Human Reproduction vol.15 no.11 pp.2433–2437, 2000

The risks associated with pregnancy in women aged 35 years or older

M.Jolly1,5, N.Sebire2, J.Harris3, S.Robinson1 and L.Regan4,6 1Section

of Endocrinology and Metabolic Medicine (The Mint Wing), ICSM at St Mary’s, 2Department of Pathology, St Mary’s Hospital, Paddington, London, W2 1NY, 3Department of Epidemiology, ICSM at St Mary’s, Paddington, London, W2 1PG, and 4Department of Reproductive Science and Medicine, ICSM at St Mary’s, Paddington, London, W2 1NY, UK 5Present

address: Centre for Fetal Care, Queen Charlotte’s Hospital, Goldhawk Road, London W6 0XG, UK 6To

whom correspondence should be addressed at: Department of Reproductive Science and Medicine, ICSM at St Mary’s, Paddington, London W2 1NY, UK. E-mail: [email protected]

The obstetric risks of adverse outcome during pregnancy in women aged ≥35 years were quantified using a retrospective analysis of data from 385 120 singleton pregnancies in the North West Thames Region, UK, between 1988 and 1997. A comparison of pregnancy outcome was made on the basis of maternal age at delivery: 18–34 years (n ⍧ 336 462), 35–40 years (n ⍧ 41 327) and women aged >40 years (n ⍧ 7331). Women aged 40 year old women, with adjusted odds ratios (OR) according to age group. Pregnant women aged 35–40 years were at increased risk of: gestational diabetes, OR ⍧ 2.63 [99% confidence interval (CI) 2.40–2.89]; placenta praevia ⍧ 1.93 (1.58– 2.35); breech presentation ⍧ 1.37 (1.28–1.47); operative vaginal delivery ⍧ 1.5 (1.43–1.57); elective Caesarean section ⍧ 1.77 (1.68–1.87); emergency Caesarean section ⍧ 1.59 (1.52–1.67); postpartum haemorrhage ⍧ 1.14 (1.09– 1.19); delivery before 32 weeks gestation ⍧ 1.41 (1.24– 1.61); birthweight below the 5th centile ⍧ 1.28 (1.20–1.36); and stillbirth ⍧ 1.41 (1.17–1.70). Women aged >40 years had higher OR for the same risks. Pregnant women aged ≥35 years are at increased risk of complications in pregnancy compared with younger women. Key words: age/obstetric/outcome/pregnancy/risk

Introduction The number of babies born to women in their late 30s has progressively increased over the past decade (General Register Office for Scotland, 1996). The published data on the risks associated with childbirth at ⬎35 years are inconsistent. It is known that older women are more likely to have pre-existing medical disorders such as diabetes mellitus or hypertension (Hansen, 1986). Some studies have demonstrated an increased © European Society of Human Reproduction and Embryology

incidence of antepartum haemorrhage, malpresentation (Roberts et al., 1994), operative vaginal delivery, Caesarean delivery (Peipert and Bracken, 1993; Cnattingius et al., 1998; Rosenthal and Paterson Brown, 1998), and fetal death (Lehmann and Chism, 1987; Fretts et al., 1995). Advanced maternal age is also postulated as an independent risk factor for low birthweight, preterm delivery (Aldous and Edmonson, 1993), placenta praevia (Williams and Mittendorf, 1993), and infants being admitted to the special care baby unit (Berkowitz et al., 1990). There is no evidence that women aged ⬎35 years with a post-term pregnancy have an increased risk of antepartum fetal compromise but their babies do not tolerate labour as well as those of younger women, with more decelerative traces and more Caesarean sections (Shapiro and Lyons, 1989). In contrast, other papers report little or no adverse outcomes associated with pregnancy in older women (Barkan and Bracken, 1987; Kirz et al., 1985; Ales et al., 1990). Pregnancy in older women is associated with many confounding factors e.g. parity, pre-existing diabetes mellitus and/ or hypertension, which should be taken into account if the risks associated with advanced maternal age are to be quantified (Chan and Lao, 1999; Gilbert et al., 1999). To clarify these issues we have reviewed a large number of consecutive singleton pregnancies using a validated database (Cleary et al., 1994a,b). We aimed to test the hypothesis that older maternal age is associated with increased risk of adverse outcomes for mother and baby and to quantify this risk after allowing for confounding factors. Materials and methods Data were derived from the St Mary’s Maternity Information System database (SMMIS) for the years 1988–1997. SMMIS is a clinical

Table I. Demographic characteristics of women grouped according to age at delivery 18–34 years (%) 35–40 years (%) ⬎40 years (%) (n ⫽ 336 462) (n ⫽ 41 327) (n ⫽ 7331) Nulliparous Parity 1 Parity 2 or more Hypertension at booking Pre-existing diabetes Asian Black Caribbean Oriental Caucasian Black African Mediterranean Others

46.2 34.4 19.4 4.7 0.4 13.9 2.8 1.3 72.9 3.1 1.8 4.2

25.0 34.2 40.8 7.0 0.7 11.8 2.9 2.8 72.0 2.9 2.0 5.8

20.5 27.3 52.2 8.9 1.0 12.6 2.8 4.1 69.4 2.6 2.6 6.0

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Table II. Antenatal characteristics and complications

Late bookinga,c,d Gestational diabetes Pre-eclampsiaa,c,d Anaemiaa,c,d Placenta praeviaa,c Abruptiona,b,c Breech presentationa,c,d

Age group (years)

Proportion (%)

18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40

10.3 8.66 10.41 1.0 2.85 4.56 0.78 0.76 0.79 10.08 10.15 11.32 0.26 0.56 0.97 0.45 0.45 0.63 2.61 3.66 4.57

Odds ratio (99% confidence interval)

0.74 (0.70–0.78) 0.82 (0.74–0.92) 2.63 (2.40–2.89) 3.98 (3.38–4.68) 1.19 (1.01–1.40) 1.25 (0.88–1.79) 0.96 (0.91–1.00) 1.04 (0.94–1.15) 1.93 (1.58–2.35) 3.09 (2.19–4.36) 0.99 (0.80–1.22) 1.40 (0.84–2.09 1.37 (1.28–1.47) 1.72 (1.50–1.98)

Late booking ⫽ booking after 19 or more completed weeks of gestation; placenta praevia ⫽ a placenta that lies partially or completely in the lower uterine segment; abruption ⫽ partial or complete separation of the placenta from its insertion in the upper segment. Additional confounding factors are indicated by the superscript letters: agestational diabetes; bpre-eclampsia; cpre-existing diabetes; dsmoking.

Table III. Maternal complications

Chest infectiona,b,c,d,f Genital tract infectiona,b,c,d Wound infectiona,b,c,d Urinary tract infectiona,b,c,d Pyrexia of unknown origina,b,c,d Pulmonary embolisma,b,c,d,f Prolonged postnatal staya,b,c,d,e

Age group (years)

Proportion (%)

18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40

0.14 0.19 0.27 0.66 0.57 0.7 0.47 0.68 1.12 0.72 0.72 1.32 1.1 1.05 1.24 0.05 0.07 0.15 19.44 20.25 25.73

Odds ratio (99% confidence interval)

0.96 (0.80–1.16) 1.03 (0.55–1.95) 0.96 (0.80–1.16) 1.22 (0.84–1.78) 1.08 (0.91–1.29) 1.33 (0.98–1.62) 0.89 (0.75–1.05) 1.41 (1.06–1.87) 0.88 (0.77–1.01) 0.86 (0.65–1.16) 1.28 (0.75–2.18) 2.38 (1.03–5.47) 1.52 (1.44–1.60) 2.10 (1.87–2.36)

Additional confounding factors are indicated by the superscript letters: agestational diabetes; bpre-existing diabetes; celective Caesarean section; demergency Caesarean section; edelivery at ⬍37 weeks gestation; fsmoking.

database recording maternity information from 18 NHS hospitals within the geographical boundaries of the North West Thames Region, UK, and contains data on ⬎80% of all deliveries in a region with a population of ⬎3.5 million. The database has been previously validated for commonly recorded variables including intrauterine death (Cleary et al., 1994a,b).

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The subjects were divided into groups according to maternal age at delivery: 18–34; 35–40; and ⬎40 years old. Women aged ⬍18 years old were excluded from the analysis. The raw frequencies of the various outcomes of pregnancy in the maternal age groups were calculated and multiple logistic regression models were then constructed to examine the magnitude and significance of the inde-

Pregnancy risks in older women

Table IV. Delivery complications

Induction of labourb,c,f Breech

deliveryb,i

Operative vaginal deliveryb,f,j Emergency Caesarean section

a,b,c,d,e,f

Elective Caesarean sectiona,b,c,d,e,f Postpartum haemorrhageb,f,g,h Postpartum haemorrhage 艌1000 mlb,f,g,h

Age group (years)

Proportion (%)

18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40

16.88 16.88 19.22 0.78 0.71 0.65 11.36 10.83 10.23 8.65 11.05 14.24 4.37 8.6 12.67 11.24 14.25 17.99 1.46 2.19 3.10

Odds ratio (99% confidence interval)

1.04 (1.00–1.08) 1.19 (1.10–1.29) 0.92 (0.78–1.08) 0.83 (0.56–1.22) 1.50 (1.43–1.57) 1.60 (1.43–1.78) 1.59 (1.52–1.67) 2.17 (1.97–2.39) 1.77 (1.68–1.87) 2.67 (2.42–2.95) 1.14 (1.09–1.19) 1.27 (1.15–1.39) 1.28 (1.16–1.41) 1.55 (1.29–1.88)

Operative vaginal delivery ⫽ use of obstetric forceps or ventouse during vaginal delivery (type not specified); postpartum haemorrhage ⫽ estimated blood loss of 艌500 ml, at delivery and for up to 24 h postpartum, excluding normal lochia; postpartum haemorrhage 艌1000 ml ⫽ estimated blood loss of 艌1000 ml, at delivery and for up to 24 h postpartum, excluding normal lochia. Additional confounding factors are indicated by the superscript letters: aabruption (partial or complete separation of the placenta from its insertion in the upper segment); bgestational diabetes; cpre-eclampsia; dplacenta praevia; ebreech; fpre-existing diabetes; gelective Caesarean section; hemergency Caesarean section; idelivery at ⬍37 weeks gestation; kinduction.

pendent effect of age. All models included maternal age, body mass index, ethnic group, parity, history of hypertension and history of diabetes mellitus. Other confounding factors of specific relevance to a particular outcome were included as appropriate. The results are presented as frequencies by age group and odds ratios (OR) with 99% confidence intervals (CI). Birthweight was expressed as a delta value (the number of SD by which the observed birthweight differed from the expected normal mean for males and females for each week of gestation) in order to account for the influence of gestational age and sex on birthweight. All analyses were carried with Statistical Analysis Software version 6.12 (SAS Institute Inc, Rayleigh, NC, USA) using a UNIX server, SUN SPARC STATION 20 running SOLARIS 2.6 operating system (Sun Microsystems Inc, Palo Alto, CA, USA).

Results Data from 385 120 singleton pregnancies were studied, women aged 18–34 years (n ⫽ 336 462), 35–40 years (n ⫽ 41327) and those ⬎40 years (n ⫽ 7331). Women aged ⬍18 years (n ⫽ 5246) were excluded from the study. Demographic characteristics of the groups are reported in Table I. The pregnancy outcome results by age group are summarized in Tables II–V, with the proportion (%) of each risk factor or outcome being presented for each of the three maternal age groups. OR with 99% CI were calculated, with the additional confounding variables included for that outcome indicated by the letters in superscript. Older women were less likely to book late, but were more likely to have a history of diabetes mellitus and hypertension

at booking. A higher proportion of the women aged 艌35 years had gestational diabetes, placenta praevia and a fetus with a breech presentation. There was no increased likelihood of anaemia in the older women and the increased risk for preeclampsia was only just significant in the 35–40 year old women. More women aged ⬎40 years old had a pulmonary embolism either during pregnancy and/or in the puerperium. Older women were more likely to have a prolonged postnatal admission. There was no difference in infectious morbidity between the age groups. Induction of labour was more common in older women who were also more likely to be delivered by Caesarean section or have an operative vaginal delivery. Despite the higher proportion of older women having a fetus with a breech presentation, fewer had a vaginal breech delivery. A greater proportion of older women had a postpartum haemorrhage of ⬎1000 ml. The risk for preterm delivery and stillbirth was significantly greater in the older women. The incidences of small for gestational age and large for gestational age babies were higher in the older women. More of the women aged 艌35 years breast-fed their babies.

Discussion The study confirms our hypothesis that advanced maternal age is an independent risk factor for certain adverse outcomes in pregnancy. Gestational diabetes mellitus was significantly more common in the older age groups despite controlling for 2435

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Table V. Fetal complications

Delivery after 42 weeks gestationb,d Delivery before 37 weeks

gestationb,c,d,f

Delivery before 32 weeks gestationb,c,d,f Stillbirth

b,c,f,j

Delta birthweight ⬍5th centileb,c,d,f Delta birthweight ⬎90th centileb,d Apgar score ⬍7a,b,d,e,f Apgar score ⬍5a,b,d,e,f Admission to SCBU ⬎24 Breast feeding

b,d,e

ha,b,d,e,f

Age group (years)

Proportion (%)

18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40 18–34 35–40 ⬎40

0.16 0.16 0.19 6.0 6.63 8.17 1.03 1.33 1.58 0.47 0.61 0.81 5.81 6.13 7.63 10.06 12.32 11.96 1.31 1.42 1.61 0.23 0.28 0.23 5.20 5.33 5.92 61.14 70.08 66.24

Odds ratio (99% confidence interval)

1.14 (0.80–1.61) 1.19 (0.57–2.50) 1.18 (1.11–1.25) 1.42 (1.26–1.60) 1.41 (1.24–1.61) 1.64 (1.25–2.14) 1.41 (1.17–1.70) 1.83 (1.29–2.61) 1.28 (1.20–1.36) 1.49 (1.29–1.71) 1.20 (1.13–1.27) 1.29 (1.14–1.45) 1.16 (1.03–1.23) 1.19 (0.92–1.55) 1.30 (1.05–1.61) 1.01 (0.60–1.69) 1.05 (0.98–1.12) 0.9 (0.85–1.15) 1.76 (1.70–1.82) 1.63 (1.52–1.75)

Delta birthweight ⫽ birthweight expressed as a delta value, i.e. the number of SD by which the observed birthweight differed from the expected normal mean for males and females for each week of gestation; SCBU ⫽ special care baby unit. Additional confounding factors are indicated by the superscript letters: aabruption (partial or complete separation of the placenta from its insertion in the upper segment); bgestational diabetes; cpre-eclampsia; dpre-existing diabetes; edelivery at ⬍37 weeks gestation; fsmoking.

confounding factors associated with decreased insulin sensitivity such as ethnicity and obesity in the logistic regression model. Glucose tolerance is a function of insulin sensitivity and insulin secretion. Pancreatic B cell function and insulin sensitivity fall with age. Women with the predisposition to type 2 diabetes are therefore more likely to have an inadequate B cell response to stimulation and be more insulin-resistant than younger women, which, when combined, make gestational diabetes more likely. The greatest differences between older women and controls were identified in the mode of delivery. One possible explanation is that obstetricians may have a lower threshold for intervention in older women. An alternative explanation is that myometrial function deteriorates with age (Rosenthal and Paterson Brown, 1998). This mechanism may also be relevant to the increased age-related risk of breech presentation and postpartum haemorrhage, as uterine atony is the most common cause of postpartum haemorrhage. There was a wider distribution of birthweight in the older women. The increased likelihood of older women delivering a small for gestational age baby may be related to poorer placental perfusion or transplacental flux of nutrients (Godfrey et al., 1999). The increased likelihood of an older woman 2436

delivering a large for gestational age baby is unlikely to be due to a genetic effect and implies differences in the fetal environment in older pregnant women compared with younger pregnant women. These differences may be due to age-related changes in maternal metabolism. Fetal macrosomia is more common in the obese non-diabetic mother, compared with lean mothers with gestational diabetes (Maresh et al., 1989). Although non-diabetic obese women are glucose tolerant by definition, their increased insulin resistance may cause other perturbations in metabolism increasing nutrient availability to the fetus. The expanded Pedersen hypothesis describes how an increased flux of nutrients across the placenta could cause fetal hyperinsulinaemia and accelerated fetal growth (Pedersen, 1977; Freinkel and Metzger, 1978). Insulin-resistant individuals have higher fasting plasma triglyceride concentrations (Robinson et al., 1993), and greater leucine turnover (Robinson et al., 1992). Amino acids stimulate secretion of insulin and so an increased flux of amino acids to the fetus would stimulate fetal hyperinsulinaemia. Triglycerides are energy rich and placental lipases can cleave triglycerides and transfer free fatty acids to the fetal circulation providing increased energy delivery to the fetus (Thomas, 1987). Older women were more likely to deliver preterm and more

Pregnancy risks in older women

likely to deliver at ⬍32 weeks gestation when there is a greater risk of perinatal morbidity and mortality. Urinary tract infection is associated with preterm labour (Heffner et al., 1993) and occurred more frequently in the women aged ⬎40 years. There was no evidence of increased genital tract infection in the older women to account for the increased risk of preterm delivery. The risk of stillbirth was significantly higher in the older women. The risks of aneuploidy and fatal congenital anomalies increase with maternal age and, despite antenatal screening, they are likely to have contributed to the increased rate of stillbirth. A past history of infertility is not recorded on SMMIS but it is likely that a higher proportion of women with previous infertility will have accumulated in the older cohorts. There is a four-fold increase in the risk of fetal death in women with previous infertility (Whitley et al., 1999). Impaired placental function has already been discussed as a possible cause for the increased incidence of small for gestational age babies in the older women and may have also contributed to the increased rate of stillbirth. There has been speculation that there are long-term effects on the offspring of delayed parenthood due to a number of mechanisms including the exposure of gametes to increased oxidative stress (Tarı´n et al., 1998) and these could also be relevant to the increased risk of stillbirth. Older women were significantly more likely to breast-feed than younger women and this may reflect more positive attitudes to breast-feeding in older women. This may be an example of one of the advantages of delayed childbirth. Older women are also likely to have greater financial resources, social stability, and age-related attributes such as emotional maturity, wisdom and experience of life (Fonteyn and Isada, 1988). In conclusion, the results of this study showed that pregnant women aged 艌35 years are at increased risk of complications in pregnancy compared with younger women.

Acknowledgements We would also like to thank Professor R.Beard, Dr J.Chapple, Professor P.Elliott, and the North West Thames consultants for allowing us to use these data and all the midwives who were chiefly responsible for collecting and entering the data. St Mary’s Hospital Joint Standing Research Committee funded the fellowship for M.J.

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