Why 40 is not the new 20!

1. Why 40 is not the new 20! A review of the associated risks of advanced maternal age

2. Dr Elisabet Joa, FRCSC • Associate Clinical Professor UBC Dept of Obstetrics and Gynecology • Post Graduate Program Director UBC • ejoa2@providencehealth.bc.ca • No conflicts of interest to disclose

3. Objectives • To review the maternal and perinatal risks of delayed child bearing • To identify the important issues to address with women of childbearing age • Identify areas of need for more research

4. Case • 38 year old G0 ♀, recently married, thinking about getting pregnant.

5. Fecundity • Classic study showed that the incidence of sterility increased from 10% at age 34 to over 85% in women at 44 years of age (Tzietze 1957). Exponential decrease in fertility after 35.

6. Fetal Loss Rate • Large study 1978-92 in Denmark (Anderson et al 2000) • 8.9% SA 20-24 year olds • 74.5% SA in the 45> years olds • Also found higher ectopic rates

7. Assistant Reproductive Technology-Success Rates in Women ≥ 40 years of age • 40 year- 40% chance of live birth • 41-30% • 42-20% • No live births at 44 • ART with autologous oocytes not offered after 45 because of minimal success rates (personal communication with Havelock)

8. Table: Risk of Down’s Syndrome and Chromosomal Abnormalities at Live Birth, According to Maternal Age* (Hook et al)

9. Maternal Risks • Chronic disease-increased prevalence of various chronic diseases (i.e. cardiovascular, endocrine) which may increase risks to mother and child • Increased rates of maternal mortality Significantly increased in women ≥ 40 and in women ≥ 45 an OR 121 has been reported compared to women aged 20-29 (Jacobsson et al 2009).Thankfully this is still a rare occurrence overall. • > 45 166.00/100,000 deliveries, 40-44 22.1/100,000, 20-29 1.4/100,000 deliveries. Jacobsson et al

10. Maternal Risks • Increased rates of multiples, hypertension, diabetes, placental abruption, placenta previa, preterm birth, operative vaginal delivery, c-sections, post partum hemorrhage and decreases VBAC (vaginal birth after c-section) rates. • Increased medical and surgical complications***

11. Mode of Delivery • A nulliparous 40 year old or older had less than a 7% chance of a normal vaginal delivery. 50% chance of c-section and 43% chance of operative vaginal delivery. • 35-39 nulliparous 37.7 % chance of c-section and 36.9% chance of operative vaginal delivery(Joseph et al 2002)

12. Longer Term Risks • Maternal- delayed childbearing associated with increased risks of breast cancer but decreased risks of uterine and cervical cancers

13. Fetal Risks • Increased rates of fetal loss • Increased rates of chromosomal abnormalities • Increased rates of congenital abnormalities (cardiac, spina bifida cleft palate, syndactyly, limb defects and male genital malformations) i.e. baseline risk of congenital abnormalities is 3.5% ≤ 25 year old mother increases to 4.5% in age 35 ≥ and 6% in 40 ≥ (Hollier et al 2000)

14. Perinatal Risks • Increased rates of macrosomia • Fetal malpresentation • ?Increased number of female offspring as women get older (Bahadur et al 2001) • Increased preterm deliveries, increased SGA infants ,both <10% and <3%.(Joseph et al 2002).

15. Perinatal risks • Increased perinatal mortality/morbidity • Morbidity defined as a 5 min apgar <3 RDS needing ventilation, BPD, IVH grade 3-4 periventricular leukomalacia, severe retinopathy of prematurity and NEC (Joseph et al 2002) • Interestingly it looks as though the higher rates of obstetrical interventations and improved neonatal care reduced stillbirth and neonatal death rates but not serious neonatal morbidity over the time period of 1988-2002 in Canada (Joseph et al 2002)

16. Perinatal Morbidity/Mortality • Sudden increase in women over 35 after 40 weeks gestation vs. in women 20-29 years • At 41 weeks 4.2/1000 (fetuses at risk) vs. 2.8/1000 • 42 weeks 5.5/1000 vs. 3/1000 (Joseph et al 2002) • Still relatively rare occurrence but does it warrant increased monitoring at term in these patients?

17. Perinatal Mortality • Perinatal mortality defined as stillbirth or death within 6 days of birth. • 1.4% in 45> older • 1.0% 40-44 • 0.5 % in 20-29 (Jacobsson et al 2009) • Similar to Canadian study (Joseph et al 2002)

18. Perinatal Morbidity and Mortality • Interestingly it looks as though the higher rates of obstetrical interventations and improved neonatal care reduced stillbirth and neonatal death rates but not serious neonatal morbidity over the time period of 1988-2002 in Canada (Joseph et al 2002) • Implications for the healthcare system? education system?

19. Longer term risks • Trisomy in grandchildren (Aageson et al 1984) • Neurological Disorders ?Autism (King et al 2009) • Diabetes? • Male infertility ( St. John et al 1997)

20. Case • 38 year old G0 ♀, recently married, thinking about getting pregnant.

21. History • Folic acid, multivitamin supplementation • Thyroid function • Weight • Exercise • Smoking • Gyne history-if there is anything that might indicate further problems conceiving I would keep this in mind and make sure I see them in 3-6 months. If they are not pregnant by then they should see a specialist ASAP.

22. Physical Exam • General physical • Weight • PAP and bimanual • STD screen • Consider thyroid testing

23. She (and her partner) need to be educated about her declining fertility and increasing abortion rates. • They should also be informed about the increased rates of chromosomal abnormalities and that they may want to consider prenatal testing.

24. This is usually enough information for the first visit. • I would recommend seeing her back soon 3 month or so to see how things are going. • Every couple/women is different so some may want “all” the information so you could talk about the increased maternal/fetal risks but really if they want a baby I don’t feel overloading them with the risks is particularly helpful (?too paternalistic?). One step at a time. • First she needs to conceive and be aware that ART is a real possibility.

25. Now she is pregnant! • Now need to address again the increased rates of miscarriage and chromosomal abnormalities-offer prenatal testing • Diet,exercise,stop smoking and vitamins • Evidence shows increase rates of pregnancy induced hypertension and gestational diabetes

26. Now she is pregnant! • See her early to arrange for prenatal screening and early ultrasound. This is both for dating (to avoid post dates induction) and because these women are at higher risk of spontaneous abortion.

27. Now she is pregnant! • Routine prenatal care making sure ultrasound is done at a place where they are experienced at OB scans because of the possible increased risks of congenital abnormalities • Talk to her about work and going off a few weeks before her due date and discuss post partum (support, breast feeding, plans for child care etc.)

28. Now she is pregnant! • Reinforce the exercise- lowers c-section rates, lower gestational diabetes rates, better placental perfusion… • Gestational diabetes screen • Near term watch for oligo and growth concerns ?more aggressive ultrasound monitoring

29. Now she is pregnant! • Consider ultrasound at 40 weeks if not delivered…. • So let’s say she is 42 year old primip now 41 weeks asking you what her chances are for a normal vaginal delivery? • It may be important to discuss the increased risks of operative vaginal delivery and c-section in our AMA patients but honestly I hesitate a bit as it may drive them to elective c-sections.

30. Summary There are increased risks to delaying childbearing the most prevalent ones being decreased fertility and increased fetal loss rates.

31. Summary • Increased perinatal morbidity/mortality. • Increased maternal morbidity / mortality. • Most outcomes are still good but clearly 40 is not the new 20.

32. Future Research • Need to monitor outcomes concerns about increased medical and surgical complications in women of AMA • Long-term implications on future generations ?the effect of older mitochondira?

33. References • Aagesen, L., Grindsted, J., Mikkelsen, M., 1984, Advanced grand maternal age on the mother’s side- a risk of giving rise to trisomy 21, Ann Hum Genet, Vol 47, Pt 4,p 297-301 • Anderson, A.M., Wohlfahrt, J., Christens, P., Olsen, J., Melbye, M., 2000, Maternal Age and fetal loss: population based register linkage study, BMJ Vol 320.,p 1708-12 • Bahadur, g., Ling, K.L., Priya, S., Davis, C.J.,Wafa, R., Ashraf, A., 2001, Sex Ratio and maternal age effect in nulliparous women receiving donor insemination, Fert Ster, Vol 75,p 219-20 • Hollier,L.M.,Leveno K.J.,Kelly, M.A.,Mcintire, D.D.,Cunningham,F.G., 2000, Maternal age and malformations in singleton births, Obstetrics Gynecology Vol 96,p 701-6 • Hook, E.B., Cross, P.K., Schreinimacher, D.M.,1983, Chromosomal Abnormality rates at amniocentesis and in live-born infants, JAMA, Vol 249,p2034-8. • Jacobsson,Bo.,Ladfur, Lars.,Milsom,Jan., 2004, Advanced Maternal Age and Adverse Perinatal Outcomes, Obstetrics and Gynecology, Vol 104, No 4.,p 727-33

34. References • Joseph, K.S.,Allen, A.C., Dodds, L., Turner, L.A.,Scott, H., Liston,R., 2005, The Perinatal Effects of Delayed Childbearing, Obstetrics and Gynecology, Vol 105, No. 6, p 1410-1418. • King,Marissa,D., Fountain, C.,Dakhlallah, B.A., Bearman, P.S.,2009,Estimated Autism Risk and older reproductive age.,American Journal of Reproductive Health, Vol 99, No. 9.,p 1673-9 • Tietze, C., 1957,Reproductive span and rate of reproduction among Hutterite women, Fertility and Sterility, Vol 8,p 89-9 • St. John, J.C., Cooke, I.D., Barratt, C.L.,1997, Mitochondrial mutations and male infertility.Nat Med,Vol3,p 124-5

35. Thank you Questions?