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Hyperfertility: the Paradox Hyperfertility: the Paradox of Plentyof Plenty

Louis Keith, MD, PhDLouis Keith, MD, PhD

Professor Emeritus, Department of Obstetrics and Professor Emeritus, Department of Obstetrics and Gynecology, Northwestern University, Chicago, ILGynecology, Northwestern University, Chicago, IL

Adjunct Professor, Department of Maternal and Child Adjunct Professor, Department of Maternal and Child Health, School of Public Health, University of Alabama Health, School of Public Health, University of Alabama

at Birminghamat Birmingham

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Basic PremiseBasic Premise

• The effects of The effects of hyperfertilityhyperfertility on on mothers are well known: witness mothers are well known: witness Shah Jehan’s wifeShah Jehan’s wife

• The effects of The effects of hyperfertilityhyperfertility on on fetal outcomes are not well fetal outcomes are not well known or studiedknown or studied

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Agreed Definitions of ParityAgreed Definitions of Parity

• Nullipara-gravidas with no priorNullipara-gravidas with no priorpregnancy > 20 weekspregnancy > 20 weeksgestationgestation

• Primapara-gravidas with 1 priorPrimapara-gravidas with 1 priorpregnancy > 20 weekspregnancy > 20 weeksgestationgestation

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Variable Definitions of ParityVariable Definitions of Parity(With no risk threshold for outcomes)(With no risk threshold for outcomes)

• MultiparaMultipara

• Grand MultiparaGrand Multipara**

• Great Grand MultiparaGreat Grand Multipara****

• Grand Grand MultiparaGrand Grand Multipara****

• Extreme Grand MultiparaExtreme Grand Multipara****

** Generally at least 8 prior deliveriesGenerally at least 8 prior deliveries

** ** Variably used for greater than 10 prior deliveriesVariably used for greater than 10 prior deliveries

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Reclassification of Parity:Reclassification of Parity:the UAB Modelthe UAB Model

Previous live Previous live birthsbirths

Fertility Fertility ClassClass

DefinitionDefinition

2-42-4 II Moderately fertileModerately fertile

5-95-9 IIII Very fertileVery fertile

10-1410-14 IIIIII Extremely fertileExtremely fertile

1515 IVIV HYPERFERTILEHYPERFERTILE

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Value of UAB Parity Value of UAB Parity ClassificationClassification

• Permits comparisons across Permits comparisons across discrete clinically relevant discrete clinically relevant groups for assessment of groups for assessment of maternal and fetal outcome maternal and fetal outcome parametersparameters

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Literature Prior to the UAB Literature Prior to the UAB Hyperfertility StudiesHyperfertility Studies

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Frequency of “High” (>5) ParityFrequency of “High” (>5) Parity(10 studies, 9 nations, 1954-2001)(10 studies, 9 nations, 1954-2001)

30%30% United Arab EmiratesUnited Arab Emirates

11%11% NigeriaNigeria

5.0%5.0% TrinidadTrinidad

0.6%0.6% CroatiaCroatia

Hong KongHong Kong

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Adverse Maternal Outcomes Adverse Maternal Outcomes with Multiparitywith Multiparity

(37 studies, 17 nations, 1865-2004)(37 studies, 17 nations, 1865-2004)

• Uterine ruptureUterine rupture• Chronic renal Chronic renal

diseasedisease• Hypertensive Hypertensive

diseasedisease• Placenta previaPlacenta previa

• PreeclampsiaPreeclampsia• Uterine inertiaUterine inertia• AnemiaAnemia• PPHPPH• AbrubtioAbrubtio• DiabetesDiabetes

Variously mentioned conditionsVariously mentioned conditions

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Factors Confounding Relations Factors Confounding Relations Between High Parity and Between High Parity and

Adverse Maternal OutcomesAdverse Maternal Outcomes

• Selection bias, i.e., low SESSelection bias, i.e., low SES

• Maternal ageMaternal age

• Disease accumulation with Disease accumulation with ageage

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Fetal Outcomes and MultiparityFetal Outcomes and Multiparity(38 studies, 13 nations, 1940-2004)(38 studies, 13 nations, 1940-2004)

• StillbirthsStillbirths

• Perinatal MortalityPerinatal Mortality

• Low BirthweightLow Birthweight

• PrematurityPrematurity

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The Great Grand Multipara The Great Grand Multipara (>10 prior live births)(>10 prior live births)

(only 11 studies, 6 nations, 1992-2002)(only 11 studies, 6 nations, 1992-2002)

• 7 of these from Middle East7 of these from Middle East

• Definitions varyDefinitions vary

• Variable study sizes (139-2709) Variable study sizes (139-2709) (ascertainment bias)(ascertainment bias)

• Non-adjustment for confounders Non-adjustment for confounders (methodological bias)(methodological bias)

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The UAB Hyperfertility The UAB Hyperfertility StudiesStudies

Thanks to Thanks to Muktar Aliyu,Muktar Aliyu, DPh, University of DPh, University of

Alabama at BirminghamAlabama at Birmingham

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Basic Hypotheses on Basic Hypotheses on HyperfertilityHyperfertility

#1: Babies born to mothers with parity #1: Babies born to mothers with parity 15 are more likely to have 15 are more likely to have adverse fetal outcomes compared adverse fetal outcomes compared to women of lower parityto women of lower parity

#2: Stillbirth rates are greater among #2: Stillbirth rates are greater among mothers with parity mothers with parity 15 compared 15 compared to mothers who are to mothers who are moderately moderately fertile (parity 2-4)fertile (parity 2-4)

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The DatabaseThe Database

• Combined natality data files and “fetal Combined natality data files and “fetal death files” from NCHS, 1989-2000death files” from NCHS, 1989-2000

• Singleton live births and fetal deaths Singleton live births and fetal deaths 20 20 weeksweeks

• Gestational age from LMP & DOBGestational age from LMP & DOB• Stillbirth (SB) / IUFD at Stillbirth (SB) / IUFD at 20 weeks 20 weeks

– Term SBTerm SB = = 37 completed gest. wks. 37 completed gest. wks.– Preterm SBPreterm SB = < 37 completed gest. wks. = < 37 completed gest. wks.– SGA stillbirthSGA stillbirth = < 10 = < 10thth %tile of birthweight for %tile of birthweight for

gest. Agegest. Age– Preterm SGA stillbirthPreterm SGA stillbirth

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MethodologyMethodology

• Exclude multiplesExclude multiples• Race/ethnicity: non-Hispanic blacks, Race/ethnicity: non-Hispanic blacks,

non-Hispanic whites, and Hispanicsnon-Hispanic whites, and Hispanics• Maternal age adjusted by direct Maternal age adjusted by direct

method of standardizationmethod of standardization• Test of hypothesis two-tailed; type I Test of hypothesis two-tailed; type I

error at 5%error at 5%• Logistic regression used where Logistic regression used where

neededneeded

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The EvidenceThe Evidence

• Hyperfertility and Maternal Hyperfertility and Maternal OutcomesOutcomes

• Hyperfertility and Fetal Hyperfertility and Fetal OutcomesOutcomes

• Hyperfertility and StillbirthsHyperfertility and Stillbirths

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The SampleThe Sample

Total BirthsTotal Births

1989-19921989-1992 11,897,78711,897,787

1993-19961993-1996 15,199,69915,199,699

1997-20001997-2000 15,221,18815,221,188

Grand TotalGrand Total 42,318,67442,318,674

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Sociodemographic characteristics of US Sociodemographic characteristics of US Mothers by Fertility Status, 1989-2000Mothers 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

Maternal education < 12 years > 12 years

21.0 76.5

42.2 54.4

50.7 43.7

54.2 38.2

<0.001

Marital status Married

74.1

63.7

74.1

80.3

<0.001

Maternal smoking Yes

12.8

16.6

11.5

8.5

<0.001

Prenatal care Adequate Not adequate

41.9 58.1

26.9 73.1

17.3 82.7

16.4 83.6

<0.001

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Temporal Trends in Rates of Birth Temporal Trends in Rates of Birth by Fertility Status, USA 1989-2000by Fertility Status, USA 1989-2000

1989-19921989-1992 1993-19961993-1996 1997-20001997-2000 P for P for TrendTrend

Total Total BirthsBirths

11,897,78711,897,787 15,199,69915,199,699 15,221,18815,221,188

Fertility Fertility StatusStatus

Rate/1000Rate/1000 Rate/1000Rate/1000 Rate/1000Rate/1000

2-42-4 725.2 540.3 548.3 <0.001<0.001

5-95-9 53.3 40.5 39.0 <0.0001<0.0001

10-1410-14 0.7 0.6 1.2 <0.001<0.001

1515 0.04 0.02 0.04 0.40.4

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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 A significant p value means that at least two of the tested groups are differentdifferent

Maternal Complications by Maternal Complications by Fertility Status, 1989-2000Fertility Status, 1989-2000

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Interim ConclusionsInterim Conclusions(all data not previously shown)(all data not previously shown)

• Birthrates have declined over the study Birthrates have declined over the study period among blacks as well as whites (by period among blacks as well as whites (by 10% and 9%, respectively)10% and 9%, respectively)

• Birthrates among Hispanics increased by Birthrates among Hispanics increased by 25%25%

• About 75% of Hispanic births occur About 75% of Hispanic births occur among immigrantsamong immigrants

• Racial/ethnic difference in fertility Racial/ethnic difference in fertility moderate for moderate level of fertility, moderate for moderate level of fertility, and greatest for very high fertility statusand greatest for very high fertility status

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The EvidenceThe Evidence

• Hyperfertility and Maternal Hyperfertility and Maternal OutcomesOutcomes

• Hyperfertility and Fetal Hyperfertility and Fetal OutcomesOutcomes

• Hyperfertility and StillbirthsHyperfertility and Stillbirths

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Crude Rates for Fetal Outcomes Crude Rates for Fetal Outcomes by Fertility Status, 1989-2000by Fertility Status, 1989-2000

0

50

100

150

200

250

LBW VLBW Preterm VeryPreterm

SGA LGA

Cru

de r

ate

per 1

000

Type I

Type II

Type III

Type IV

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AORs for Growth Indices by AORs for Growth Indices by Maternal Fertility Status, 1989-2000Maternal Fertility Status, 1989-2000

Type II Type III Type IV Low birth weight* 1.27 1.35 1.38 Very low birth weight*

1.20 1.44 1.57

Preterm 1.43 1.59 1.55 Very preterm* 1.40 1.66 2.05 SGA 1.02 0.94 1.01 LGA 1.25 1.70 1.56 * p for trend <0.001.* p for trend <0.001.

Adjustment for maternal complications was performed using the Adjustment for maternal complications was performed using the confounding effects of maternal education, maternal age, maternal race, confounding effects of maternal education, maternal age, maternal race, year of birth, marital status, adequacy of prenatal care, and maternal year of birth, marital status, adequacy of prenatal care, and maternal smoking during pregnancy.smoking during pregnancy.

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Interim ConclusionsInterim Conclusions

• Increasing fertility is a risk factor for Increasing fertility is a risk factor for LBW, VLBW, preterm and very LBW, VLBW, preterm and very preterm delivery in a dose-dependant preterm delivery in a dose-dependant fashion after 5 deliveriesfashion after 5 deliveries

• Macrosomic babies occur in greater Macrosomic babies occur in greater than expected incidence among than expected incidence among women with greater than 5 birthswomen with greater than 5 births

• Shortened gestation rather than size Shortened gestation rather than size restriction (SGA) is affected by restriction (SGA) is affected by hyperfertilityhyperfertility

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The EvidenceThe Evidence

• Hyperfertility and Maternal Hyperfertility and Maternal OutcomesOutcomes

• Hyperfertility and Fetal Hyperfertility and Fetal OutcomesOutcomes

• Hyperfertility and StillbirthsHyperfertility and Stillbirths

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Crude Stillbirth Rates by Crude Stillbirth Rates by Fertility Status, 1989-2000Fertility Status, 1989-2000

2.8

14.4

21.6

5.0

0

5

10

15

20

25

Type I Type II Type III Type IV

Cru

de r

ate

per

100

0

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AORs for Stillbirth by AORs for Stillbirth by Fertility Status, 1989-2000Fertility Status, 1989-2000

0

0.5

1

1.5

2

2.5

3

3.5

Type II Typ e III Type IV

Ad

jus

ted

od

ds

ra

tio

Adjusted estimates were generated by taking into account the confounding effects of maternal 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, 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).maternal smoking during pregnancy and selected maternal complications (p for trend < 0.001).

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Type-specific stillbirth rates Type-specific stillbirth rates by fertility status, 1989-2000by fertility status, 1989-2000

0

10

20

30

40

50

60

70

Termstillbirth

Pretermstillbirth

SGAstillbirth

Sti

llb

irth

Rat

es Type I

Type II

Type III

Type IV

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Type-specific stillbirth rates Type-specific stillbirth rates by fertility status, 1989-2000by fertility status, 1989-2000

0

50

100

150

200

250

300

350

Preterm and SGA stillbirth

Sti

llb

irth

Rat

es Type I

Type II

Type III

Type IV

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Stillbirth Rates in Type IV with Stillbirth Rates in Type IV with Dose Effect, p for trend < 0.001Dose Effect, p for trend < 0.001

0

10

20

30

40

50

60

70

Rate per 1000 Adjusted OR

15

16

17

>=18

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Interim ConclusionsInterim Conclusions

• The risk of stillbirth increases The risk of stillbirth increases incrementally with ascending fertility incrementally with ascending fertility in hyperfertile women, implying a in hyperfertile women, implying a dose effect relationshipdose effect relationship

• Women who are moderately fertile (2-Women who are moderately fertile (2-4) have lowest risk and women who 4) have lowest risk and women who are hyperfertile (are hyperfertile ( 15) have highest 15) have highest riskrisk

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Explanation for UAB findingsExplanation for UAB findings

• Micronutrient depletion has never been Micronutrient depletion has never been studied and could apply in USstudied and could apply in US

• ““Maternal Depletion Syndrome” used in Maternal Depletion Syndrome” used in countries where under-nutrition is common countries where under-nutrition is common — may not apply in US— may not apply in US

• Uterine overexhaustion may lead to fetal Uterine overexhaustion may lead to fetal under-nutrition via scar tissue at prior under-nutrition via scar tissue at prior placental sitesplacental sites

• Maternal age and disease state may affect Maternal age and disease state may affect fetal outcomes but not studied in hyperfertile fetal outcomes but not studied in hyperfertile womenwomen

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LimitationsLimitations

• No access to No access to autopsy dataautopsy data or cause of or cause of deathdeath

• No data regarding No data regarding birth spacingbirth spacing

• No data regarding No data regarding domestic activitiesdomestic activities which may relate to preterm laborwhich may relate to preterm labor

• No data on No data on negative health behaviorsnegative health behaviors or or psychosocial stressorspsychosocial stressors

• No data on No data on religious influencesreligious influences on fertility on fertility

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AdvantagesAdvantages

• Population-based data minimizes Population-based data minimizes bias due to selectionbias due to selection

• Sample size sufficient to provide Sample size sufficient to provide acceptable level of precision in acceptable level of precision in estimatesestimates

• This data improves understanding of This data improves understanding of the link between extreme fertility and the link between extreme fertility and the risk of fetal demisethe risk of fetal demise

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Applications of Applications of UAB Hyperfertility StudiesUAB Hyperfertility Studies

• Findings apply to counseling for women with Findings apply to counseling for women with increasing parityincreasing parity

• Prenatal care less adequate with increasing Prenatal care less adequate with increasing fertilityfertility

• Very preterm delivery increases in a dose-Very preterm delivery increases in a dose-dependant fashion (after 5 deliveries)dependant fashion (after 5 deliveries)

• Macrosomic babies increase among women Macrosomic babies increase among women with greater than 5 birthswith greater than 5 births

• Stillbirths increase in a dose dependent Stillbirths increase in a dose dependent fashion among hyperfertile womenfashion among hyperfertile women