent fetal reduction. The remaining 72 cases were used in the study. These consisted of 56 twin sets and 16 triplet sets. The methods of assisted reproductive techniques consisted of 2 from clomiphene, 6 from superovulation, 3 from gamete intrafallopian transfer, and 61 from in vitro fertilization. The non–assisted reproductive techniques group consisted of 124 multiple pregnancies with 108 twin sets and 16 triplet sets. Demographics are shown in Table I. No significant difference was found in maternal age at delivery, parity, or presence of medical problems predating the pregnancy. This was done as a check on the matching process. Table I also shows that the mean gestational age at diagnosis was significantly different between the groups (P < .001). As expected, twins and triplets in the assisted reproductive techniques group were diagnosed at an earlier gestational age than in the spontaneous group. Mean gestational age at the first prenatal visit showed no significant difference for the twin sets, but a significant difference was found between the triplet set (P = .02), with ear-
Infant A B C
Assisted reproductive techniques triplets (g) (n = 16)
Non–assisted reproductive techniques triplets (g) (n = 16)
Statistical significance
1754 ± 593 1781 ± 735 1551 ± 639
1703 ± 592 1683 ± 642 1664 ± 623
NS NS NS
lier first prenatal visits for the assisted reproductive techniques triplets. Hospitalization during pregnancy was more common for the assisted reproductive techniques twin sets (P = .01), mostly for maternal reasons. No difference was seen in hospitalization rates for the triplets, but the numbers were comparatively small. When complications of pregnancy were assessed, no significant differences were found between the groups for rate of preterm premature rupture of membranes, preterm labor, pregnancy-induced hypertension, or gestational diabetes. Cervical cerclage rates were not significantly different between twin groups, but between the triplet groups cerclage was significantly different between the groups, with no cerclages performed for the spontaneous triplets but 5 performed for the assisted reproductive techniques triplets (P = .05). This information is shown in Table II. No significant differences were found in gestational age at delivery, with the mean gestational ages for twins being 35.4 ± 3.3 versus 34.6 ± 4.5 weeks for the assisted reproductive techniques and nonassisted reproductive techniques twins, respectively. Similarly for the assisted reproductive techniques versus non–assisted reproductive techniques triplets, the mean gestational ages at delivery were 32.4 ± 3.3 and 32.6 ± 3.8, respectively. The gestational ages at delivery date were also analyzed after they were stratified into groups <24 weeks, 24 to 28 weeks, 28 to 32 weeks, 32 to 36 weeks, and >36 weeks. Again, no differences were seen. Birth weight data are shown in Tables III and IV. No differences in mean birth weight were seen. Again data were stratified into weight groupings with no effect on the result of the analysis. Similarly no difference was seen in the method of delivery between either the twin or triplet sets. Assessment of fetal outcomes revealed no differences in Apgar scores <7 at 5 minutes. Admission rates to the neonatal intensive care unit and mean number of days in the neonatal intensive care unit were not significantly different. Overall morbidity was not different between the groups. Specifically, no significant differences were found between the groups for days of ventilation, inci-
Fitzsimmons, Bebbington, and Fluker 1165
Volume 179, Number 5 Am J Obstet Gynecol
Table V. Perinatal mortality Stillbirth
Neonatal death
Perinatal mortality
0
2
2
13
11
24
Assisted reproductive techniques triplets
2
1
3
Non–assisted reproductive techniques triplets
0
3
3
Assisted reproductive techniques twins Non–assisted reproductive techniques twins
Comments From same pregnancy; monochorionic: A, Potter’s syndrome; B, renal failure 12 caused by twin-to-twin transfusion syndrome in monochorionic pregnancy; 10 deaths in dichorionic pregnancies: Preterm premature rupture of membranes, abruptio placentae, prematurity; 1 monoamniotic pregnancy had no death 1 at 34 wk: A and B >2000 g, healthy; C only 365 g, inconclusive autopsy; 1 at 25 wk 3 d: 680 g, meningitis and cardiomyopathy, died on day 192; 1 stillborn at 27 wk 3 d All 3 caused by extreme prematurity; delivered at 23 wk 3 d; 8 monochorionic had no deaths
Comment dence of hyaline membrane disease, intracranial hemorrhage, neonatal seizures, sepsis, or necrotizing enterocolitis. No significant difference was noted in the number of infants who died in the neonatal intensive care unit. No difference was found in the numbers of babies who were discharged from the hospital <7 days after delivery or in the number of babies who were discharged with their mother. Type of placentation was significantly different between the two groups. Two cases of monochorionic twinning were among the twin assisted reproductive techniques group, whereas 34 sets of twins were monochorionic in the non–assisted reproductive techniques group. Eight sets of triplets had at least 1 monochorionic placentation in the non–assisted reproductive techniques group, whereas all the assisted reproductive techniques triplets resulted from implantation of 3 embryos. Table V shows that overall perinatal mortality was significantly increased in spontaneous twin gestations compared with twins resulting from assisted reproductive techniques (24 vs 2; P = .003). In the control group 10 cases of twin-to-twin transfusion syndrome were documented. These all met the clinical criteria for the diagnosis and had anastomoses proved by pathologic assessment of the placenta. In 5 twin pairs both twins died as a direct result of twin-to-twin transfusion syndrome. One case occurred in which 1 twin was delivered alive and the second died. Among the causes of death for the other twins, preterm labor, preterm premature rupture of membranes, and abruptio placentae were cited as causes of prematurity. One case of a monoamniotic twin pregnancy was uncomplicated. When the data for perinatal mortality were controlled for the presence of monochorionic placentation, a statistically significant difference was still present in the perinatal mortality between the twin groups (0 vs 12; P = .01). No difference was seen in the perinatal mortality in triplets between the two groups.
The outcome of multiple gestation resulting from assisted reproductive techniques has been a subject of controversy. Patients want to know the safety and quality of the outcome that they will have when they undergo medical intervention to achieve pregnancy. Some believe that because of advanced maternal age and factors related to the cause of the patient’s infertility that the resulting pregnancy may be more complicated than that originating from spontaneous conception. Patients often ask about the effects of the medication needed for in vitro fertilization on the quality of the pregnancy. To date, information specifically addressing the perinatal and neonatal outcome of multiple gestations arising from assisted reproductive techniques compared with those resulting from spontaneous conceptions is still limited. In 1995 Petersen et al10 prospectively compared 90 in vitro fertilization with 90 non–in vitro fertilization pregnancies. The study population consisted of singletons, twins, and triplets. Rates of toxemia, preterm labor, intrauterine growth restriction, and abruptio placentae were similar when overall in vitro fertilization and control pregnancies were compared regardless of fetal number. Their study concluded that the birth weights of twins and triplets were not significantly different between in vitro fertilization and control groups. No other perinatal or neonatal morbidity/mortality outcomes were reported. The focus of this paper was clearly singletons because only 16 twin and 4 triplet gestations were included, making conclusions about this subgroup difficult. In 1993 Lipitz et al9 did a prospective study comparing the outcome of 106 triplet pregnancies arising from assisted reproductive techniques and spontaneous pregnancies. Their results suggest no difference with respect to perinatal morbidity and mortality. They concluded that no significant difference occurred in rates of premature rupture of membranes, premature contractions, pregnancy-induced hypertension, or gestational diabetes
1166 Fitzsimmons, Bebbington, and Fluker
between the groups. They also concluded that no significant difference was present in neonatal complications. This study included 99 assisted reproductive techniques pregnancies and only 7 spontaneous triplet conceptions. Although this may provide information on assisted reproductive techniques pregnancies, it is difficult to draw comparisons with spontaneously conceived pregnancies with such a small comparison group. More recently, Bernasko et al4 observed 105 assisted reproductive techniques and 279 non–assisted reproductive techniques twin pregnancies and compared maternal and neonatal outcomes. In a study with size and design similar to ours they concluded that the incidence of discordant birth weight was higher for assisted reproductive techniques but overall perinatal outcome was similar for the 2 groups. In their study elective cesarean sections were 4 times more likely to occur in twins resulting from assisted reproductive techniques, but no statistically significant difference was found in the frequency of antepartum or intrapartum complications. The non– assisted reproductive techniques group was assembled from all the remaining twins in their perinatal database once the assisted reproductive techniques twins had been removed. Their groups were significantly different, with the assisted reproductive techniques group containing more nulliparous patients and a greater percentage of women aged 35 or older. These factors were controlled for in the matching process for our study. Olivennes et al11 also compared perinatal outcome of 154 twins from in vitro fertilization with 164 spontaneously conceived twins and found that no associated increase in adverse perinatal outcomes was present. In general, the findings of this study are supported by the previous literature, except that our spontaneously conceived twin pregnancies had higher mortality rates than did twins in the assisted reproductive techniques group. This seems to be due mostly to an increase in monochorionicity in spontaneous twins and the subsequent development of twin-to-twin transfusion syndrome that occurred in 10 cases and resulted in 12 deaths. However, even when the mortality resulting from monochorionic placentation is removed, an excess perinatal mortality is still seen in the dichorionic placentation group that results from spontaneous conception. The reason for this is a higher rate of complications resulting in prematurity. This difference may be real or may be due to bias introduced by the study of patients delivered in a tertiary care center. Our triplet data did not show a significant difference between the groups for perinatal mortality, but our sample size for this group may be too small to detect a difference. When controlled for age, parity, and the absence of medical problems, mean gestational age at delivery, birth weight, rate of preterm labor, preterm premature rupture of membranes, pregnancy-induced hypertension,
November 1998 Am J Obstet Gynecol
neonatal morbidity, and incidence of gestational diabetes were not significantly different between the groups. This has important counseling and management implications for antenatal care. Pregnancies from assisted reproduction are likely to undergo greater scrutiny, and this could serve as a confounding variable. In this study we attempted to track this and to quantify it by totaling the number of prenatal visits. Mean gestational age at diagnosis was significantly earlier in the assisted reproductive techniques group as would be expected. The number of prenatal visits, however, was not different for the twin groups. For triplets, assisted reproductive techniques pregnancies had, on average, 9.6 prenatal visits compared with 6.8 in spontaneous triplets (P = .02). As well, assisted reproductive techniques triplets had significantly more use of cervical cerclage. This difference in attention and intervention did not confer a better outcome on this group. Many limitations can be associated with the use of retrospective studies that can influence outcomes. Changing standards of perinatal care over the course of the period of observation can influence outcomes, but no such change occurred. Any minor deviations would equally affect both groups of multiple gestations and is controlled for by our ability to match within calendar years. Matching of assisted reproductive techniques to non–assisted reproductive techniques for maternal age, absence of underlying medical problems, and parity was an attempt to control for other factors that may influence outcome. A risk of selection bias is associated with the study of patients at a tertiary care maternity hospital because one would expect that more of the multiple gestations with complications would be delivered there. The frequency of monochorionic placentation in the spontaneous conception group is no different than that expected in the general twin population. The completeness of charting is also often a factor, but the use of standardized recording and coding resulted in complete data being available on all cases. Bias in the collection of data was minimized by the use of a standardized data collection form. Small numbers of patients may allow for type II error, especially in regard to the outcome of the triplet pregnancies. Callahan et al1 argued that the higher rate of multiples arising from assisted reproductive techniques adds a considerable burden to the costs of health care. Multiple gestations are associated with more preterm deliveries and perinatal complications. However, our study does not suggest that outcomes of assisted reproductive techniques multiple pregnancies would likely be more of an economic burden than those from spontaneous conceptions. Any additional burden would appear to be a direct effect of the increased numbers of multiples because of assisted reproductive techniques.
Fitzsimmons, Bebbington, and Fluker 1167
Volume 179, Number 5 Am J Obstet Gynecol
Our study did not address long-term outcomes of the infants from these multiple pregnancies. Brandes et al,12 however, followed multiples from in vitro fertilization and matched them with control infants. They found no significant difference in mental developmental indexes between the two groups. When patients with multiple gestations from assisted reproductive techniques are counseled, the data from this study do not suggest the need to advise selective reduction for twin pregnancies. In triplet pregnancies, we cannot conclude that more intensive care is advised or is of benefit. In this study assisted reproductive techniques twins had a lower perinatal mortality than spontaneously conceived twins, but triplets did not appear to show any difference in mortality between the groups. Perinatal and neonatal morbidity may be affected favorably by assisted reproductive techniques, but this finding requires further confirmation. In twin gestations closer follow-up of assisted reproductive techniques conceptions than with those conceived spontaneously does not seem to be needed.
3.
4.
5.
6.
7.
8. 9.
10.
11. REFERENCES
1. Callahan T, Hall J, Ettner S, Christiansen C, Greene M, Crowley W. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med 1994;331:244-9. 2. Friedler S, Mashiach S, Laufer N. Births in Israel resulting from
12.
in-vitro fertilization/embryo transfer, 1982-1989: National Registry for the Israeli Association for Fertility Research. Hum Reprod 1992;7:1159-63. Medical Research Council Party on Children Conceived by In Vitro Fertilisation. Births in Great Britain resulting from assisted conception, 1978-87. BMJ 1990;300:1229-33. Bernasko J, Lynch L, Lapinski R, Berkowitz R. Twin pregnancies conceived by assisted reproductive techniques: maternal and neonatal outcomes. Obstet Gynecol 1997;89:368-72. Cunningham FG, MacDonald PC, Leveno KJ, Gant NF, Gilstrap LC. Williams’ obstetrics. 19th ed. Norwalk (CT): Appleton & Lange; 1993. Rizk B, Doyle P, Tan SL, Rainsbury P, Betts J, Brinsden P, et al. Perinatal outcome and congenital malformations in in-vitro fertilization babies from the Bourn-Hallam group. Hum Reprod 1991;6:1259-64. Tan SL, Doyle P, Campbell S, Beral V, Rizk B, Brinsden P, et al. Obstetric outcome of in vitro fertilization pregnancies compared with normally conceived pregnancies. Am J Obstet Gynecol 1992;167:778-84. Thorp J, Turney L, Bowes W. Outcome of multifetal gestations: a case-control study. J Matern Fetal Med 1994;3:23-6. Lipitz S, Seidman D, Alcalay M, Achiron R, Mashiach S, Reichman B. The effect of fertility drugs and in vitro methods on the outcome of 106 triplet pregnancies. Fertil Steril 1993;60:1031-4. Petersen K, Hornnes PJ, Ellingsen S, Jensen F, Brocks V, Starup J, et al. Perinatal outcome after in vitro fertilization. Acta Obstet Gynecol Scand 1995;74:129-31. Olivennes F, Kadhel P, Rufat P, Fanchin R, Fernandez H, Frydman R. Perinatal outcome of twin pregnancies obtained after in vitro fertilization: comparison with twin pregnancies obtained spontaneously or after ovarian stimulation. Fertil Steril 1996;66:105-9. Brandes J, Scher A, Itzkovits J, Thaler I, Sarid M, GershoniBaruch R. Growth and development of children conceived by in vitro fertilization. Pediatrics 1992;90:424-9.