PEARLS FROM PREGNANCY April 2002 Karen M. Chacko, MD

PEARLS FROM PREGNANCY

April 2002

Karen M. Chacko, MD

The Obstetric Interview• Did you have diabetes during pregnancy?• Did you have preeclampsia or complications

during pregnancy?• Did you have blood pressure problems during

pregnancy?• Did you have a clot during pregnancy or with

OCP use?• Did you have thyroid problems after pregnancy?• Was your baby small at birth?

Gestational Diabetes Mellitus

• Formerly, every woman had 50 g OGTT done at 24-28 weeks

• New (January 1999) ADA criteria exempt women <25 years old, BMI <27, no FHx, not Hispanic /Native American /Asian /African American /Pacific Islander

• GDM complicates ~4% of pregnancies

Follow-up of GDM

• Greenberg (1995) : 94 women with GDM given 75 g OGTT at 6 weeks post-partum, 34% with abnl. test:

18% classified as IGT16% classified as Diabetic

• IGT patients become diabetic at a rate of 1-5% per year

Follow-up of GDM

Greenberg, cont’d• Three predictive variables

insulin requirementspoor glycemic control (2 hr pp >150)50g OGTT value (>200)

• If insulin requirements were >100 units/day, 100% of these women had an abnl. 6 week postpartum OGTT

Follow-up of GDM

• Damm (1995) 91 women with diet-treated GDM given 75 gm OGTT at 8 weeks post-partum, 29.7% with abnormal test

16.5% classified as diabetic

13.2% with IGT

Follow-up of GDM

• Kjos (1995): 675 Latino women with diet-controlled GDM screened pp with 75 gm OGTT and then followed at 5 years, overall 47% incidence of diabetes at 5 years

Initial OGTT % diabetic at 5 years

IGT 80%

normal 12%

Glycemic Control and Malformations

• Lucas (1989)correlated A1C at <16 weeks gestation to rate of malformations

HgbA1C none major minor

>10 64.7% 11.8% 23.5%

8.0-9.9 87.1% 4.8% 8.1%

<7.9 95.2% 1.6% 3.2%

Recommendations for the PCP

• ADA position: if glucose levels are normal postpartum after GDM, reassessment should be done at a minimum every 3 years. Women with IGT/IFG should have more frequent screening

• Fasting glucose is acceptable as screening method (do not have to employ an OGTT)





Preeclampsia and Pregnancy

• Preeclampsia risk factors include:

Hypertension Extremes of Age

Primigravid state Family History

Obesity Renal Disease

Diabetes mellitus Smoking (?)

Hypercoagulable stateInterbirth Interval

Preeclampsia and Hypercoagulable States

• Several studies have looked at the incidence of Factor V Leiden among women with preeclampsia (Kupferminc, Dekkar, Lindoff, Dizon-Townson)

• Studies done that include a “full” hypercoagulable workup (Kupferminc, Dekkar)

Preeclampsia and Factor V Leiden

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Kupferminc Dekkar

Factor V

Controls

Lindoff Dizon-Townson

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Preeclampsia and Hypercoagulable States

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percent withabnormalitywith appropriatecutoff value

Dekkar

Complicated Pregnancies and Hypercoagulable States

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25Fa

ctor

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Kupferminc 1999

Factor V and fetal loss

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controls

% o

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Fetal Loss and Hypercoagulable States

02

46

810

1214

161820

Factor V Prothrombin MTHFR

casescontrols

% of

patients

Martinelli 2000

Hypercoagulability and Recurrent Fetal Loss

• Foka 2000 • 80 Greek women with

2 or more losses and 100 controls

• Greek population prevalence of Factor V= 4.3% and PT=2.8%

02468

101214161820

FactorV

PT MTHFR

cases

controls

Hypercoagulability and Recurrent Fetal Loss

Foka cont’d

1st trimester 2nd trimester

Factor V 14.7%31.5%

PT 8.1%10.5%

Thrombophilic Women and pregnancy

• Preston (1996): 571 women with known thrombophilias followed during a collective 1524 pregnancies compared with 395 controls having 1019 pregnancies

Stillbirth OR 3.6 (1.4-9.4)

Miscarriage OR 1.27 (0.94-1.71)

Combined defects overall OR 14.3 (2.4-86)


• Perform a directed hypercoagulable workup in women with a history of severe/early-onset/recurrent preeclampsia, stillbirths, fetal loss, abruption, IUGR

• With regards to miscarriage/stillbirth, primary considerations should be lupus anticoagulant, PT, and Factor V





Hypertensive disorders of pregnancy

• Four basic subdivisions of hypertensive disorders during pregnancy:

Chronic hypertension

Chronic with superimposed preeclampsia

Preeclampsia or eclampsia

Transient (gestational) hypertension/ PIH

(Mis)classification schemes

• Fisher (1981): 176 pregnancies complicated by a hypertensive disorder (almost all were labeled as preeclamptic by chart review), all with renal biopsy done postpartum54% with biopsy compatible with preeclampsia alone25% primips incorrectly diagnosed65% multips incorrectly diagnosed


• Reiter (1994): 186 women with HTN in pregnancy; BP, U/A, lytes, renal imaging, microscopy

8% of preeclamptics found to have underlying renal disorder (essential HTN, sponge kidney, reflux nephropathy)

16% of gestational HTN with underlying disorder (essential HTN,sponge kidney, thin basement membrane disease)

Normalization of Blood Pressure

• Ferrazzani (1994)

159 women with gestational HTN

mean of 6 days pp to normalization

(DBP <80 for 3 consecutive days)

110 women with preeclampsia

mean of 16 days pp to normalization

If >50 days pp with elevated BP, reclassify as chronic HTN

Progression to Chronic Hypertension

• Adams (1961) avg 20 years of follow-up

systolic >140 diastolic >90

severe preecl. 43% 40%

mild/PIH 58% 60%

normotensive 26% 21%

nulliparous 41% 35%

Progression to Chronic Hypertension

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Preeclamptic

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Predicting Ischemic Heart Disease

• Hannaford (1997) 214,356 woman-years of follow-up

RR for preeclamptics vs. normotensives

HTN 2.35 (CI 2.08-2.65)

Acute mi 2.24 (CI 1.42-3.53)

Chronic isch. 1.74 (CI 1.06-2.86)

Heart Dz.

Angina 1.53 (CI 1.09-2.15)

Prediciting Ischemic Heart Disease

• Mann (1996): 77 women under the age of 45 with acute mi and history of preeclampsia, 207 controls

preecl. plus RR p-valuenone 3.0 <0.01cigarettes 3.8 <0.01HTN 2.8 <0.02OCPs 2.8 <0.02all 2.8 <0.05


• Women with a hypertensive disorder first recognized during pregnancy should normalize BP by 2 months maximum

• Risk of progression to chronic HTN much higher in women with gestational HTN/ PIH

• Normotensive pregnancies predict decreased future risk of hypertension

• Hypertensive disorders may predict future risk of ischemic heart disease





DVT or PE during pregnancy or on OCPs

• PE is one of the leading causes of maternal mortality

• Pregnancy by itself will increase the levels of coagulation factors I, VII, VIII, X and will decrease the level of total Prot. S

• 40% of postpartum DVTs present after discharge from the hospital

Factor V and VTE

• Faioni (1996): a series of 493 patients with arterial or venous clot, 15% found to possess Factor V Leiden (controls 2%)

• Among the female patients with Factor V, the inciting event was felt to be pregnancy, postpartum state, or OCP use in 67%

Factor V and VTE

• Hellgren (1995): women with DVT or PE during pregnancy (n=34), OCP use (n=28), and controls (n=75)20/34 (59%) of pregnant women with h/o thrombosis with Factor V Leiden9/28 (32%) of women on OCPs with thrombosis with Factor V Leiden10% of controls with Factor V Leiden

Pregnancy-related VTE

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Fact

or V PT

MT

HFR

casescontrols

• Grandone (1998)• 42 patients with

DVT in pregnancy vs. 213 controls

• coexistence of>1 mutation in 21.4%

% of patients

Pregnancy-related VTE

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Fact

or V PT

V

/PT

AT

III/

C/S

cases

controls

• Gerhardt 2000• 119 women with VTE

during pregnancy or puerperium, 223 controls

OCPs and DVT

• Martinelli (1998): 80 patients with DVT (61% on OCPs) vs. 120 controls (32% on OCPs)

DVT no DVT

Factor V 19% 3%

Prothrombin 18% 3%

Prot C/S/ATIII/APLA 16% 3%

Factor V and VTE• Vandenbroucke (1994): 155 women with DVT

and 169 controls without DVT35/155 (23%) of women with DVT have Factor V Leiden mutation vs. 6/169 (3.5%) of controls109/155 (70%) women on OCPs or with usage within the 6 months prior to DVTRR thrombosis from OCPs 3.8 (2.4-6.0)RR thrombosis with Factor V 7.9 (3.2-19.4)RR for OCPs plus Factor V 34.7 (7.8-154)

DVT and Factor V

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pregnancy

OCPs

controls

Screening and OCPs?

• Vandenbroucke (1996): to prevent one death from PE, 20,000 women with Factor V mutation would have to be denied OCPs for one year and 400,000 women would have to be screened to find them

• Middledorp (1998): in order to prevent 3 VTEs, you would have to withhold 1000 carriers from OCPs

Prophylaxis and Pregnancy?

• Middledorp (1998): if we were to use prophlyactic heparin for Factor V carriers in pregnancy, 980 of 1000 women would be treated unnecessarily in attempts to prevent a VTE

Recommendations for the PCP• Women with a DVT or PE during either

pregnancy or while on OCPs deserve a hypercoagulable work-up

• Prophylaxis during pregnancy is not feasible

• Mass screening prior to prescribing OCPs has not proven feasible

• Women with a known disorder should never receive combined OCPs




OCP use?• Did you have thyroid problems after

pregnancy?• Was your baby small at birth?

Postpartum Thyroiditis

• Complicates 4-7% of pregnancies

• Incidence among Type 1 diabetics 22.5%

• Biopsy shows lymphocytic infiltration

• Closely associated with presence of anti-microsomal (anti-peroxidase) antibodies

Postpartum thyroiditis - three phases

• Thyrotoxic phase (1-3 months): mild symptoms or asymptomatic, decreased RAIU

• Hypothyroid phase (4-8 months): clinically hypothyroid or psychiatric symptoms

• Euthyroid phase (within one year): significant proportion go on to develop permanent hypothyroidism

Who is at risk for PPT?

• Mestman (1999), Gerstein (1993)

previous pregnancy with PPT

presence of antimicrosomal Ab

FHx of thyroid disease

TSH >2 at 12 weeks gestation

prior autoimmune disease, especially Type 1 DM

HLA haplotypes assoc. with Hashimoto’s

Postpartum Thyroiditis

•Anitmicrosomal antibodies are the most closely correlated with the development of PPT

•10% of pregnant women overall will have positive titers and of those with positive titers, 50% may develop PPT

•Positive titer yields OR of developing PPT 86.6 (45.9-163.2)

Thyroiditis and Depression

• Harris (1992):

145 women , thyroid anitbody positive - 43% with postpartum mental illness

229 women, thyroid antibody negative - 28% with postpartum mental illness

p<0.005

Thyroiditis and Depression

• Pop (1993):

9/27 microsomal antibody positive women with depression (33%)

52/266 microsomal antibody negative women with depression (19.5%)

RR for depression in antibody positive 1.73

(CI 0.92-3.28)

Incidence of Ongoing Hypothyroidism

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Treatment- PPT•Hyperthyroid phase - nothing or beta-blockers

•Hypothyroid phase - often requires treatment with L-thyroxine, wean after 6 months therapy and recheck TSH


• TSH at one year postpartum in women with PPT or history of pp depression

• Yearly screening with TSH in women with prior history of PPT as approximately 5% per year will become hypothyroid

• Screening prior to next pregnancy in women with a history of PPT or Type I DM





Selected Etiologies of Low Birth Weight

• HTN

• Smoking

• Alcohol

• Cocaine/crack abuse

• Physical/mental abuse

Mechanisms of Low Birth Weight

• Direct: abruptio placentae, fetal fractures, uterine rupture, liver/spleen rupture, pelvic fractures, antepartum hemorrhage, premature contractions, PROM, infection, exacerbation of chronic conditions

• Indirect: decreased access to prenatal care, increased stress, behavioral risks (smoking, alcohol, drugs), inadequate nutrition

HTN and Birth Weight

• Surian (1984): normotensive IUGR 2.3% and hypertensive IUGR 15.6%

• Bellomo (1999): neonatal weight in normotensive pregnancies 3336 gm vs. an average weight of 2911 gm in hypertensives (p<0.001)

Smoking and Birth Weight

• Overall, 26% of reproductive age women are smokers and 31% of women between the ages of 8-34 years smoke at least 1 ppd (Fried, 1993)

• Smoking accounts for 20-30% of low birth weight babies and 10% of infant mortality

• Babies are 150-250 gm (Fried, 1993) to 458 gm (Bernstein, 1997) lighter on average vs. nonsmokers

Alcohol and Low Birth Weight

• Little (1980): women who were abstinent but formerly alcoholic had birthweights 258 gm less on average, current alcoholics were average 493 gm lighter

• Passaro (1996): 10,539 women drinking 1-2 drinks/day with at least one binge or 3 drinks/day had a mean birthweight 150 gm less

Cocaine and fetal outcome

• Associated with preterm labor, spontaneous abortion, IUGR, limb reduction defects

• Among women aged 18-25, estimated 4.8% have used in the last year and 1.6% within the last month

• Among women 26-34, 4.5% have used within the past year and 1.1% within the last month (Richardson, 1993)

Cocaine and Fetal Outcomes

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Preterm

IUGR

LBW

Controls

Frequency of Abuse

• Eisenstat (1999)

1/4 women are abused at some point during their lives

1/7 women have been abused within the past year

1/6 women are abused during pregnancy

Picking up on Abuse

• Suspect if failure or delay in obtaining prenatal care

• Linked to complications in pregnancy:

miscarriage

abruption

PROM

antepartum hemorrhage

low birth weight

Estimates of Abuse During Pregnancy

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Bullock McFarlane Helton Hillard Campbell

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Meta-Analysis of Abuse During Pregnancy

• Gazmararian (1996): meta-analysis of 13 studies of prevalence of abuse during pregnancy (11/13 involved physical abuse only)

• Estimated abuse in 3.9-8.3%

• Studies asking >1 time per patient or in the third trimester range 7.4-20.1%

(Under)estimates of Abuse During Pregnancy

• McFarlane (1991)

8% of women reported abuse on a standard intake form

29% reported abuse when asked directly by a physician

Abuse and Low Birth Weight

• Bullock (1989): compared public and private hospital settings along with abused and non-abused women

battered controls p-value

low b.w. 12.5% 6.6% <0.02

private/lbw 17.5% 4.2% <0.001

public/lbw 10.0% 9.6% NS


• Recognize hidden underlying factors that can predispose to low birth weight

• Ask directed questions about abuse in addition to already asked questions about smoking/alcohol/drugs

• Ask more than once

Summary of Recommendations for the PCP

• Women with GDM should have screening for diabetes and should be followed with yearly screening thereafter - optimization of glucose control prior to conception is crucial

• Women with a hypertensive disorder are at increased risk for chronic hypertension, recurrent preeclampsia, and increased future risk of ischemic heart disease


• Women with severe/early-onset preeclampsia, IUGR, stillbirth or recurrent miscarriages should have a hypercoagulable workup

• Women with a DVT or PE during pregnancy or while on OCPs need a hypercoagulable workup; mass screening prior to prescribing or conceiving not indicated


• Women with a history of postpartum thyroiditis are at high risk of becoming permanently hypothyroid and need yearly TSH screening

• Women with low birth weight babies could have a number of different contributing factors, including (but not limited to) tobacco, alcohol, cocaine, and abuse

Case Presentation

• 16 y.o. G1P0 presented at 35 weeks gestation with RUQ pain, BP 186/110, elevated transaminases, platelet count of 114K, and urine dip 3+ for protein

• She was hospitalized for preeclampsia and had a normal delivery

• Prior to discharge, she is started on a combined OCP

Case cont’d

• 2 months later, she returns with a DVT and hepatic vein thrombosis

• Workup included Prot C/S levels, Factor V Leiden - all unrevealing

• Past records from her pregnancy include a prolonged PTT of 40.2 seconds (control 23.4-33.8 seconds)

Case cont’d

• 1:1 dilutiion and RVVT both prolonged• PTT corrected with phospholipid

neutralization test• Diagnosis: antiphospholipid antibody

syndrome secondary to lupus anticoagulant • What would you have done if she had come

to see you post-partum prior to the use of combined OCPs

Cost savings analysis

• Gregory (1993): assumed incidence of DM among GDM pregnancies at 5 years 30-50% and a rate of conversion to DM per year of 6.7%

• Using dietary/exercise strategies, even if only 10% of cases were delayed for 10 years, $71 million 1990 dollars would be saved by the tenth year


• Ihle (1987): 84 pts. with ‘early-onset’ preeclampsia; 24 hr urine, U/A, lytes, biopsy (if rbc’s), IVP

67% of primips had underlying renal abnormalities

63% of multips had underlying renal abnormalities

Predicting Ischemic Heart Disease

• Jonsdottir (1995) follow-up of 7543 hypertensive pregnancies for ischemic heart disease

Hypertensives vs. normals RR 1.47 (1.05-2.02)

Eclamptics vs. normals RR 2.61 (1.11-6.12)

Preeclamptics vs. normals RR 1.90 (1.02-3.52)

Recurrent DVT

• DeStefano (1999) - general population – RR first DVT (heterozygous Factor V) 7– RR first DVT (homozygous Factor V) 80– RR first DVT (heterozygous PT) 2.7-3.8

– RR recurrent DVT (hetero. Factor V) 1.1– RR recurrent DVT (hetero. V/PT) 2.6

Drugs and Abortion

• Ness (1999): 400 women with spontaneous abortion vs. 570 women with intact pregnancy at 22 weeks. Hair and urine analysis for cocaine and tobacco.

spont. abortion intact preg OR

cocaine pos. 28.9% 20.5% 1.4 (1.0-2.1)

tobacco pos. 34.6% 21.8% 1.8 (1.3-2.6)

Documents

PEARLS FROM PREGNANCY April 2002 Karen M. Chacko, MD