Impact of Advanced Maternal Age on Pregnancy Outcome

ORIGINAL ARTICLES Impact of Advanced Maternal Age on Pregnancy Outcome Muhieddine ａＮＭｾ Seoud, M.D.,' Anwar H. Nassar, M.D.,' Ihab M. Usta, M.D.,' Ziad Melhem, M.D.,' Alia Kazma, M.S.,' and Ali M. Khalil, M.D.' ABSTRACT The aim of this study was to compare the pregnancy outcome and delivery complications in women 40 years or older (cases) to that of women 20 to 30 years old (controls). Over a 5-year period, 319 cases had a singleton delivery in our institution. These women were compared with 326 controls. Parity was significantly higher in cases compared with controls (3.2 vs. 1.8). Advanced maternal age, compared with younger age, was associated with significantly higher rates of preterm delivery (16.0 vs. 8.0%), cesarean delivery (CS) (31.3 vs. 13.5%), and the occurrence of one or more antepartum complications (29.5 vs. 16.6%). When the two groups were subdivided according to parity, rates of preterm delivery, CS, preeclampsia, gestational diabetes, chronic hypertension, and labor induction were each significantly higher among older multiparas compared with control multiparas. However, only preterm delivery, CS rates, and uterine fibroids were found to be significantly higher in older nulliparous compared with young nulliparous women. We conclude that multiparous women at least 40 years old have a higher antepartum complication rate including intrauterine fetal death compared with younger women. KEYWORDS: Advanced maternal age, pregnancy outcome An increasing number of women are delaying their childbirth because of social, economical, and educational factors. In developed countries, women are more involved with their professional career and thus delay their childbearing until the fourth and fifth decade, and most of them are nulliparous at the time of delivery. In developing countries, most of these women are multiparous. Women above the age 35 have traditionally been termed "elderly gravidas."1,2 Recently, more interest has been focused on women who are more than 40 years old especially with the widespread use of as- American Journal oJPerinatology, Volume 19, Number 1,2002. Address for correspondence and reprint requests: Dr. Muhieddine A.-F. Seoud, American University of Beirut, 850 Third Avenue, New York, NY 10022. lDepartment of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon. Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0735-1631,p;2002,19,01,001,008,ftx,en;ajp36770x. 1 2 AMERICAN JOURNAL OF PERINATOlOGY/VOLUME 19, NUMBER 1 2002 sisted reproductive technologies. There are several reports of pregnancies with egg donation even in postmenopausal women above the age of 50.3,4 Only a few years ago, such women were discouraged from getting pregnant because of the higher maternal and perinatal morbidity and mortality.I,2,S However, recently many studies have shown a favorable outcome in such elderly pregnant women. 6,7 We, thus, conducted our study to try to determine the frequency of adverse obstetrical outcome in women 40 years or older in comparison with women 20 to 30 years old at our institution. MATERIALS AND METHODS Between January 1992 and December 1996, 329 women 40 years or older (cases) were delivered of a singleton pregnancy beyond 20 weeks of gestation at the American University of Beirut Medical Center. These women were compared with another group of 329 women (controls), between the ages of 20 to 30 years, who delivered immediately after each case. After excluding 13 patients with incomplete data, 319 cases and 326 controls were entered for analysis. Cases and controls were matched for parity, (nulliparous to nulliparous and multiparous to multiparous). Nulliparas included women who had not previously delivered a viable fetus (> 24 weeks of gestation). Multiparas included women who had at least one prior pregnancy that progressed beyond 24 weeks of gestation, regardless of the actual parity number. Multiple gestations, with their inherent increased risk of adverse outcome,S were excluded. We studied the following pregnancy complications and outcomes: preterm delivery (defined as delivery at <37 weeks of gestation), chronic hypertension, gestational diabetes, preeclampsia, fibroid uterus, intrauterine growth restriction (defined as fetal weight <5th percentile for gestational age), placental abruption, operative vaginal delivery, cesarean delivery, birth weight, Apgar score at 5 minutes <7, congenital malformation, and intrauterine fetal death (IUFD). The same variables were compared after stratification according to parity. Data analysis was performed using SPSS statistical program. Independent sample Student's t-test was used for comparison of means of continuous variables with normal or approximately normal distributions. Discrete variables were analyzed by using Chi-square analysis for assessment of association or for comparison of independent proportions. A p value of <0.05 was considered statistically significant. Multiple stepwise logistic regression analysis was used to identify the multivariate predictors of the following adverse outcomes: cesarean section (CS), preterm delivery, and obstetrical complications (gestational diabetes, preeclampsia, and placental abruption). The independent variables included in the model were maternal age (at least 40 years or 20 to 30 years) and parity (nulliparous or multiparous) and relevant co-variates. RESULTS The mean age of women above 40 was 41.7 ± 2.1 years compared with 26.5 ± 3.2 years in the control group. Whereas 9.4% of the patients over age 40 had used assisted reproductive technology, this was used in only 2.1% of the control group (p = 0.000). Gravidity (5.2 ± 3.2 vs. 3.2 ± 1.6; p = 0.000) and parity (3.2 ± 2.7 vs. 1.8 ± 1.3; p = 0.000) were significantly higher in cases compared with controls. The mean gestational age at delivery was significantly lower in the study group (38.1 ± 3.1 weeks vs. 38.8 ± 2.8 weeks;p = 0.011). Although more cases required induction compared with controls (15.4 vs. 9.5%; P = 0.000), there was no significant difference in the rate of operative vaginal delivery (24.7 vs. 29.4%) or in the duration of labor (374 ± 244 minutes vs. 373 ± 281 minutes). Inductions were done for a medical or obstetrical indication in 65.3% of cases versus 41.9% of controls. Cesarean delivery was significantly higher in cases compared to controls (n = 100; 31.3% vs. n = 44; 13.5%). The most frequent in- ADVANCED MATERNAL AGE ON PREGNANCY OUTCOME/SEOUD ET AL r dications for CS in cases and controls were prior CS (43.2 vs. 50.0%), nonreassuring fetal tracing (16.8% vs. 15.9%), abnormal presentation (11.6% vs. 18.2%), and arrest disorders (10.5 vs. 4.5%), respectively. Moreover, parity did not seem to affect the indication for CS in either group. Advanced maternal age was associated with a higher rate of pregnancy complications including preterm delivery, gestational diabetes, preeclampsia, chronic hypertension, and uterine myomas compared with controls (Table 1). There was one maternal death in the advanced maternal age group. This was a 43-year-old multigravida with no prenatal care who presented at 39 weeks' gestation with eclampsia and was delivered by cesarean section of a live female newborn with Apgar scores of 3 and 4 at 1 and 5 minutes, respectively. Her postpartum course was complicated by intracerebral hemorrhage to which she succumbed. Table 2 summarizes the perinatal outcome variables. The study group had a significantly higher number of IUFDs. Mter excluding the 2 study pa- 3 --4 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 19, NUMBER 1 2002 Table 4 Perinatal Outcome in Pregnancies Above the Age of 40 Years: Analysis by Parity Nulliparous ul Multiparous :::0:40 Years n= 53 20-30 Years n= 51 Birth weight (g)t 3075 ± 804 5-min Apgar score <7 (%) 2.0 Congenital malformation (%) Intrauterine fetal death (%) hi nl p :::0:40 Years n= 266 20-30 Years n= 275 P n: 3228 ± 628 0.460 3163 ± 757 3214 ± 630 0.228 0.0 0.05* 15 12 0.345 ti d 19 0.0 0.977* 19 0.7 0.430 5.6 19 0.664 5.3 11 0.014 II *Cells with expected frequency <5 are more than 33%. tData presented as means ± standard deviation. aJ tients where the IUFD occurred intrapartum during termination for a prenatally diagnosed chromosomal abnormality (trisomy 21), the mean gestational age at intrauterine fetal death was 31.2 weeks in the cases versus 23.3 weeks in the controls. All 4 fetal weeks' deaths in the control group occurred at ｾＲＴ gestation while only (4/17) 24.0% of such deaths occurred at this gestational age in the cases. Of the remaining 13 IUFD, 8 (61.5%) did not have an identi- fiable risk factor (preeclampsia, diabetes, postdates or prematurity). In Tables 3 and 4, the obstetrical, medical, and perinatal complications were analyzed according to parity. Multiparous cases had significantly higher rates of preterm delivery, CS, preeclampsia, gestational diabetes, chronic hypertension, and labor induction compared with multiparous controls. However, only preterm delivery, CS rates, and a ( 2 VI o c h s r, c Table 5 Maternal Morbidity in Pregnancies Over 40: Results of the Multiple Regression Models OR 95%CI Risk factors for cesarean delivery I Age (V) 20-39 lOa :::0:40 2.67 177-4.02 0.0000 153-3.99 0.0002 5.32-16.6 0.000 102-3.06 0.04 3.09-15.7 0.000 146-3.16 0.000 Obstetric complications None lOa Single or multiple 2.47 Risk factors for preterm delivery Obstetrical complications None lOa Single or multiple 9.40 Age (V) 20-39 lOa 2:40 177 Risk factors for obstetrical complications Medical complications No lOa Yes 6.98 Age (V) 20-39 lOa :::0:40 2.14 ADVANCED MATERNAL AGE ON PREGNANCY OUTCOME/SEOUD ET AL v i :l uterine fibroids were found to be significantly higher in nulliparous cases compared with younger nulliparas. The only significant difference in perinatal outcomes was a higher rate of IUFD in multiparous cases compared with multiparous controls despite similar birth weights, rates of depressed newborns, and congenital malformations (Table 4). In nulliparous women, the numbers in each category were too small to draw meaningful conclusions. The results of the multiple stepwise regression analysis are listed in Table 5. Parity was not found to have a significant impact on the variables analyzed. The OR for a CS delivery was 2.7 in women above 40, 2.5 with one or more obstetrical complications. In addition, the OR for preterm delivery was 1.8 for women above 40, and 9.4 in the presence of an obstetrical complication. Moreover, for obstetrical complications the OR was 7.0 for patients who had preexisting medical complications (hypertension, anemia, thyroid disorders, cardiac diseases, renal disorders, diabetes), while the OR for obstetrical complications was 2.1 in women over 40. DISCUSSION Until recently, advanced maternal age was considered one of the risk factors for an adverse maternal and perinatal outcome. However, more women in developed countries are delaying their childbirth for various reasons and recent studies have reported a more favorable outcome. 6,7 In developing countries, pregnancies above 40 are, in most cases, just a continuation of the reproductive life of these women. This study is one of the largest to compare a group of women at least 40 years old, to a matched group, aged 20 to 30, who are usually considered to have the lowest maternal and perinatal morbidity and mortality. The majority of women in the study group were multiparous (83.7%), a rate similar to reports from the same region.7 Despite controlling for parity, the mean parity was significantly higher in elderly women compared with controls. This is due to the fact that multiparity was defined as at least one previous pregnancy that has reached viability stage, not taking into account the actual parity number. Medical or obstetrical indications accounted for 65.3% of labor inductions in cases versus 41. 9% in controls. This might have contributed to the higher incidence of labor induction seen in cases compared with controls. Pregnancy complications were twice more likely to occur in elderly pregnant women compared with controls. Preterm deliveries were twice as common in older women. The difference in preterm delivery rate remained significantly higher in cases even after excluding patients with medical or obstetrical indications for induction (11.3 vs. 4.6%), indicating an inherent increased risk for spontaneous preterm labor in elderly women. The incidence of gestational diabetes' preeclampsia, chronic hypertension was also higher in the cases. It is worth mentioning that testing for gestational diabetes is universal for all our obstetrical patients regardless of age. Thus, the higher incidence of gestational diabetes observed in the elderly women is not secondary to understating the incidence in the younger women. The reasons for this increased frequency of complications vary according to the complication. Chronic hypertension and gestational diabetes are easier to explain, as both are affected by age. The incidence of chronic hypertension increases with age, and older women have more difficulty with their carbohydrate metabolism with most studies suggesting at least doubling of the incidence.7,8 Moreover, preeclampsia is reported to be more frequent at the extremes of reproductive age. The etiology of preeclampsia is still unclear and it is frequently difficult to separate preexisting hypertension from pregnancy induced hypertension. In fact, some studies did not find a higher incidence of preeclampsia in older women. 9 In our series, preeclampsia, chronic hypertension, and gestational diabetes were more frequent in multiparous elderly women compared with multiparous controls. This did not hold true for 5 6 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 19, NUMBER 1 2002 nulliparas. The cesarean section rate was 2.5 times higher in our study groups compared with controls and this was true for both nulliparous and multiparous patients. This has been reported in virtually all studies. 7,10 The most frequent indications in both groups were repeat CS, followed by nonreassuring fetal tracing, and abnormal presentation. However, the chance of delivering by CS was almost doubled for any indication in cases compared with controls. In some studies the incidence of abnormal labor is higher in older patients, the basis of which is not clear. 6 This was not demonstrable in our study. The presence of a higher rate of obstetrical complications and chronic medical illnesses in the study group might have contributed indirectly to the higher incidence of CS. These patients are more likely to have elective repeat CS and abnormal fetal heart tracings. Although 15.2% of cases had cesarean delivery for a nonreassuring fetal heart tracing compared with 14.3% in controls, there was no difference in the percentage of Apgar score <7 at 5 minutes in both groups which might be explained by the fact that physicians might have a lower threshold to perform a CS in this group of patients with a "precious pregnancy." This might have been a contributing factor to the rather high incidence of cesarean delivery in cases knowing that the average rate of primary CS is 14.4% while the rate of total CS is about 23.1% at our institution. Perinatal outcome was also significantly affected by age. Although the incidence of intrauterine growth restriction was similar in both groups in our series, older women had a higher incidence of intrauterine fetal death and infants with Apgar scores <7 at 5 minutes. Even after excluding the 4 cases of fetal death occurring :524 weeks' gestation and the 5 cases in which there was an identifiable risk factor for fetal death, 61.5% of cases of IUFD occurred without an identifiable risk factor in the advanced maternal age group versus none in the controls. If this is reproduced in other studies, then routine antenatal fetal heart resting might have to be recommended in pregnant women at age 40 or more. This increased risk has been reported in some, 8 but not all previous studies. 6 The higher incidence of medical and obstetrical complications might explain some, but not all, cases of intrauterine fetal death. Congenital malformations were diagnosed antenatally in most of the cases and were found to be similar in cases and controls. Both minor and major anomalies, defined as anomalies that had a major impact on neonatal morbidity or mortality such as polycystic kidney disease, were included. Only a minor anomaly (cleft lip) was incidentally found in 1/17 of all the intrauterine fetal deaths that occurred in the elderly group. Thus, congenital anomalies were not a major contributor to the higher incidence of fetal death seen in the cases. In some studies, the incidence of chromosomal abnormalities was similar in elderly and younger women, and this was attributed to the aggressive prenatal genetic counseling and screening that these women have in developed countries. 6 In our population, the acceptance rate of prenatal diagnosis is low especially in the young population l l and this might explain why the 3 cases of chromosomal abnormalities were seen in the advanced maternal age group (0.9%). Furthermore, the results of the multiple regression analysis emphasized the importance of each variable in terms of the outcome. It is evident that as far as the high CS rate and the preterm delivery, age and obstetrical complications are more important than parity. Medical complication are more important than age in relation to the development of obstetrical complications. The above data is important to counsel women over the age of 40 who are ｧｮｩｲｾ､ｳｯ｣ pregnancy. REFERENCES 1. Kane SH. Advanced maternal age and the primigravida. Obstet GynecoI1967;29:409-414 2. Hansen JP. Older maternal age and pregnancy outcome: a review of the literature. Obstet GynecoI1986;41:726-712 3 4 5 6 7 ADVANCED MATERNAL AGE ON PREGNANCY OUTCOME/SEOUD ET AL i :l v v s e .1 r e .t r d II II e )f It 'e 'e lｬｾ g a. a l2 3. Sauer MV, Paulson RJ, Lobo RA. Pregnancy in women 50 or more years of age: outcomes of 22 consecutively established pregnancies from oocyte donation. Fertil Steril 1995;64:11-15 4. Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after natural menopause. Lancet 1993;341:321-323 5. Seoud M, Toner JP, KruithoffC, Muasher S]. Outcome of twin, triplet and quadruplet IVF pregnancies: the Norfolk experience. Ferti! SteriI1992;57:825-834 6. Bianco A, Stone J, Lynch L, Lapinsky R, Berkowitz G, Berlowitz RL. Pregnancy outcome at age 40 and older. Obstet GynecoI1996;87:917-922 7. Dulitzki M, Soriano D, Schiff E, Chetrit A, Mashiach S, Seidman DS. Effect of very advanced maternal age on 8. 9. 10. 11. pregnancy outcome and rate of Cesarean delivery. Obstet GynecoI1998;92:935-939 Naeye RL. Maternal age, obstetric complication, and the outcome of pregnancy. Obstet Gynecol 1983;61:210-215 Yassin SY, Beydoun SN. Pregnancy outcome at greater than or equal to 20 weeks' gestation in women in their 40s: a case-control study. J Reprod Med 1988;33:209-212 Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: pregnancy outcome in 24,032 cases. Obstet GynecoI1999;93:9-14 Zahed L, Nabulsi M, Bou-Ghanem M, Usta 1. Acceptance of prenatal diagnosis for genetic disorders in Lebanon. Prenat Diagn 1999;19:1109-1112 7