Medical Disorders of Pregnancy

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Medical Disorders of Pregnancy

• Hassan A Shehata MRCOG MRCPI
• Consultant Obstetrician, Gynaecologist
  Obstetric Physician
• Epsom St. Helier University Hospitals NHS Trust
• St. Heliers Hospital 3 October 2006

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CEMACH 2002-2004 Breakdown of direct causes
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CEMACH 2002-2204 Breakdown of indirect causes
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CEMACH 2002-2004 Leading Causes of Death
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Diabetes - Classification
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Effect of pregnancy on DM

• Normal pregnancy
• Fall in fasting BG
• Rise in post-prandial BG
• Insulin resistance relative glucose intolerance
• Glucose tolerance decrease with increasing
  gestation due to hPL, glucagon cortisol
• Renal threshold for glucose falls
• Rise in insulin requirements x 2
• Deterioration in nephropathy (reversible)
• Two fold risk of progression of retinopathy

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CEMACH 2006

• Women in UK with pre-existing (type 1 or type 2)
  diabetes are poorly prepared for pregnancy
• The recent CEMACH report highlighted the fact
  that across the country, only 1 in 3 women were
  documented as receiving any kind of preconception
  counselling or having a preconception HbA1c
  measurement
• The level of uptake of folic acid supplements
  before conception was very poor (39) which is
  particularly concerning given the increased risk
  (3.4-fold) of neural tube defect
• Even amongst those take folic acid, few were
  prescribed the higher dose (5mg) as recommended
  by the National Service framework (NSF) Diabetes

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Type 2 DM

• Previous reports of type 2 diabetes being
  perceived as far less common in women of
  childbearing age as well as less serious
  condition
• However, it has become increasingly apparent that
  both these perceptions are mistaken
• The prevalence of type 2 diabetes in young people
  is increasing and accounts for over a 1/4 of
  pregnant women with pre-existing diabetes and in
  some parts of the country including London this
  rises to 45
• Over-representation of black, Asian and other
  minority groups (49 compared with only 9 of
  women with type 1 diabetes) and a strong
  association with social deprivation
• It is now clear that adverse pregnancy outcomes
  are as common in women with type 2 diabetes as
  those with type 1 diabetes
• Risk of perinatal mortality and congenital
  malformation are equivalent and babies of women
  with type 2 diabetes are more likely to be large
  in size for gestational age and delivered pre-term

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Feto-maternal blood glucose relationships

• Glucose crosses the placenta by a process of
  facilitated diffusion
• Fetal plasma glucose levels are similar to those
  of the mother
• Fetal insulin secretion occurs from 10 weeks
  gestation
• There is a brisk fetal insulin response to raised
  plasma glucose levels in diabetic pregnancy
• Sustained fetal hyperglycaemia secondary to
  maternal hyperglycaemia can result in fetal
  ?-cell hyperplasia

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HbA1c

• Level is raised in diabetes
• Reflects diabetic control over the previous 2 or
  3 months
• Estimation has proved a valuable additional aid
  to be on the look-out for major congenital
  abnormalities

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Effect of pre-existing DM on pregnancy

• Increased risk of congenital abnormalities
• Increased perinatal mortality
• late unexplained intrauterine death
• Increased risk of pre-eclampsia
• Increased perinatal morbidity
• Prematurity
• Macrosomia

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Congenital Abnormalities

• 2 - 4 fold increase ie. 10 risk
• Directly related to glycaemic control
• Correlated with HbAIC
• Very small risk if HbAIC lt 50 above upper limit
  of normal
• Sacral agenesis
• CHD
• Skeletal / NTD

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Perinatal Mortality

• IUD is rare
• Related to fetal acidaemia
• Related to maternal BG
• Cannot predict with
• biophysical profile
• CTG
• Umbilical artery Doppler

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Perinatal Morbidity
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Management of DM in Pregnancy

• Pre-pregnancy counselling
• Combined clinic (single physician obstetrician)
• HBGM with meter
• Aim for normoglycaemia
• fasting 4-6 mmol/l
• 1 hr pp 4-8 mmol/l
• 2 hrs pp 4-7 mmol/l
• Diet /- Insulin
• Monitor control of IDDM with HbA1C
• Glucagon kit for IDDMs
• Screen for retinopathy

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Pre-pregnancy counselling (PCC)

• Optimize glycaemic control
• Risk of major congenital malformations is
  increased x 3/4.
• Risk correlates with HbA1C.
• Assess presence / severity of complications
• Hypertension
• Retinopathy
• Nephropathy
• Stop oral hypoglycaemics

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PCCContraindications to pregnancy in DM

• Ischaemic Heart Disease
• Untreated proliferative diabetic retinopathy
• Hypertension and severe renal impairment (Cr gt
  250)
• Severe gastroparesis

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Obstetric Management

• Ultrasound
• to detect congenital abnormalities
• to assess fetal growth / polyhydramnios
• Screen for pre-eclampsia
• Timing of delivery
• Risk of IUD vs. risk of RDS
• Risk of macrosomia and shoulder dystocia vs. CS
• 38 - 40 weeks
• Caution with steroids and beta-sympathomimetics

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Intrapartum and postpartum care

• Continuous FHR monitoring
• IV dextrose and variable IV insulin
• BG 5-8 mmol/l
• Halve rate of insulin post partum
• Pre-pregnancy insulin SC dose when eating
• Prophylactic antibiotics if CS
• Neonatal BG 4 hours
• Feed neonate early

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Recommendations

• Plan pregnancy
• Pre-pregnancy counselling
• Tertiary centre / joint clinic / diabetes nurse
  specialist / diabetes midwife/ dietician
• Monitor using post-prandial BGs
• Basal bolus insulin regimen
• Monitor fetus and time delivery
• Post-pregnancy counselling

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Hyperthyroidism

• Prevalence in pregnancy is up to 0.2
• Graves disease - up to 90 of cases
• Untreated - dangerous for mother baby

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Hyperthyroidism - Clinical Features

• Many of the typical features are common in normal
  pregnancy
• Discriminatory features include weight loss,
  tremor, a persistent tachycardia, lid lag and
  exophthalmos
• If thyrotoxicosis occurs for the first time in
  pregnancy, it usually presents late in the first
  or early in the second trimester.

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Normal ranges for TFT in pregnancy
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Hyperthyroidism - Effect of Pregnancy

• Thyrotoxicosis often improves during pregnancy
  especially in the second and third trimesters.
• Exacerbations may occur in the first trimester,
  possibly related to hCG production, and in the
  puerperium

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Hyperthyroidism - Effect on Pregnancy

• If severe and untreated, it is associated with
  inhibition of ovulation and infertility
• Higher incidence of miscarriage, placenta
  abruption, pre-term delivery and PET
• Neonatal hyperthyroidism, prematurity,
  intrauterine growth retardation, fetal death and
  stillbirths
• Poorly controlled thyrotoxicosis may lead to a
  thyroid crisis (storm) in the mother and heart
  failure, particularly at the time of delivery.
• The possibility of retrosternal extension of a
  goitre which can cause tracheal obstruction

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Hyperthyroidism - Diagnosis

• A raised free T4 or free T3. Normal pregnant
  ranges for each trimester must be used
• TSH is suppressed, although this may be a feature
  of early pregnancy.
• Differentiation from hyperemesis gravidarum may
  be difficult

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Hyperthyoidism - Management

• Graves disease often improves, flares postpartum
• CBZ (up to 15mg) PTU (up to 150mg) cross
  placenta
• ?-Blockers are safe
• Thyroidectomy is rarley necessary-
• Who fail to achieve euthyroidism
• intolerant to drugs
• with dysphagia or stridor related to a large
  goitre
• with confirmed or suspected thyroid malignancy

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Hypothyroidism

• Prevalence is in the order of 1
• Commonest is autoimmune destructive thyroiditis
• Untreated - associated with infertility,
  miscarriage and fetal loss

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Hypothyroidism - Clinical Features

• Features are common in normal pregnancy
• Discriminatory features in pregnancy are cold
  intolerance, slow pulse rate and delayed
  relaxation of the tendon (particularly the ankle)
  reflexes.
• It is associated with other autoimmune diseases,
  for example, pernicious anaemia, vitiligo and
  type-I diabetes mellitus

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Hypothypidism - Diagnosis

• Low free T4.
• The TSH is raised, although this may be a feature
  of normal late pregnancy, or occasionally early
  pregnancy
• The finding of thyroid autoantibodies may help
  confirm the diagnosis, but these are present in
  10-20 of the population and should not be used
  in isolation

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Hypothypidism - Effect of Pregnancy

• Pregnancy itself probably has no effect on
  hypothyroidism
• If the dose does need to be increased in
  pregnancy, this is usually because of inadequate
  replacement prior to pregnancy

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Hypothypidism - Effect on Pregnancy

• Severe and untreated - inhibition of ovulation
  and infertility.
• Those who do become pregnant and remain untreated
  have an ? rate of miscarriage, fetal loss, PET
  LBW
• An association between untreated hypothyroidism
  in the mother and reduced IQin the offspring.
• With adequate replacement, the maternal and fetal
  outcome is usually good

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Hypothyroidism - Management

• Small amounts of thyroxine cross the placenta -
  fetus is not at risk
• Most will be on maintenance doses of thyroxine of
  100-150 ug/day
• Euthyroid women will not usually require any
  adjustment to dose
• TFT should be checked in all women, ideally
  pre-conceptually, or at least during the first
  trimester
• Replacement with thyroxine should begin
  immediately
• With adequate replacement, thyroid function
  should be checked once in each trimester

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Epilepsy Effect of Pregnancy

• About 1/3 of women experience an increased
  frequency of fits
• Poorly controlled epileptics are more likely to
  detriorate
• In most (54) , the frequency of fits is not
  altered

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Epilepsy Effect on Pregnancy

• There is no increased risk of miscarriages
• The fetus is relatively resistant to short
  episodes of hypoxia
• The risk of the child developing epilepsy is
  increased (4)
• Teratogenic effects of anticonvulsants

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Epilepsy - Anticonvulsants

• All cross the placenta and are teratogenic
• Not much difference in the risk of the four
  principle AEDs
• Background risk 3
• Untreated epileptic 4
• 1 drug 7
• 2 or more drugs 15
• Val carb phenytoin 50

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Epilepsy - Management

• Assess need for treatment
• Optimize control treat patient not drug level
• Monotherapy if possible
• Counsel re teratogenesis
• Give folate 5 mg / day

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Migraine

• It can occur as a pregnancy-related phenomenon
  without any prior history
• Pre-existing migraine (50-80) often improves in
  pregnancy
• Hemiplegic migraine may mimic TIA
• Ergotamine, sumatriptan pizotifen should be
  avoided
• Low-dose aspirin, beta-blockers, tricyclic
  antidepressants calcium antagonists may be used
  for prophylaxis

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Asthma Effect of Pregnancy

• May improve, deteriorate or remain unchanged
• Mild disease unlikely problems
• Possible postnatal deterioration
• Deterioration of disease is commonly caused by
  reduction or cessation of medication

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Asthma Effect on Pregnancy

• Mostly no adverse effects
• Severe, poorly controlled asthma may adversely
  affect the fetus
• No association with PET, prem. labour, LBW, IUGR
  and neonatal morbidity

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Asthma - Management

• Treatment differs little from Mx in non-pregnant
  patient
• Education and reassurance concerning the safety
  of asthma medications
• Inhaled, oral and intravenous steroids and
  inhaled, nebulized and intravenous beta-agonists
  are safe
• Do not withold a chest X-ray if necessary

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Physiological changes of thrombotic/fibrinolytic
system

• Increase in levels of factors VIII, IX, X and
  fibrinogen
• Decrease in fibrinolytic activity
• Decrease in antithrombin III and protein S
• Venodilation and decreased flow in lower limbs
  leads to venous stasis

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Pulmonary Embolism (PE)

• PE is the major cause of maternal death
• 3 of direct deaths
• 1.4 deaths per 100,000 maternities
• 35 women died from TED in 1997-9
• 31 PE 4 cerebral thrombosis
• 13 antenatally (8 in 1st trimester)
• 17 postnatally (7 after Caesarean, 10 after
  vaginal delivery

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Acute Episodes - ? PE

• Chest X-ray
• Arterial blood gas analysis
• pO2 - 13 kPa (100mmHg) standing, 11kPa
  (83mmHg) supine
• pCO2 - 4 kPa (30mmHg)
• SO2 drop by gt 6mmHg
• Electrocardiography
• V/Q scan or spiral CT
• D dimers not helpful
• Thrombophilia screen

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Estimated radiation to the fetus and excess risk
of childhood cancer following common diagnostic
procedures

• Estimated radiation to the fetus
  (mGy) Probability of fatal cancer to
• age 15y
• Conventional X-ray
• Chest 0.01 lt1 in 1000,000
• Pelvis 1.1 1 in 300,000
• Skull 0.01 lt1 in 1000,000
• Spine 1.7 1 in 20,000
• Computerized Tomography
• Chest (inc. spiral) 0.06 1 in 560,000
• Pelvimetry 0.2 1 in 170,000
•  
• Nuclear Medicine
• Lung perfusion (Tc 99m) 0.2 1 in 170,000
• Lung ventilation (Tc 99m) 0.3 1 in 110,000

Childhood fatal malignancy background risk is
1650,000
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V/Q scan Spiral CT
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Pathological MRI specimen
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TED - Mx

• If DVT or PE is diagnosed or strongly
  suspected, anticoagulation with heparin should
  be commenced
• Therapeutic-dose i.v. heparin or LMWH for 12
  weeks
• Then prophylactic LMWH for up to 6 weeks
  postpartum or longer (total of 6 months)

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Drug transfer

• Most drugs have a molecular weight below 1000
  daltons (D)
• Drugs ? 1000 D cross the placenta (? 600 D cross
  easily)
• Main determinant of the drug concentration in the
  embryo/fetus is the mother's blood concentration
• Other factors-
• lipid solubility protein binding
• degree of ionization at physiologic pH
• placental blood flow surface area available for
  transfer

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• The processes that govern the passage of a
  drug into milk are similar to the placenta

• maternal serum concentration is the main
  determinant
• the milk pH is slightly acidic in comparison to
  serum pH so weak bases could become trapped in
  milk (ion trapping)

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Type of Effects

• Teratogenicity (i.e. thalidomide) - readily
  detected at, or shortly after, birth
• Long term latency (i.e. DES - increased risk of
  vaginal adenocarcinoma after puberty, or
  abnormalities in testicular function and semen
  production)
• Impaired intellectual or social development (i.e.
  exposure to phenobarbitone- alters programming of
  brain)
• Predisposition to metabolic diseases (i.e. Barker
  hypothesis - low birthweight associated with
  increased risk of diabetes, hypertension, heart
  disease in adulthood)

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Teratogenesis

• It is defined as structural or functional (e.g.
  renal failure) dysgenesis of the fetal organs
• Typical manifestations include
• congenital malformations with varying severity
• intrauterine growth restriction
• carcinogenesis
• fetal demise
• In humans, the critical time for drug-induced
  congenital malformations is in the first
  trimester
• Drug-induced toxicity can occur at any time
  during gestation

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Malformations

• The overall incidence of
• major congenital malformations is around 2-3
• minor malformations is 9
• It has been estimated that
• 25 are due to genetic or chromosomal
  abnormalities
• 10 due to environmental causes including drugs
• 65 of unknown aetiology
• The part played by drugs is probably small

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Organogenesis

• The critical time for drug-induced congenital
  malformations is usually the period of
  organogenesis
• about 20 to 55 days after conception
• about 34 to 69 days after the first day of the
  LMP
• Interference in this process causes a teratogenic
  effect
• If a drug is given after this time it will not
  produce a major anatomical defect, but more of a
  functional one

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Timing of the development of major body
structures in the embryo and fetus Hanretty KP
et al. Identifying abnormalities. In Rubin PC,
ed. Prescribing in pregnancy, 2nd ed. London BMJ
Publishing 1995 8-21
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Pregnancy risk categories - FDA

• Category A Controlled human studies have
  demonstrated no fetal risk levothyroxin
• Category B Animal studies indicate no fetal
  risk, OR animal studies suggest a potential for
  harm, but no well-controlled human studies
  paracetamol
• Category C No adequate human or animal studies
  OR potential fetal effects in animal studies, but
  no available human data - theophyllin
• Category D Evidence of fetal risk, but benefits
  outweigh risks - ACE inhibitors
• Category X Evidence of fetal risk. Risks
  outweigh any benefits - statins, vitamin A
  analogues

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Contraindicated drugs
Absolute Relative
Cytotoxic Busulphan, Cyclophosphamide, Methotrexate Vitamin A analogues Etretinate, Isotretinoin Thalidomide Cardiovascular drugs Angiotensin-converting-enzyme inhibitors, Losartan, Amiodarone Antibiotics Ciprofloxacin, Chloramphenicol (3rd trimester), Vancomycin, Trimethoprim (1st trimester) Antifungal drugs Griseofulvin, Ketoconazole, Fluconazole, Itraconazole, Terbinafine Anti-inflammatory drugs NSAIDs (3rd trimester), COX-2 inhibitors, Colchicine Endocrinological drugs DES, Chlorpropamide, Sulphonylureas Radioactive iodine, Sex hormones, Octreotide Antihelminthic drugs Mebendazole Cytotoxic Azathioprine Psychotropic drugs Antipsychotic drugs - Lithium Anticoagulants Warfarin Anticonvulsants Carbamazepine, Phenytoin, Sodium valproate, Lamotrigine, Felbamate, Gabapentin, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin Endocrinological drugs Carbimazole, Propylthiouracil Cardiovascular drugs Beta-blockers Antibiotics Aminoglycosides, Nitrofurantoin (3rd trimester)
Shehata HA, Nelson-Piercy C. Drugs in pregnancy.
Drugs to avoid. Best Pract Res Clin Obstet
Gynaecol. 2001 15(6)971-86
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Natural Remedies

• Black Cohosh
• used for treating symptoms of PMS
• can produce uterine contractions
• Chamomile
• used in inflammation of the skin, mouth, throat
  colds
• contains hydroxycoumarin, which is a relative of
  the coumarin anticoagulants
• Ma Huang / Ephedra
• used for treating sinus congestion, cold and
  "natural weight-loss treatment
• over 1000 reports of potential adverse
  occurrences have been registered with the FDA
  regarding cardiovascular events
• adverse events have included kidney stones and
  hepatic injury

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Natural Remedies

• Quinine
• used for treating malaria, muscle cramps, fever,
  GIT disturbances
• has been used as a drug to promote abortion
• should be avoided during pregnancy because of a
  risk for causing miscarriage or stillbirth
• Iodides
• can be purchased in some remedies for treating
  symptoms of a cold or the flu
• can cause fetal thyroid gland dysfunction when
  used after 1st trimester
• St. John's Wort
• a very weak antidepressant
• not recommend during pregnancy due to its
  uterotonic effects
• no side effects were observed in infants during
  breastfeeding

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Elicit Drugs

• amphetamines, and heroin, according to a 2003
  study by the CDC and Prevention
• These and other illicit drugs may pose various
  risks for unborn babies and pregnant women
• Some of these drugs can cause a baby to be born
  too small or to have withdrawal symptoms, birth
  defects, or learning or behavioral problems
• However, because most pregnant women who use
  illicit drugs also use alcohol and tobacco (which
  also pose risks to unborn babies), it often is
  difficult to determine which health problems are
  caused by a specific illicit drug

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Cocaine

• Increase the risk of miscarriage
• preterm labour or IUGR
• Increased risk of lifelong disabilities such as
  mental retardation and cerebral palsy
• Cocaine-exposed babies also tend to have smaller
  heads, which generally reflect smaller brains
• Some studies suggest that cocaine-exposed babies
  are at increased risk of birth defects, including
  urinary-tract defects and, possibly, heart
  defects
• Cocaine also may cause an unborn baby to have a
  stroke, which can result in irreversible brain
  damage or a heart attack, and sometimes death.
• placental abruption
• Feeding difficulties and sleep disturbances,
  jittery and irritable.
• Greater chance of dying of sudden infant death
  syndrome (SIDS).

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Marijuana

• IUGR. These effects are seen mainly in women who
  use marijuana regularly (6 or more times a week)
• Premature delivery
• After delivery, some babies undergo
  withdrawal-like symptoms including excessive
  crying and trembling
• Couples who are planning pregnancy also should
  keep in mind that marijuana can reduce fertility
  in both men and women, making it more difficult
  to conceive
• Some did not find any increased risk of learning
  or behavioral problems, however, others found
  children are more likely to have subtle problems
  that affect their ability to pay attention and to
  solve visual problems
• Exposed children do not appear to have a decrease
  in IQ

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Ecstasy amphetamines

• The use of Ecstasy has increased dramatically in
  recent years. To date there have been few studies
  on how the drug may affect pregnancy
• One small study did find a possible increase in
  congenital heart defects and, in females only,
  clubfoot
• Babies exposed to Ecstasy before birth also may
  face some of the same risks as babies exposed to
  other types of amphetamines
• Methylamphetamine, also known as speed, ice,
  crank and crystal meth may cause an increased
  risk of birth defects, including cleft palate,
  and heart and limb defects
• Contribute to maternal high blood pressure 
  IUGR, premature delivery, and PPH
• After birth, babies who were exposed to
  amphetamines appear to undergo withdrawal-like
  symptoms, including jitteriness, drowsiness and
  breathing problems.

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Heroin

• Common complications include miscarriage,
  placental abruption, poor fetal growth, premature
  rupture of the membranes, premature delivery and
  stillbirth
• Low birthweight and serious prematurity-related
  health problems during the newborn period,
  including breathing problems and brain bleeds,
  sometimes leading to lifelong disabilities
• Most babies of heroin users suffer from
  withdrawal symptoms after birth, including fever,
  sneezing, trembling, irritability, diarrhea,
  vomiting, continual crying and, occasionally,
  seizures
• Babies exposed to heroin before birth also face a
  ten-fold increased risk of sudden infant death
  syndrome (SIDS)

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Heroin

• A pregnant woman who uses heroin should not
  attempt to suddenly stop taking the drug as this
  can put her baby at increased risk of miscarriage
  or premature birth
• She should consult a doctor or drug treatment
  center about treatment with methadone
• Although infants born to mothers taking methadone
  also may show some signs of dependence on the
  drug, they can be safely treated in the nursery
  and generally do far better than babies born to
  women who continue to use heroin
• Some studies suggest that children exposed to
  heroin before birth are at increased risk of low
  IQ (in the mentally retarded range) and of
  serious behavioral problems

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Teratogen Information Services

• United Kingdom
• National Teratology Information Service (NTIS)
• Newcastle [phone]
• United States
• Organization of Teratology Information Services
• Utah [phone] (for referral to nearest
  service)
• World Wide Web address http//orpheus.uscd.edu/ct
  is/
• Canada
• Motherisk Program
• Toronto [phone]
• World Wide Web address http//www.motherisk.org

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Thank you !