Hyperfertility: the Paradox
of Plenty
Louis Keith, MD, PhD
Professor Emeritus, Department of Obstetrics and
Gynecology, Northwestern University, Chicago, IL
Adjunct Professor, Department of Maternal and Child
Health, School of Public Health, University of Alabama
at Birmingham
1
Basic Premise
• The effects of hyperfertility on
mothers are well known: witness
Shah Jehan’s wife
• The effects of hyperfertility on
fetal outcomes are not well
known or studied
2
Agreed Definitions of Parity
• Nullipara-gravidas with no prior
pregnancy > 20 weeks
gestation
• Primapara-gravidas with 1 prior
pregnancy > 20 weeks
gestation
3
Variable Definitions of Parity
(With no risk threshold for outcomes)
• Multipara
• Grand Multipara*
• Great Grand Multipara**
• Grand Grand Multipara**
• Extreme Grand Multipara**
* Generally at least 8 prior deliveries
** Variably used for greater than 10 prior deliveries
4
Reclassification of Parity:
the UAB Model
Previous live
births
Fertility
Class
Definition
2-4
I
Moderately fertile
5-9
II
Very fertile
10-14
III
Extremely fertile
 15
IV
HYPERFERTILE
5
Value of UAB Parity
Classification
• Permits comparisons across
discrete clinically relevant
groups for assessment of
maternal and fetal outcome
parameters
6
Literature Prior to the UAB
Hyperfertility Studies
7
Frequency of “High” (>5) Parity
(10 studies, 9 nations, 1954-2001)
30%
United Arab Emirates
11%
Nigeria
5.0%
Trinidad
0.6%
Croatia
Hong Kong
8
Adverse Maternal Outcomes
with Multiparity
(37 studies, 17 nations, 1865-2004)
Variously mentioned conditions
• Uterine rupture
• Chronic renal
disease
• Hypertensive
disease
• Placenta previa
•
•
•
•
•
•
Preeclampsia
Uterine inertia
Anemia
PPH
Abrubtio
Diabetes
9
Factors Confounding Relations
Between High Parity and
Adverse Maternal Outcomes
• Selection bias, i.e., low SES
• Maternal age
• Disease accumulation with
age
10
Fetal Outcomes and Multiparity
(38 studies, 13 nations, 1940-2004)
•
•
•
•
Stillbirths
Perinatal Mortality
Low Birthweight
Prematurity
11
The Great Grand Multipara
(>10 prior live births)
(only 11 studies, 6 nations, 1992-2002)
• 7 of these from Middle East
• Definitions vary
• Variable study sizes (139-2709)
(ascertainment bias)
• Non-adjustment for confounders
(methodological bias)
12
The UAB Hyperfertility
Studies
Thanks to
Muktar Aliyu, DPh, University of
Alabama at Birmingham
13
Basic Hypotheses on
Hyperfertility
#1: Babies born to mothers with parity
 15 are more likely to have adverse
fetal outcomes compared to women
of lower parity
#2: Stillbirth rates are greater among
mothers with parity  15 compared
to mothers who are moderately
fertile (parity 2-4)
14
The Database
• Combined natality data files and “fetal
death files” from NCHS, 1989-2000
• Singleton live births and fetal deaths  20
weeks
• Gestational age from LMP & DOB
• Stillbirth (SB) / IUFD at  20 weeks
– Term SB =  37 completed gest. wks.
– Preterm SB = < 37 completed gest. wks.
– SGA stillbirth = < 10th %tile of birthweight for
gest. Age
– Preterm SGA stillbirth
15
Methodology
• Exclude multiples
• Race/ethnicity: non-Hispanic blacks,
non-Hispanic whites, and Hispanics
• Maternal age adjusted by direct
method of standardization
• Test of hypothesis two-tailed; type I
error at 5%
• Logistic regression used where
needed
16
The Evidence
• Hyperfertility and Maternal
Outcomes
• Hyperfertility and Fetal
Outcomes
• Hyperfertility and Stillbirths
17
The Sample
Total Births
1989-1992
11,897,787
1993-1996
15,199,699
1997-2000
15,221,188
Grand Total
42,318,674
18
Sociodemographic characteristics of US
Mothers by Fertility Status, 1989-2000
Type I
N=
25,187,143
%
Type II
N=
1,844,210
%
Type III
N=
36,826
%
Type IV
N=
1,206
%
P value
Maternal age (years)
<20
20-29
30-39
? 40
5.1
54.7
38.4
1.8
0.2
34.0
57.9
7.9
0.02
6.2
60.9
32.9
0.0
3.9
37.1
59.0
<0.001
Race
Caucasian
Non-Caucasian
79.4
15.9
67.3
26.1
66.0
23.9
67.7
22.9
<0.001
21.0
76.5
42.2
54.4
50.7
43.7
54.2
38.2
<0.001
74.1
63.7
74.1
80.3
<0.001
12.8
16.6
11.5
8.5
<0.001
41.9
58.1
26.9
73.1
17.3
82.7
16.4
83.6
<0.001
Maternal education
< 12 years
> 12 years
Marital status
Married
Maternal smoking
Yes
Prenatal care
Adequate
Not adequate
19
Temporal Trends in Rates of Birth
by Fertility Status, USA 1989-2000
1989-1992
1993-1996
1997-2000
P for
Trend
Total
Births
11,897,787
15,199,699
15,221,188
Fertility
Status
Rate/1000
Rate/1000
Rate/1000
2-4
725.2
540.3
548.3
<0.001
5-9
53.3
40.5
39.0
<0.0001
10-14
0.7
0.6
1.2
<0.001
15
0.04
0.02
0.04
0.4
20
Maternal Complications by
Fertility Status, 1989-2000
Type I
N=
20,891,771
%
Type II
N=
1,542,354
%
Type III
N=
28,123
%
Type IV
N=
893
%
P value
Diabetes
2.7
3.6
4.6
6.9
<0.0001
Chronic
Hypertension
0.7
1.1
1.9
3.4
<0.0001
Pre-eclampsia
2.2
2.0
2.6
3.5
<0.0001
Abruptio
0.6
0.9
1.3
1.5
<0.0001
Placenta previa
0.4
0.6
0.8
1.4
<0.0001
A significant p value means that at least two of the tested groups are
different
21
Interim Conclusions
(all data not previously shown)
• Birthrates have declined over the study
period among blacks as well as whites (by
10% and 9%, respectively)
• Birthrates among Hispanics increased by
25%
• About 75% of Hispanic births occur
among immigrants
• Racial/ethnic difference in fertility
moderate for moderate level of fertility,
and greatest for very high fertility status
22
The Evidence
• Hyperfertility and Maternal
Outcomes
• Hyperfertility and Fetal
Outcomes
• Hyperfertility and Stillbirths
23
Crude Rates for Fetal Outcomes
by Fertility Status, 1989-2000
250
Type I
Type II
Type III
Type IV
Crude rate per 1000
200
150
100
50
0
LBW
VLBW
Preterm
Very
Preterm
SGA
LGA
24
AORs for Growth Indices by
Maternal Fertility Status, 1989-2000
Low birth weight*
Very low birth
weight*
Preterm
Very preterm*
SGA
LGA
Type II
1.27
1.20
Type III
1.35
1.44
Type IV
1.38
1.57
1.43
1.40
1.02
1.25
1.59
1.66
0.94
1.70
1.55
2.05
1.01
1.56
* p for trend <0.001.
Adjustment for maternal complications was performed using the
confounding effects of maternal education, maternal age, maternal race,
year of birth, marital status, adequacy of prenatal care, and maternal
smoking during pregnancy.
25
Interim Conclusions
• Increasing fertility is a risk factor for
LBW, VLBW, preterm and very
preterm delivery in a dose-dependant
fashion after 5 deliveries
• Macrosomic babies occur in greater
than expected incidence among
women with greater than 5 births
• Shortened gestation rather than size
restriction (SGA) is affected by
hyperfertility
26
The Evidence
• Hyperfertility and Maternal
Outcomes
• Hyperfertility and Fetal
Outcomes
• Hyperfertility and Stillbirths
27
Crude Stillbirth Rates by
Fertility Status, 1989-2000
25
21.6
Crude rate per 1000
20
14.4
15
10
5.0
5
2.8
0
Type I
Type II
Type III
Type IV
28
AORs for Stillbirth by
Fertility Status, 1989-2000
3.5
3
Adjusted odd s ratio
2.5
2
1.5
1
0.5
0
Type II
Typ e III
Type IV
Adjusted estimates were generated by taking into account the confounding effects of maternal
education, maternal age, maternal race, year of birth, marital status, adequacy of prenatal care,
maternal smoking during pregnancy and selected maternal complications (p for trend < 0.001).
29
Stillbirth Rates
Type-specific stillbirth rates
by fertility status, 1989-2000
70
60
50
40
Type I
Type II
30
20
10
0
Type III
Type IV
Term
stillbirth
Preterm
stillbirth
SGA
stillbirth
30
Type-specific stillbirth rates
by fertility status, 1989-2000
Stillbirth Rates
350
300
Type I
250
Type II
200
Type III
150
Type IV
100
50
0
Preterm and SGA stillbirth
31
Stillbirth Rates in Type IV with
Dose Effect, p for trend < 0.001
70
60
50
15
40
16
30
17
20
>=18
10
0
Rate per 1000
Adjusted OR
32
Interim Conclusions
• The risk of stillbirth increases
incrementally with ascending fertility
in hyperfertile women, implying a
dose effect relationship
• Women who are moderately fertile (24) have lowest risk and women who
are hyperfertile ( 15) have highest
risk
33
Explanation for UAB findings
• Micronutrient depletion has never been
studied and could apply in US
• “Maternal Depletion Syndrome” used in
countries where under-nutrition is common
— may not apply in US
• Uterine overexhaustion may lead to fetal
under-nutrition via scar tissue at prior
placental sites
• Maternal age and disease state may affect
fetal outcomes but not studied in hyperfertile
women
34
Limitations
• No access to autopsy data or cause of
death
• No data regarding birth spacing
• No data regarding domestic activities
which may relate to preterm labor
• No data on negative health behaviors or
psychosocial stressors
• No data on religious influences on fertility
35
Advantages
• Population-based data minimizes
bias due to selection
• Sample size sufficient to provide
acceptable level of precision in
estimates
• This data improves understanding of
the link between extreme fertility and
the risk of fetal demise
36
Applications of
UAB Hyperfertility Studies
• Findings apply to counseling for women with
increasing parity
• Prenatal care less adequate with increasing
fertility
• Very preterm delivery increases in a dosedependant fashion (after 5 deliveries)
• Macrosomic babies increase among women
with greater than 5 births
• Stillbirths increase in a dose dependent
fashion among hyperfertile women
37