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PEARLS FROM PREGNANCY
April 2002
Karen M. Chacko, MD
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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?
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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
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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
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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
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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
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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%
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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%
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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)
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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?
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Preeclampsia and Pregnancy
• Preeclampsia risk factors include:
Hypertension Extremes of Age
Primigravid state Family History
Obesity Renal Disease
Diabetes mellitus Smoking (?)
Hypercoagulable stateInterbirth Interval
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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)
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Preeclampsia and Factor V Leiden
0
5
10
15
20
25
30
Kupferminc Dekkar
Factor V
Controls
Lindoff Dizon-Townson
% o
f P
atie
nts
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Preeclampsia and Hypercoagulable States
0
5
10
15
20
25
30
percent withabnormalitywith appropriatecutoff value
Dekkar
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Complicated Pregnancies and Hypercoagulable States
0
5
10
15
20
25Fa
ctor
V
PT g
ene
Hom
ocys
tein
eC
/S/A
TII
I/A
CLA
casescontrols
Kupferminc 1999
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Factor V and fetal loss
05
101520253035404550
Brenner Rai Grandone Belasch
cases
controls
% o
f pa
tien
ts
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Fetal Loss and Hypercoagulable States
02
46
810
1214
161820
Factor V Prothrombin MTHFR
casescontrols
% of
patients
Martinelli 2000
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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
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Hypercoagulability and Recurrent Fetal Loss
Foka cont’d
1st trimester 2nd trimester
Factor V 14.7%31.5%
PT 8.1%10.5%
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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)
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Recommendations for the PCP
• 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
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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?
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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
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(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
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(Mis)classification schemes
• 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)
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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
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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%
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Progression to Chronic Hypertension
0
10
20
30
40
50
60
Adams
Sibai
Nisel
l
Lindeb
erg
Preeclamptic
PIH
Controls% o
f pa
tien
ts
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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)
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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
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Recommendations for the PCP
• 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
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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?
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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
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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%
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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
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Pregnancy-related VTE
0
5
10
15
20
25
30
35
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
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Pregnancy-related VTE
05
1015202530354045
Fact
or V PT
V
/PT
AT
III/
C/S
cases
controls
• Gerhardt 2000• 119 women with VTE
during pregnancy or puerperium, 223 controls
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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%
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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)
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DVT and Factor V
0102030405060
Hel
lgre
nV
ande
nbro
ucke
Gra
ndon
eM
artin
elli
Ger
hard
t
pregnancy
OCPs
controls
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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
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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
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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
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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?
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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
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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
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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
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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)
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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
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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)
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Incidence of Ongoing Hypothyroidism
05
10152025
3035
Tach
iO
thm
anJa
nns
on
Am
ino
Ras
mus
sen
Nik
olai
Sol
omon
% o
f pa
tien
ts
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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
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Recommendations for the PCP
• 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
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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?
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Selected Etiologies of Low Birth Weight
• HTN
• Smoking
• Alcohol
• Cocaine/crack abuse
• Physical/mental abuse
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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
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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)
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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
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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
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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)
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Cocaine and Fetal Outcomes
01020304050
3-D Column 2
SprauveCalhoun
BatemanCherukuri
% o
f pa
tien
ts
Preterm
IUGR
LBW
Controls
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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
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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
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Estimates of Abuse During Pregnancy
0
5
10
15
20
25
Bullock McFarlane Helton Hillard Campbell
% o
f pa
tien
ts
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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%
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(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
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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
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Recommendations for the PCP
• 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
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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
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Summary of Recommendations for the PCP
• 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
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Summary of Recommendations for the PCP
• 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
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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
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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)
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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
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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
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(Mis)classification schemes
• 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
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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)
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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
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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)