PEARLS FROM PREGNANCY

1
PEARLS FROM PREGNANCY

• April 2002
• Karen M. Chacko, MD

2
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?

3
Gestational Diabetes Mellitus

• Formerly, every woman had 50 g OGTT done at 24-28
  weeks
• New (January 1999) ADA criteria exempt women lt25
  years old, BMI lt27, no FHx, not Hispanic /Native
  American /Asian /African American /Pacific
  Islander
• GDM complicates 4 of pregnancies

4
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 IGT
• 16 classified as Diabetic
• IGT patients become diabetic at a rate of 1-5
  per year

5
Follow-up of GDM

• Greenberg, contd
• Three predictive variables
• insulin requirements
• poor glycemic control (2 hr pp gt150)
• 50g OGTT value (gt200)
• If insulin requirements were gt100 units/day, 100
  of these women had an abnl. 6 week postpartum OGTT

6
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

7
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

8
Glycemic Control and Malformations

• Lucas (1989)correlated A1C at lt16 weeks gestation
  to rate of malformations
• HgbA1C none major minor
• gt10 64.7 11.8 23.5
• 8.0-9.9 87.1 4.8 8.1
• lt7.9 95.2 1.6 3.2

9
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)

10
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?

11
Preeclampsia and Pregnancy

• Preeclampsia risk factors include
• Hypertension Extremes of Age
• Primigravid state Family History
• Obesity Renal Disease
• Diabetes mellitus Smoking (?)
• Hypercoagulable state Interbirth Interval

12
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)

13
Preeclampsia and Factor V Leiden
of Patients
Lindoff
Dizon-Townson
14
Preeclampsia and Hypercoagulable States
Dekkar
15
Complicated Pregnancies and Hypercoagulable States
Kupferminc 1999
16
Factor V and fetal loss
of patients
17
Fetal Loss and Hypercoagulable States
of patients
Martinelli 2000
18
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
  PT2.8

19
Hypercoagulability and Recurrent Fetal Loss

• Foka contd
• 1st trimester 2nd trimester
• Factor V 14.7 31.5
• PT 8.1 10.5

20
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)

21
Recommendations for the PCP

• Perform a directed hypercoagulable workup in
  women with a history of severe/early-onset/recurre
  nt preeclampsia, stillbirths, fetal loss,
  abruption, IUGR
• With regards to miscarriage/stillbirth, primary
  considerations should be lupus anticoagulant, PT,
  and Factor V

22
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?

23
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

24
(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 postpartum
• 54 with biopsy compatible with preeclampsia
  alone
• 25 primips incorrectly diagnosed
• 65 multips incorrectly diagnosed

25
(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 lt80 for 3 consecutive days)
• 110 women with preeclampsia
• mean of 16 days pp to normalization
• If gt50 days pp with elevated BP, reclassify as
  chronic HTN

27
Progression to Chronic Hypertension

• Adams (1961) avg 20 years of follow-up
• systolic gt140 diastolic gt90
• severe preecl. 43 40
• mild/PIH 58 60
• normotensive 26 21
• nulliparous 41 35

28
Progression to Chronic Hypertension
of patients
29
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)

30
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-value
• none 3.0 lt0.01
• cigarettes 3.8 lt0.01
• HTN 2.8 lt0.02
• OCPs 2.8 lt0.02
• all 2.8 lt0.05

31
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

32
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?

33
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

34
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

35
Factor V and VTE

• Hellgren (1995) women with DVT or PE during
  pregnancy (n34), OCP use (n28), and controls
  (n75)
• 20/34 (59) of pregnant women with h/o
  thrombosis with Factor V Leiden
• 9/28 (32) of women on OCPs with thrombosis with
  Factor V Leiden
• 10 of controls with Factor V Leiden

36
Pregnancy-related VTE

• Grandone (1998)
• 42 patients with DVT in pregnancy vs. 213
  controls
• coexistence ofgt1 mutation in 21.4

of patients
37
Pregnancy-related VTE

• Gerhardt 2000
• 119 women with VTE during pregnancy or
  puerperium, 223 controls

38
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

39
Factor V and VTE

• Vandenbroucke (1994) 155 women with DVT and 169
  controls without DVT
• 35/155 (23) of women with DVT have Factor V
  Leiden mutation vs. 6/169 (3.5) of controls
• 109/155 (70) women on OCPs or with usage within
  the 6 months prior to DVT
• RR 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)

40
DVT and Factor V

41
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

42
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

43
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

44
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?

45
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

46
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

47
Who is at risk for PPT?

• Mestman (1999), Gerstein (1993)
• previous pregnancy with PPT
• presence of antimicrosomal Ab
• FHx of thyroid disease
• TSH gt2 at 12 weeks gestation
• prior autoimmune disease, especially Type 1 DM
• HLA haplotypes assoc. with Hashimotos

48
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)

49
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
• plt0.005

50
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)

51
Incidence of Ongoing Hypothyroidism
of patients
52
Treatment- PPT

• Hyperthyroid phase - nothing or beta-blockers
• Hypothyroid phase - often requires treatment with
  L-thyroxine, wean after 6 months therapy and
  recheck TSH

53
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

54
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?

55
Selected Etiologies of Low Birth Weight

• HTN
• Smoking
• Alcohol
• Cocaine/crack abuse
• Physical/mental abuse

56
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

57
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 (plt0.001)

58
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

59
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

60
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)

61
Cocaine and Fetal Outcomes
Preterm

IUGR
LBW
Controls
of patients
Sprauve
Bateman
Calhoun
Cherukuri
62
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

63
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

64
Estimates of Abuse During Pregnancy
of patients
65
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 gt1 time per patient or in the
  third trimester range 7.4-20.1

66
(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

67
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 lt0.02
• private/lbw 17.5 4.2 lt0.001
• public/lbw 10.0 9.6 NS

68
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/drug
  s
• Ask more than once

69
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

70
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

71
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

72
(No Transcript)
73
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

74
Case contd

• 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)

75
Case contd

• 11 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

76
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

77
(Mis)classification schemes

• Ihle (1987) 84 pts. with early-onset
  preeclampsia 24 hr urine, U/A, lytes, biopsy (if
  rbcs), IVP
• 67 of primips had underlying renal
  abnormalities
• 63 of multips had underlying renal abnormalities

78
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)

79
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

80
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)