Maternal and neonatal morbidity associated with in vitro fertilization

Maternal and neonatal morbidity associated with in vitro fertilization Christopher P. Tallo, MD, Betty Vohr, MD, William Oh, MD, Lewis P. Rubin, MD, David B. Seifer, MD, a n d Ray V. Haning Jr., MD From the Cincinnati Children's Hospital, Cincinnati, Ohio, and the Neonatal Follow-up Clinic, Department of Pediatrics and Division of Reproductive Endocrinology, Brown University School of Medicine, Rhode Island Hospital, and Women and Infants" Hospital of Rhode Island, Providence

Objective: The purpose of this case-control study was to examine the maternal and neonatal morbidities associated with in vitro fertilization (IVF) in a single large teaching hospital. It was hypothesized that IVF mothers would have more perinatal complications and IVF infants would have higher mortality and morbidity rates than non-IVF control subjects. Methods: One hundred forty-three gestations resulting from 101 IVF pregnancies, which included singletons (n = 62), twins (n = 72), and triplets (n = 9), were compared with equal numbers of non-IVF control subjects. Each pregnancy was matched by maternal age, race, insurance type, neonatal gender, order of gestation, order in delivery, and date of delivery (___6months). Among the 143 matched gestations, six IVF and seven control infants died, leaving 137 IVF and 136 control neonates for comparison. Results. The IVF mothers had more pregnancyqnduced hypertension (21% vs 4%), premature labor (44% vs 22%), labor induction (25% vs I%), and preterm delivery (37% vs 21%). The IVF infant survivors had a lower mean (±SD) birth weight (2623 ± 857 gm vs 3006 ± 797 gm), more frequent occurrence of low birth weight (42% vs 27%), and shorter gestations (37 ± 4 vs 38 ± 3 weeks). The IVF infants had longer hospitalizations, more days of oxygen therapy, more days of continuous positive airway pressure, and an increased prevalence of respiratory distress syndrome, patent ductus arteriosus, and sepsis. Conclusions: Couples who undergo IVF appear to be at increased risk of having low birth weight and preterm infants, and multiple gestations account for most of the neonatal morbidities. Both the mothers who conceive multiple gestations by means of IVF and their neonates are at an increased risk of having multiple morbidities. (J PEDIATR1995;127:794-800) A wide array of reproductive techniques now exist to assist couples with conception. Induction of ovulation, in vitro fertilization, gamete intrafallopian transfer, and zygote intrafallopian transfer are a few of the modalities now in use to increase the probability of becoming pregnant. A recent

increased incidence of multiple-gestation pregnancies is a direct result of the use of these interventions.1 In IVF, an egg, aspirated under ultrasound guidance from the ovary, is fertilized in vitro and transferred transcervically into the uterIVF PHI

Submitted for publication Feb. 17, 1995; accepted June 23, 1995. Reprint requests: Betty R. Vohr, MD, Department of Pediatrics, Women and Infants' Hospital, 101 Dudley St., Providence, RI 02905. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$5.00 + 0 9/23/67321

794

In vitro fertilization Pregnancy-inducedhypertension

ine cavity, where implantation takes place. 2 Several embryos are typically transferred; thus the multiple gestation rate is increased by as much as 20-fold, yielding an estimated IVF multiple gestation rate of 15% to 30%. 3 Multiple gestation

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795

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Figure. Study subject recruitment, May 1988 through March 1993. is associated with low birth weight and prema~Jrity, 4, 5 and IVF pregnancies also have been associated with higher rates of fetal loss, low birth weight, premature delivery, and perinatal morbidity. 6-u Recently, questions have been raised about safety, cost, and efficacy of these reproductive techniques.3, 12 The objective of this study was to assess the maternal and neonatal morbidities in a large IVF program and to compare them with those in a closely matched case-control pregnancy group. We hypothesized that IVF pregnancies would be associated with higher maternal and neonatal morbidity rates. METHODS

This case-control study was conducted at Women and Infants' Hospital, Providence, R.I. The study sample was derived from 763 IVF procedures performed between May 1, 1988, and March 30, 1993, by the Women and Infants' Hospital Department of Reproductive Endocrinology. One hun-

dred thirteen IVF pregnancies progressed beyond the twentieth week of gestation. This sample included multiple gestations that had been reduced in number (12 IVF; 2 control), electively or spontaneously, before 20 weeks. Records were available for 101 IVF study pregnancies, which resulted in 143 IVF gestations, including 62 singleton pregnancies, 36 twin pregnancies, and 3 triplet pregnancies (Figure). Each IVF mother was matched to a control mother by age (-+3 years), race, type of insurance provider (public or private), and order of gestation (singleton, twin, or triplet). Each IVF infant was matched by gender, order of delivery in multiple gestations, and date of delivery (_+6 months). Death was defined as stillbirth or neonatal death. Six IVF and seven control infants died, leaving 137 IVF and 136 control infant survivors for comparison of morbidities. The survivors included 62 singleton and 68 twin infants in each group, and 7 IVF triplets and 6 control triplets. Data on infertility diagnoses, preexisting medical condi-

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Tallo et al.

The Journal of Pediatrics November 1995

T a b l e I. Maternal characteristics Characteristic

Age (yr) (Range) White race Private insurance Gravida 1 >1 Para 0 l ---2

T a b l e III. Complications of labor and delivery

IVF (n = 101)

Control (n = 101)

33 -+ 4 (25-43) 99 101

33 _+4 (25-41) 101 101

NS NS

54 47

28 73 /

0.01

83 15 3

34 41 ]. 26 J

IVF

Control

p

Complication

(n = 101)

(n = 101)

p

NS

Failure to progress Prolonged rupture of membranes Maternal fever Induction of labor Cesarean section Primary Secondary

8 14 3 25 50 45 5

3 6 2 1 29 21 8

NS NS NS 0.0001* NS*

0.001

Values are expressed as mean -+ SD. NS, Not significant. Table

Chi-square analyses. NS, Not significant. *The effects remained significant for induction of labor but not cesarean section after control for parity with hierarchicallogisticregression analyses. T a b l e IV. Maternal factors related to maternal morbidities

II.Prenatal complications IVF

Complication

Polyhydramnios Oligohydramnios Pregnm~cy-induced hypertension Intrauterine growth retardation Gestational diabetes mellitus Premature cervical dilation Premature labor Tocolysis

IVF Control (n = 101) (n = 101)

3 4 21 2 16 5 44 23

3 1 4 2 9 1 22 14

p

NS NS 0.0002* NS NS NS 0.001' NS

Chi-square analyses. NS, Not significant. *The effectsremained statisticallysignificantafter controllingfor parity using hierarchical logistic regression analyses. tions, prenatal complications, complications of labor and delivery, and neonatal outcomes were obtained from maternal prenatal records, hospital records, and neonatal records. Length of gestation for control infants was calculated as the difference between the date of the last menstrual period and the date of birth, concordant with early ultrasound and neonatal examinations. For IVF pregnancies, length of gestation was calculated by subtracting 14 days from the date of the embryo transfer. Preterm delivery was defined as any delivery that occurred before 37 weeks of gestation. Infants were classified by birth weight as appropriate in size for gestational age, small for gestational age, or large for gestational age on the basis of the Colorado Intrauterine Growth Charts. 13 Low birth weight was defined as a birth weight of 2500 gm or less. Multiple neonatal characteristics, including duration of hospitalization, duration of oxygen therapy, days of mechanical ventilation, and days of continuous positive airway pressure were collected. Patent ductus arteriosus was defined as the presence of indicative clinical findings confirmed by echocardiogram. Sepsis was defined as positive results on blood or spinal fluid culture.

PItt present* Primigravida Multiple birth Prepregnancy hypertension Parity ->l Premature labort PIH Multiple birth Prepregnancy hypertension Induction of laboa~ PItt Prepregnancy hypertension Abnoru~al fetal tracing PROM

Control

No.

(%)

No.

(%)

16 10 2 2

(76) (48) (10) (10)

4 4

(100) (100) None None

10 30 3

(23) (68) (7)

3 20

(14) (91) None

10 3 2 3

(40) (12) (8) (12)

None None None 1 (100)

PROM, Premature rupture of membranes. *IVF, n = 21; control, n = 4. tIVF, n = 44; control, n = 22. :~IVF, n = 25; control, n = 1. Statistical methods included analyses of variance with appropriate post hoc tests for continuous variables and chisquare analyses for categorical variables. Because parity was not evenly distributed between the IVF and control study groups and may affect the study outcome variables, all significant findings were reanalyzed with hierarchical logistic regression analyses for categorical outcome variables and hierarchical multiple regression analyses for continuous outcome variables, with the effects of parity partialed out. The study was approved by the W o m e n and Infants' Hospital Institutional Review Board. RESULTS Maternal characteristics. Table I shows the maternal characteristics of the IVF study subjects and control subjects. Thirty-five IVF and control mothers were older than 35 years

The Journal of Pediatrics Volume 127, Number 5

of age. All mothers were white except for two black mothers in the IVF group, and all had private insurance. The two gestations of black infants were both triplets, and racematched control subjects were not available. Fifty-three percent of IVF mothers and 28% of control mothers were classified as primigravid (p <0.01). Primary infertility was diagnosed in 99 IVF mothers. In nearly half of these mothers (48%), the assigned diagnosis was a tubal factor. Male factor infertility (20%), endometriosis (16%), ovulatory factor (1%), uterine factor (1%), and unknown (13 %) accounted for the remaining causes. Two IVF cases had secondary infertility. One control mother had a prior history of infertility but conceived the study gestation with no reproductive assistance. The incidence of known preconception medical conditions, including heart disease (6 IVF subjects, 6 control subjects), chronic hypertension (5 IVF, 2 control), anemia (5 1VF, 1 control), asthma (5 IVF, 4 control), colitis (3 IVF, 2 control), thyroid disease (4 IVF, 4 control), recurrent urinary tract infection (2 1VF, 4 control), systemic lupus erythematosus (2 IVF, 2 control) or other autoimmune disorders (3 IVF, 0 control), and seizure disorder (2 IVF, 1 control), did not differ significantly between IVF and control subjects. Overall, 37% of IVF and 26% of control mothers (not significant) had one or more of the preconception medical conditions. Perinatal course. Table II summarizes the pregnancy complications for the IVF and the control gestations. There was a fivefold greater occurrence of pregnancy-induced hypertension in the IVF group than in the control group; premature labor occurred twice as often. No significant differences were observed in the occurrence of polyhydramnios, oligohydramnios, intrauterine growth retardation, gestational diabetes mellitus, premature cervical dilation, or tocolysis. Complications associated with labor and delivery are reported in Table III. The IVF deliveries were associated with significantly more inductions of labor with oxytocin, and IVF mothers had significantly more cesarean sections. These significant findings were reanalyzed by methods that covaried for parity using hierarchical logistic regression: the effects remained significant for PIH, premature labor, and induction of labor but not for cesarean section. Table IV shows the maternal factors related to maternal morbidities. Multiple birth was the strongest predictor of premature labor and primary cesarean section for both IVF and control patients. PIH was the maternal risk factor most strongly correlated with induction of labor among IVF patients. By chi-square analyses, IVF mothers with singleton pregnancies were at increased risk of PIH (p <0.05), premature labor (p <0.04), and induction of labor (p <0.0001) in comparison with mothers having singleton control pregnancies. Neonatal outcome. Table V shows the characteristics of the IVF and the control neonatal survivors. The groups were

Tallo et al.

797

matched for gender. The IVF infants had lower birth weight, even when singleton and multiple survivor subgroups were considered separately. Gestation was shorter in the total IVF group, and more IVF infants were born preterm. Seventy-one percent of IVF twin and 100% of IVF triplet gestations resuited in low birth weight infants, compared with 43% of twin control gestations (p <0.001) and 83% of triplet control gestations (not significant). More than half (59%) of 1VF twin gestations ended in delivery before 37 weeks, compared with 37% of control twin gestations (p <0.01). IVF infants had a longer hospitalization; this difference was attributed to the multiple gestations (Table V). To rule out confounding effects of maternal parity, we performed hierarchical logistic regression and multiple regression analyses for all newborn outcome variables listed in Table V. After the effects of parity were partialed out, all differences identified between the study groups remained statistically significant. Table VI shows the neonatal morbidities of the IVF and the control subjects. Although the total IVF sample had evidence of more morbidity than control subjects, morbidity of IVF singletons was similar to that of control singletons. The IVF twins received more days of oxygen therapy and more days of therapy with continuous positive airway pressure, and had more frequent respiratory distress syndrome and higher incidences of patent ductus arteriosus and sepsis. The analyses of the triplet data were limited by small sample size; the number of days of oxygen administration was significantly higher for 1VF triplets. DISCUSSION The results of this closely matched case-control study indicate that IVF mothers have more perinatal complications and that morbidity and mortality rates are higher in IVF infants than in a spontaneously conceived control population. The findings are consistent with previous reports on IVF pregnancies. 7-12 Our procedure success rate is consistent with published data. 12 By the criteria of race and socioeconomic status the IVF group was at low risk, but by age, at high risk. Previous reports have suggested that poor obstetric outcome may be attributed to advanced maternal age and previous low parity. 14 Our study groups were closely matched for maternal age, but parity did differ; most IVF mothers were nulliparous before birth of the study subject(s), as one would expect in an IVF population. After control for parity, however, the mothers in our sample remained at greater risk of PIH, premature labor, and induction of labor. Their incidence of P1H was much higher than in the general population and in our study control population. Factors associated with PIH in this IVF population included primigravid status, multiple birth, and prepregnancy hypertension; PIH was the strongest predictor of induction of labor. Although multiple pregnancy was associated with PIH, sin-

798

Tallo et al.

The Journal of Pediatrics November 1995

Table V. Neonatal survivor characteristics and outcome Overall survivors

Characteristic

Male/female Birth weight (gm)* Range (gm) LBW (-<2500 gm): No. (%) Gestational age (wk)* Range (wk) Preterm delivery (<37 wk): No. (%) SGA: No. (%) Hospitalization (days)* Range (days)

Singleton survivors

IVF (n = 137)

Control (n [] 136)

74/63 2623 4- 857 560-4400 58 (42)

73/63 3006 4- 797 1220-5335 37 (27)

37 ÷ 4 24-42 51 (37)

38 -+ 3 32-43 29 (21)

0.002

15 (11) 14 4- 23 2-117

8 (6) 6 -+ 8 1-51

NS 0.0003

p

NS 0.0002 0.008

IVF (n = 62)

Control (n = 62)

38/24 3268 4- 497 2125-4400 3 (5)

36/26 3594 _+511 2030-5335 3 (3)

39 4- 2 34-42 6 (10)

0.009

40 _+ 1 34-43 1 (2)

1 (1.6) 3 4- 1 2-8

1 (1.6) 3 -+ 3 1-21

p

NS 0.0005 NS NS 0.04 NS NS

Analyses of variance. Chi-squareand Fisher exact analyses for categoricalvariables.All significantfindings were reexaminedin analysesthat covariedfor parity. Hierarchical logistic regression and Hierarchicalmultipleregressionanalyses were used. All effects remained significantwhen parity was statisticallycontrolled. NS, Not significant;LBW, low birth weight; SGA, small for gestational. *Values are expressed as mean +- SD.

Table VI. Neonatal morbidity during the study period Singleton survivors

Overall survivors Characteristic

IVF (n = 137)

Control (n = 136)

p

IVF (n [] 62)

Control (n = 62)

p

Days of oxygen therapy Days of mechanical ventilation Days of CPAP RDS treated with surfactant PDA treated with indomethacin Culture-proven neonatal sepsis

3.2 4- 16 2.4 4- 14 1.6 4- 7 17 (12%) 14 (10%) 6 (4%)

0.2 4- 1 0.2 4- 1 0.3 4- 2 5 (4%) 3 (2%) 0

0.03 NS 0.04 0.007 0.006 0.014

0.1 4- 0.3 0 0 0 0 0

0.2 + 0.8 0.t 4- 0.6 0.3 -+ 0.3 1 (2%) 0 0

NS NS NS NS NS NS

Analyses of variance. Chi-square and Fisher exact analyses for categorical variables. NS, Not significant; CPAP,continuous positive airway pressure; RDS, respiratory distress syndrome; PDA, patent ductus artefiosus.

gleton IVF pregnancies also showed greater risk of PIH, premature labor, and primary caesarean section. Doyle et al.ll reported that the risks of prematurity, low birth weight, and small size for gestational age were independent of both age and parity. After matching for age, race, type of insurance, and date of delivery, and controlling for parity, we also identified increased incidences of prematufity, low birth weight, and small size for gestational age in the IVF population, consistent with the findings of Doyle et al.u and indicating that these complications are secondary to the infertility status of the couple or the IVF treatment. Williams et al. 15 demonstrated an association between low birth weight and maternal infertility history. Further, a history of infertility predisposes infants to intrauterine growth retardation and shorter gestational ages) 6 In our study population, intrauterine growth retardation did not differ between groups. It is difficult to identify a cohort of women with a history of infertility who spontaneously conceive for comparison with

IVF mothers. One study reported that IVF pregnancies did not have a higher rate of prematurity in comparison with spontaneously conceived pregnancies in women with a history of infertility, 17 again supporting the important contribution of infertility tO risk. In vitro fertilization causes high numbers of multiple births,l, 3, 9,18-20 which increases the risk for perinatal and neonatal complications. Dividing the study IVF neonates into subgroups of singletons and multiples (twins and triplets) allowed us to evaluate neonatal complications relative to order of gestation. Infant deaths were evenly distributed between the IVF and the control pregnancies, and we conclude that neonatal deaths were associated with multiple birth rather than with IVF per se. After the effects of parity were partialed out, the prematurity rate remained higher among IVF triplets, twins, and singletons. Two large independent studies TM 12 that examined the morbidity associated with IVF singleton gestations found a

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Tallo et al.

Triplet survivors

Twin survivors IVF (n = 68)

Control (n = 68)

33/35 2212 -+ 629 880-3945 48 (71)

35/33 2571 -+ 644 i220-3785 29 (43)

35 -+ 3 28-41 40 (59)

37 -+ 3 32-40 25 (37)

13 (19) 17 -+ 20 2-78

7 (10) 9 -+ 10 2-51

799

p

NS 0.001 0.001 0.03 0.01 NS 0.002

IVF (n = 7)

Control (n = 6)

3/4 895 -+ 198 560-1060 7 (100)

2/4 1950 -+ 457 1450-2555 5 (83)

NS 0.0002

27 -+ 2 24-28 7 (100)

34 -+ 2 32-36 3 (50)

0.0001

1 (14) 82 -+ 31 54-117

0 17 -+ 11 4-30

NS 0.0006

Twin survivors

p

NS

0.03

Triplet survivors

IVF (n = 68)

Control (n [] 68)

p

IVF (n = 7)

0.7 -+ 2 0.6 -+ 2 2.6 -+ 9 12 (18%) 10-(15%) 4 (6%)

0.1 -+ 0.4 0.2 -+ 1 0.4 -+ 2 2 (3%) 1 (2%) None

0.04 NS 0.059 0.006 0.005 0.045

54 +_47 40 _+54 6-+8 5 (71%) 4 (57%) 2 (29%)

greater risk of prematurity than in control infants but did not show a greater risk of low birth weight or small size for gestational age. Although singletons had significantly lower birth weight than control singletons, the average birth weight for the IVF singleton group was well within the normal range. Therefore we conclude that this difference does not pose any clinically relevant risk to IVF singletons. However, IVF multiple gestations are plagued by significantly higher overall morbidity rates. Boulot et al. 18 similarly found that 26 IVF triplet pregnancies had an average gestational age of 34 weeks with a mean birth weight of 1880 gin, leading to a perinatal death rate of 4%; they considered this outcome to be favorable in comparison with naturally conceived triplet gestations. W e conclude that IVF multiple gestations are associated with a significantly greater risk of low birth weight and the morbidity associated with prematurity. Two strategies have been proposed for reducing the level of maternal and neonatal morbidity associated with IVF. First, the number of high-order gestations created by IVF

Control (n = 6)

2+3 1+ 1 2-+3 2 (33%) 2 (33%) 0

p

0.02 NS NS NS NS NS

could be reduced if fewer embryos were transferred per IVF cycle. This approach, however, would reduce the probability that a pregnancy would be successfully achieved with IVF, increase the probability that a couple would have to participate in repeated IVF cycles, and increase the substantial economic burden associated with treating infertility. This strategy would, however, decrease the medical, emotional, and financial hardships associated with high-order gestations. Second, fetal reduction has been used as a means of decreasing morbidity associated with high-order IVF pregnancies. 19 This alternative may not be available to couples who are ethically opposed to abortion. In addition, this procedure may place the pregnancy at risk of miscarriage. Recently, two studies have drawn attention to the high economic cost of successful delivery with IVF. 3' 12 Callahan et al. 3 reported that the primary contributor to cost is multiple gestation and concluded that if all multiple-gestation IVF pregnancies had been singleton pregnancies, the predicted health care savings in one hospital would have been

800

Tallo et al.

The Journal of Pediatrics November 1995

3 million dollars annually. The equation for cost-effective infertility treatment needs to include a mechanism for reducing the incidence of premamrity. Long-term neurodevelopmental results are also an indicator of the effectiveness of IVF. a°' at Brandes et al.2t examined the 5-year neurodeveiopmental outcomes after IVF and found that these children did not differ from their naturally conceived counterparts. Our data, however, which demonstrate an increased risk of prematurity and low birth weight, indicate that outcome may be less favorable than previously reported. The higher social and economic status of ramifies who use IVF procedures may, however, have a positive impact on developmental outcome despite the increased risk of pregnancy and neonatal morbidities. The assistance of Irving Dark with the data analyses is gratefully acknowledged. REFERENCES

1. Seoud MA, Kruithoff C, Muasher SJ. Outcome of triplet and quadruplet pregnancies resulting from in vitro fertilization. Eur J Obstet Gynecol Reprod 13iol 1991;41:79-84. 2. Seibel MM. A new era in reproductive technology. N Engl J Med 1988;318:828-34. 3. Callahan TL, Hall JE, Ettuer SL, Christiansen CL, Greene MF, Crowley WF. 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. 4. Botting 13J, Davies IM, MacFarlane AJ. Recent trends in the incidence of multiple births and associated mortality. Arch Dis Child 1987;62:941-50. 5. Luke t3, Keith LG. The contribution of singletons, twins and triplets to low birth weight, infant mortality and handicap in the United States. J Reprod Med 1992;37:661-6. 6. Lancaster PAL and Australian In Vitro Fertilization Collaborative Group. High incidence of preterm births and early losses in pregnancy after IVF. 13MJ 1985;291:1160-3. 7. Berai V, Doyle P, MRC Working Party on Children Conceived by In Vitro Fertilisation. Births in Great Britain resulting from assisted conception, 1978-87. BMJ 1990;300:1229-3.

8. Rufat P, Olivennes F, de Mouzon J, Deban M, Frydman R. Task force report on the outcome of pregnancies and children conceived by in vitro fertilization, France 1987-1989. Fertil Steril 1994;61:324-30. 9. Seoud MA, Toner JP, Kruithoff C, Muasher SJ. Outcome of twin, triplet, and quadruplet in vitro fertilization pregnancies: the Norfolk experience. Fertil Steril 1992;57:825-34. 10. Wang JX, Clark AM, Kirby CA, et al. The obstetric outcome of singleton pregnancies following in vitro fertilization/gamete intra-fallopian transfer. Hum Reprod 1994;9:141-6. 11. Doyle P, Beral V, Macononchie N. Preterm delivery, low birth weight and small-for gestational-age in livebom singleton babies resulting from in-vitro fertilization. Hum Reprod 1992; 7:425-8. 12. Neumann PJ, Gharib SD, Weinstein MC. The cost of a successful delivery with in vitro fertilization. N Engl J Med 1994;331:239-43. 13. Lubchencho LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from livebom birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793-800. 14. Hershlag A, Kaplan EH, Loy RA, DeChemey AH, Lavy G. Heterogeneity in patient populations explains differences in in vitro fertilization programs. Fertil Steril 1991;56:9i3-7. 15. Williams M, Goldman M, Mittendorf R, Monson R. Subfertility and the risk of low birth weight. Fertil Steril 1991;56:66871. 16. Ghazi H, Spielberger C, Kallen B. Delivery outcome after infertility: a registry study. Fertil Steril 1991;55:726-32. 17. Sannders DM, Matthew W, Lancaster PAL. The Australian register: current research and future role--a preliminary report. Ann NY Acad Sci 1988;541:7-12. 18. Boulot P, Hedon B, Pelliccia G, et al. Favourable outcome in 33 triplet pregnancies managed between 1985-1990. Eur J Obstet Gynecol Reprod Biol 1992;43:123-9. 19. Melgar CA, Rosenfeld DL, Rawlinson K, Greenberg M. Perinatal outcome after multifetal reduction to twins compared with nonreduced multiple gestations. Obstet Gynecol 1991;78:763-7. 20. Cohen J, Mayaux MJ, Guitrand Moscata ML. Pregnancy outcomes after in vitro fertilization: a collaborative study on 2342 pregnancies. Ann NY Acad Sci 1988;541:1-6. 21. Brandes JM, Sher A, Itzkovits J, Thaler I, Sarid M, GeroshoniBaruch R. Growth and development of children conceived by in vitro fertilization. Pediatrics 1992;90:424-9.

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