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February 2011 Pre-eclampsia
“A common human-specific disease of pregnancy characterised by novel and
progressive hypertension and proteinuria after 20 weeks gestation.”
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February 2011 Clinical features• Hypertension
• Proteinuria
• Fetal growth restriction
• Abdominal pain
• Headaches
• Visual scotoma
• Deranged LFTs
• Thrombocytopenia
• Haemolysis
• DIC
• Hyperreflexia
• Seizures
• Renal failure
• Death
εκ-λαμψια
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February 2011Demographic and clinical risk factors
1. Older mothers (>40 years, RR=2)2. Primigravidae (RR=3)3. Previous pre-eclampsia (RR=7)4. Family history of pre-eclampsia (RR=3)5. Obesity (BMI>35, RR=4)6. New sexual partner7. Diabetes mellitus (RR=4)8. Chronic hypertension (40x higher prevalence in cases)9. Chronic kidney disease10. Thrombophilia11. Connective tissue diseases (RR=6)12. Multiple pregnancies (RR=3)
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February 2011 Diagnosis
• No gold standard diagnostic test
• No (reliable) animal models
• Variable diagnostic criteria used
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February 2011Diagnosis
International Society for the Study of Hypertension in Pregnancy (ISSHP, 2001)
Research definition
De novo hypertension (systolic blood pressure >140mmHg, diastolic blood pressure >90mmHg) after 20 weeks’ gestation plus proteinuria (greater than 300mg/d or protein:creatinine ratio >30mg/mmol).
Clinical definition
As above but “in the absence of proteinuria the disease is highly suspect when increased blood pressure is accompanied by:
• 2-8% of pregnancies– 32,000 affected pregnancies/year in UK– 6,500,000 affected pregnancies/year
worldwide
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February 2011 Epidemiology
• Directly led to the death of 18 mothers in the UK from 2002-2005
• Implicated in 135 stillbirths in the UK in 2006
Lewis.G editor. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: Reviewing maternal deaths to make motherhood safer - 2003-2005. London: CEMACH; 2007
Acolet D editor. Confidential Enquiry into Maternal and Child Health (CEMACH) Perinatal Mortality 2006: England,Wales and Northern Ireland. London: CEMACH; 2008
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February 2011 Epidemiology
Directly implicated in 68,000 maternal deaths per year
worldwide.
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February 2011Treatment of pre-eclampsia
Deliver the fetusand placenta
Serial monitoringof fetal growth
Blood pressurecontrol
Clinical surveillanceof impending
eclampsia or HELLP
Magnesiumsulphate + betamethasone
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February 2011Prevention of pre-eclampsia
What is the pathological process?
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February 2011Prevention of pre-eclampsia
Geneticpredisposition
Immunologicaldysfunction
Abnormalplacentation
Endothelialdysfunction
Coagulationabnormalities
Cardiovascularmaladaptation
Abnormaltrophoblast
invasion
Decreaseduteroplacental
perfusion
Disorderedendothelinmetabolism
Cytokines and growth factors
Cardiovascularor renal disease
ADMA / nitric oxideimbalance
Imbalancedprostaglandinmetabolism
Relaxin/metalloprotease-2
deficiency
Anti-AT2 IgG
Anti-cardiolipinIgG and IgM
Anti-spermatazoaantibodies
STOX-1mutation
ACEpolymorphisms
NOSpolymorphisms
TNF-α
IL-6
IL-1α
Fasligand VEGF PlGF
s-Flt-1
Endoglin
COMT deficiency
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February 2011Prevention of pre-eclampsia
Diuretics
Progesterone
Vitamin C and E
GTN
Calcium supplements
GarlicAspirin
L-arginine
Vitamin B6
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February 2011Prevention of pre-eclampsia
Calcium supplements Systematic review
14949 women
All women
52% relativerisk reduction
High risk women
78% relativerisk reduction
Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst.Rev. 2006 Jul 19;3:CD001059.
Dietary calcium is adequate in most patients.Supplementation only recommended with dietary insufficiency
Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG 2007 Aug;114(8):933-943.
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February 2011Prevention of pre-eclampsia
AspirinSystematic review
37560 women
All women
17% relativerisk reduction
High risk women
25% relativerisk reduction
NNT = 72 NNT = 19
Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst.Rev. 2007 Apr 18;(2)(2):CD004659.
Patients die from fluid overloadPatients don’t die from kidney failure
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February 2011What’s new in pre-eclampsia?
Angiogenic factors
Podocyturia
Predicting pre-eclampsia
Biomarkers
Laboratory Imaging
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February 2011Angiogenic factors and pre-eclampsia
Gene expression profiling of placental tissue from women
with and without pre-eclampsia (PE)1
Up-regulation of soluble fms-like
tyrosine kinase-1(s-Flt-1)1
s-Flt-1 increased in serum in PE2
s-Flt-1 increased in urine in PE3
Binds to VEGF and Placental Growth Factor (PlGF) antagonising their function
Serum PlGF decreased in PE2 Urine PlGF decreased in PE3
1 Maynard S, Min J-Y et al. J. Clin. Invest 2003;111:6492 Levine RJ, Maynard SE et al. NEJM 2004;350:672
3 Buhimsci CS, Magloire L et al. Obstet Gynecol 2006;107:1103
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sVEGF-R1
sFlt-1
sVEGF-R1
sFlt-1
VEGF
VEGF
VEGF-R1
Flt-1VEGF-R2
Flk-1
VEGF-R2
sVEGF-R1
sFlt-1
Survival, migration and differentiation of
endothelial cells
Tyrosine kinase
No signal
VEGF
VEGFVEGF
PlGF PlGF
PlGF
Activation of VEGF-R2 by transphosphorylation
Displacement of VEGF from inactive receptors
Destabilise inactive VEGF-R heterodimers
Endothelial cell
VEGF-R1
Placenta
Normal pregnancyPre-eclampsia
AngiogenesisAnti-angiogenesis
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February 2011Other supportive evidence
s-Flt-1
Hypertension Proteinuria
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February 2011Other supportive evidence
Hypertension Proteinuria
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February 2011Other supportive evidence
…in humans?
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Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J.Matern.Fetal.Neonatal Med. 2008 Jan;21(1):9-23.
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February 2011Diagnosis of pre-eclampsia will change
International Society for the Study of Hypertension in Pregnancy (ISSHP, 2001)
Research definition
De novo hypertension (systolic blood pressure >140mmHg, diastolic blood pressure >90mmHg) after 20 weeks’ gestation plus proteinuria (greater than 300mg/d or protein:creatinine ratio >30mg/mmol).
Clinical definition
As above but “in the absence of proteinuria the disease is highly suspect when increased blood pressure is accompanied by:
50% of patients with pre-eclampsiahave no risk factors
90% of patients with risk factorsdo not develop pre-eclampsia
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February 2011Current clinical practice
Demographic and clinical risk factors Frequent monitoring
Aspirin
Uterine artery doppler(20-24 weeks)
High risk – 14.4%
No uterine artery notch – 9.2%Uterine artery notch – 30%
Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization Systematic Review of Screening Tests for Preeclampsia. Obs. Gynecol. 2004;104(6),1367-1391
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February 2011Predicting pre-eclampsia
Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization Systematic Review of Screening Tests for Preeclampsia. Obs. Gynecol. 2004;104(6),1367-1391
“As of 2004,there is no clinically usefulscreening test to predict
the developmentof pre-eclampsia.”
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February 2011Combining biomarkers
Giguère Y, Charland M, Bujold E et al. Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review. Clin Chem 2010;56(3):361-374
PlGF + PAPP-A + PI + mean arterial pressure + “multiple maternal demographic factors”@ 11-13 weeks
Sensitivity 93%Specificity 95%
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011Combining biomarkers
Giguère Y, Charland M, Bujold E et al. Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review. Clin Chem 2010;56(3):361-374
“Numerous papers have been published on potential biomarkers for identifying women predisposed to
development of PE before the onset of clinical symptoms…
…new tests that will contribute to better predictive performance characteristics of a PE-risk model need to be
developed.”
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
A two stage pathological process
0 5 10 15 20 25 30 35 40 weeks
Impairedtrophoblastinvasion of
myometrium
Poor spiralartery adaptation
Placentalischaemia
Abnormalimplantation
Clinical manifestationsof pre-eclampsia
Generalisedmaternal
endothelialdysfunction
Systemic release ofpro-inflammatory
and antiangiogenicmediators
Hypertension Proteinuria
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011Participants
155 patients assessedfor eligibility
129 patients enrolled
126 patients provided≥ 1 urine sample
27 were excluded16 identified as chronic hypertension7 declined consent2 identified as diabetes mellitus1 leaving country during pregnancy
A renal biopsy during pregnancy should be considered for which of the following:
1. De novo nephrotic syndrome at 37 weeks2. Persistent invisible haematuria, urine PCR 55
mg/mmol and serum creatinine 99 µmol/l from booking3. Severe de novo hypertension and proteinuria at 26
weeks4. ANCA positive, oliguric AKI with blood and protein and
a creatinine of 446 µmol/l at 33 weeks5. BP 141/89, urine blood ++, protein ++, creat 131
µmol/l, ANA +ve, dsDNA +ve at 23 weeks
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011 Question 6
What is the chance of a woman with serum creatinine 200 µmol/l at conception needing dialysis within a year of pregnancy?
1. 1 in 6
2. 1 in 5
3. 1 in 4
4. 1 in 3
5. 1 in 2
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011 Question 7
A woman on PD thinks she might be pregnant. Serum βHCG is equivalent to an 8 week old fetus. Ultrasound scanning does not show a fetal heart rate as expected. What advice should be given?
1. Molar pregnancy likely – requires hysteroscopy and curettage
2. Measure serum alfa-fetoprotein3. Repeat serum βHCG and ultrasound in 1 – 2 weeks4. Diagnosis of missed abortion – consolation5. Explain βHCG is elevated in ESRD
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011 Question 8
A 32 year old with asthma, previous depression and diabetic nephropathy develops gestational hypertension. Which treatment is most appropriate?
You are asked to see a 26 year old following her first pregnancy which ended in severe pre-eclampsia yesterday at 35 weeks. She is oliguric and creatinine has climbed from 121 to 158 µmol/l in 24 hours. CVP is 4 mmHg and BP 185/83 mmHg on labetalol 200mg bd. Renal ultrasound shows mild left hydronephrosis.
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011 Question 9You are asked to see a 26 year old following her first pregnancy which
ended in severe pre-eclampsia yesterday at 35 weeks. She is oliguric and creatinine has climbed from 121 to 158 µmol/l in 24 hours. CVP is 4 mmHg and BP 185/83 mmHg on labetalol 200mg bd. Renal ultrasound shows mild left hydronephrosis.
What is the most appropriate management plan?
1.Ask how the baby is and repeat bloods in 6 hours
2. Oral magnesium glycerophosphate 2 tabs bd3. Aspirin 75mg od4. Nephrostomy left kidney5. IV colloid 500ml stat followed by 0.9% sodium
chloride – 1000ml/4 hours
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011
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February 2011 Question 10
How are babies made?
1. Nobody knows
2. When a mummy and a daddy love each other very much they give each other a special kiss
3. By a woman sitting on a seat warmed by a man’s bottom