Pregnancy Over 35 Years of Age

Advanced maternal age (AMA) in pregnancy refers to a pregnant woman whose age will be greater or equal to 35 years at the estimated due date (or EDD). Successful pregnancy outcomes occur in women with advanced maternal age but there is an increased risk of infertility and pregnancy complications. The pregnancy complications may include aneuploidy or a chromosomal abnormality, spontaneous abortion or miscarriage, and medical complications such as gestational diabetes mellitus (GDM), hypertension, or fetal growth restriction (birth weight below the tenth percentile).

The percentage of pregnancies in women greater than or equal to 35 years of age was 14% prior to 1941, decreased to 5% in the 1970s and again reached 14% in 2002. The increased number of pregnancies in women over 35 years of age relates to factors such as delay/timing of marriage, second marriages, improved contraceptive method with delay of conception, and improved education opportunities and career advancement for women. The mean age of first time mothers has increased from 24.6 years in 1970 to 27.7 years in the year 2000.¹

Time to achieve conception has increased in women of advanced maternal age or over 35 years of age. The rate of conception and a live birth decreases with increasing age. The rates of childlessness in women at 25 to 29 years of age, 30 to 34 years of age, 35 to 39 years of age, and 40 to 44 years of age were 9, 15, 30, and 64 percent.³

The probability of clinical pregnancy following intercourse on the most fertile day was 50, 40 and 30 percent for women aged 19 to 26 years, 27 to 34 years and 35 to 39 years respectively with males of the same age.⁴

Reduced fertility or fecundity is generally related to the decreased quality and number of eggs or ovocytes as well as hormonal changes, which occur in older women. In addition, older women have a greater risk of endometriosis, pelvic infections, leiomyomas (fibroids), all of which may lead to decreased fertility.

Older women have pregnancy complications at a higher rate than younger women. Pregnant women with advanced maternal age have an increased risk of spontaneous abortion or miscarriage due to a decline in egg or ovocyte quality as well as changes in uterine and hormonal function. The overall risk of spontaneous abortion is approximately 10%.

The calculated risk of spontaneous loss in each age group is: < 30 years of age (12 percent), 30 to 34 years (15 percent), 35 to 39 years (25 percent), 40 to 44 years (51 percent) and greater than 45 years (93 percent).⁵

The pregnancy loss rate or miscarriage rate after documentation of fetal cardiac activity on an ultrasound for a patient less than 30 years is 5 percent, 31 to 34 years is 8 percent, 35 to 39 years is 13 percent, and greater than or equal to 40 is years 22 percent.⁶

The risk of ectopic pregnancy in women over the age of 35 years occurred 4 to 8 times more often than in younger women.⁷ Ectopic pregnancy may lead to significant hemorrhage, a loss of reproductive function, and in rare cases maternal death. There is a progressive increase in the risk of aneuploidy or chromosomal abnormalities with increasing maternal age. Congenital malformations including heart defects, clubfoot, and diaphragmatic hernia also appear with increasing frequency in children of older women with no other medical complications.⁸

Medical complications occur in higher frequencies in women with AMA. Hypertension or elevation of blood pressure is the most frequent medical problem seen in pregnancy. Older women have a threefold increased risk of hypertension in pregnancy compared to younger women. The incidence of preeclampsia (hypertension and proteinuria) is 3 to 4 percent in the general population. The risk of preeclampsia is 5 to 10 percent in women over the age of 40. Over the age of 50, the risk of hypertension in pregnancy is 35 percent.^{10, 11}

Diabetes mellitus also increases with increasing maternal age. The rate of pregestational diabetes mellitus and gestational diabetes (GDM) increases three to sixfold in women 40 years or older compared to women aged to 20 to 29 years.¹²

Advanced maternal age is associated with a significant proportion of both preterm deliveries (PTD) as well as low birth rate. Prospective studies in nulliparous women (first pregnancy) with singleton pregnancies showed a significant increase in both preterm delivery and fetal growth restriction in women aged 35 to 40 compared to those of 20 to 24 years.

Studies have demonstrated an increased risk of fetal stillbirth in older women aged 35 to 39 years of age. As compared to younger women, the increased risk of stillbirth is present even after controlling for risk factors such as hypertension, diabetes mellitus, bleeding, multiple gestation, and congenital anomalies.^{14, 15}

The risk of pregnancy-related maternal mortality for women 35 to 39 years of age was more than twice that of women aged 25 to 29 years (21 versus 9 per 100,000 live births); the mortality risk for women over 40 years older was fivefold higher (46 versus 9 per 100,000 live births).¹⁶

In summary, advanced maternal age is associated with a reduction in fertility and an increased risk of adverse pregnancy outcomes.

Issues that should be explored prior to pregnancy include:

1. A consultation with a Maternal Fetal Medicine Specialist should be considered prior to conception with the women with pregestational medical problems and advanced maternal age.

2. If conception does not occurred after six months of unprotected intercourse, consult a Reproductive Endocrinologist to optimize the chance of conception.

3. Because of the risk of an abnormal karyotype or aneuploidy one may consider the use of donor eggs or oocytes from a patient less than 35 years of age or use prenatal diagnosis for diagnosis of aneuploidy. Prenatal diagnosis may consist of invasive and/or non-invasive tests. Some of the test include:

   1. First trimester screen – an ultrasound measuring the nuchal translucent or fold of skin in the back of the fetal neck and a fingerstick drop of blood for a PAPP-A (pregnancy associated plasma protein A) and beta hCG (beta human chorionic gonadotropin) may be performed between 11 and 13 6/7 weeks gestation (EGA). The detection rate for trisomy 21 (Down syndrome), trisomy 13 and trisomy 18 is approximately 85% with a false positive rate of 5% with this first trimester screen.

   2. Chorionic villus sampling (CVS) at 9 to 12 weeks gestation for karyotype or chromosomal analysis.

   3. Amniocentesis at 15 to 18 weeks gestation for karyotype or chromosome analysis and alpha fetal protein level.

   4. Maternal serum alpha fetal protein level (with first trimester screen) for detection of fetal neural tube defects at 15 to 18 weeks gestation.

   5. Ultrasound at 18 to 22 weeks gestation for detection of fetal congenital anomalies or birth defects.

4. Any pre-existing medical condition such as chronic hypertension or pre-gestational diabetes mellitus should be under good control prior to achieving conception.

5. Test of fetal well being such as a nonstress test (NST) or a biophysical profile (BPP) may be initiated at 32 weeks gestation. A NST monitors the fetal heart rate for 20 to 40 minutes. A BPP monitors fetal movements, tone, breathing and amniotic fluid volume for 30 minutes.

Editorial provided by Dr. George VanBuren, Department of Obstetrics and Gynecology/Division of Maternal and Fetal Medicine at University Hospital in Cleveland, OH.