Name : Tejal R Lakhan

MSc Biostatistics and Demography

CASE CONTROL STUDY

MACMOHAN’S 1981 STUDY OF COFFEE AND PANCREATIC CANCER

Brian MacMahon (1923 2007) was a British American epidemiologist who chaired the Department of Epidemiology at Harvard from 1958 until 1988.

In 1981, he published a paper in the New England Journal of Medicine, a case control study on coffee drinking and pancreatic cancer.

The study concluded that "coffee use might account for a substantial proportion of the cases of this disease in the United States."

WHO WERE CASES AND CONTROLS ?

The cases were patients with a histologically confirmed diagnosis of pancreatic cancer in 11 Boston and Rhode Island hospitals from 1974 to 1979.

Controls were the patients with other diseases who were hospitalized by the same physicians who had hospitalized the cases.

One finding in this study was an apparent dose response relationship between coffee drinking and cancer of the pancreas.

When such a relationship is observed , it is difficult to know whether the disease is caused by the coffee drinking or by some factor closely related to coffee drinking.

Because smoking is a known risk factor for the cancer of the pancreas.

And because coffee drinking is closely related to cigarette smoking .

The authors analysed the data after stratifying for smoking history.

The relationship with coffee drinking held both for current smokers and for those who had never smoked .

The association was not affected by controlling for cigarette use.

What MacMohan and co-workers found was that the level of coffee drinking in cases was greater than the level of coffee drinking in controls.

The investigators would like to be able to establish that the level of coffee drinking observed in the controls is what would be expected in the general population without pancreatic cancer .

And cases demonstrate excessive coffee drinking .

But the problem is :

Which physicians are most likely to admit patients with cancer of pancreas to the hospital ?

Gastroenterologists are often the admitting physicians.

Many of there other hospitalized patients ( who served as controls ) also have gastrointestinal problems.

The persons who served as controls may very well have reduced their intake of coffee, either because of a physician’s instructions or because of their own realization that reducing their coffee intake could relieve their symptoms.

Thus, the observed difference in coffee drinking between pancreatic cancer cases and controls may not necessarily have been the result of cases drinking more coffee than expected , but rather of the controls drinking less coffee than expected.

MacMohan and his colleagues subsequently repeated their analysis but separated controls with gastrointestinal illness from controls with other conditions .

They found that the risk associated with coffee drinking was indeed higher when the comparison was with controls with gastrointestinal illness but that the relationship between coffee drinking and pancreatic cancer persisted, at a lower level ,even when the comparisons was with controls with other illness.

MacMahon's group, failed to confirm the association

When a difference in exposure is observed between cases and controls , we must ask whether the level of exposure observed in the controls is really the level expected in the population in which the study was carried out or whether perhaps given the manner of selection .

The controls may have particularly high or low level of exposure that might not be representative of the level in the population in which the study was carried out.

CONCLUSION

COHORT STUDY

DUTCH FAMINE STUDY ( EFFECTS OF STARVATION )

The winter of 1944–45 is known as the ‘Hunger Winter’ in The Netherlands, which was occupied by the Germans in May 1940.

It was a famine that took place in the German-occupied part of the Netherland, especially in the densely populated western provinces north of the great rivers, during the winter of 1944-45, near the end of World War 2.

HISTORYDespite the war, nutrition in The Netherlands had generally been adequate up to October

1944.

Thereafter, food supplies became increasingly scarce.

By November 26, 1944. Widespread starvation was seen especially in the cities of the western Netherlands.

Food supplies were restored immediately after liberation on May 5, 1945.

On the basis of these historical data it was possible to accurately define the beginning and the end of the famine period

The famine affected fertility, weight gain during pregnancy, maternal blood pressure, infant size at birth and central nervous system development.

The reduction in fertility was greater among manual workers than among those in other occupations.

A decline in mean birth weight of 300 g was seen among those exposed to maternal undernutrition during the third trimester.

the famine created what can be regarded as a ‘natural experiment’ in which exposure to famine is assigned based on an individual's time and place of birth.

This design was used to examine how maternal undernutrition during specific gestational time windows may affect the subsequent life course of offspring who experienced the famine in-utero.

What does the study cover?The primary aims of the study are

(i) to examine whether changes in maternal nutrition in pregnancy affect the risk among offspring for metabolic and cardiovascular disease in adulthood.

(ii) to identify critical time windows of pregnancy at which fetal programming might occur.

(iii) to document to what extent the time windows of prenatal programming might differ with respect to the adult risk of Type 2 diabetes mellitus, blood pressure and obesity and

(iv) to validate the performance of selected morphological measures of the hand (e.g. fingertip ridge-count differences and digit-length ratios) as specific markers of disturbances in early gestation. The study also included measures of other outcomes of interest such as cognitive status and depressive symptoms.

Who is in the sample? 3307 live-born singleton births at three institutions in famine-exposed cities (the

midwifery training schools in Amsterdam and Rotterdam and the university hospital in Leiden) were identified.

(i) all 2417 births between February 1, 1945 and March 31, 1946 (infants whose mothers were exposed to the famine during or immediately preceding that pregnancy) and

(ii) a sample of 890 births from 1943 and 1947 as time controls (infants whose mothers did not experience famine during this pregnancy). The sample of controls included an equal number of births for each month, allocated across the three institutions according to their size.

At the time the large majority of deliveries (70% or more) were scheduled to occur at home.

The client mix at the two midwifery schools consisted of low-risk pregnancies to women of lower socioeconomic status whose home environment was unsuitable for delivery.

The client mix in Leiden also included higher-risk pregnancies identified during prenatal care and emergency admissions following complications of labour or delivery.

Whenever possible, we also enrolled a same-sex sibling of each member of the birth series as controls. For participants recruited as siblings, no information from prenatal or delivery records is available.

How often have they been followed up?

Members of the study population were traced to their current address in 2003. A telephone interview and medical examination were conducted in 2003–05.

What has been measured?

Birth records

They extracted the following information from the pregnancy and delivery medical records:

mother's and infant's names; address; age at delivery; occupation; religion; last menstrual period (LMP); gravidity and parity; lifetime number of spontaneous abortions; date of first prenatal visit; weight, height and blood pressure at prenatal visits; date and time of delivery; maternal postpartum weight (two clinics only): obstetrical presentation; mode of delivery; sex; birth weight; crown-to-heel length; head circumference; placental weight (two clinics only) and vital status at discharge. Abstraction of records of the 3307 birth records was completed in May 2003.

They submitted the names and addresses at birth to the local population registers with a request to provide a current address. They then invited by mail all traced members of the birth cohort to participate in the study.

they conducted a telephone interview, followed by a clinical examination at the Leiden University Medical Center. All study protocols and materials for data collection were approved by the human subjects committees of all the participating institutions.

Participants provided oral consent at the start of the interview and written informed consent at the start of the clinical examination for all study procedures.

Telephone InterviewThe telephone interview included questions on sociodemographic

characteristics and socioeconomic status.

In addition, they collected information on health and reproductive history, on current health status, on prevalent medical conditions such as stroke and cardiac problems, on high blood pressure and on diabetes.

They also collected information on smoking and drinking habits. For selected conditions, participants were asked for information on their parents and siblings.

Clinical examinations

Participants were asked to fast overnight before a morning appointment; over 95% complied with this request.

On their arrival at the clinic, they first obtained written informed consents for study examinations and blood collection and storage, including consent for later study of DNA.

They then measured blood pressure with an automated blood pressure monitor with digital readout, recorded three successive electrocardiogram (ECG) readings and drew a blood sample to obtain fasting measures of lipids, glucose and insulin.

a standardized food frequency questionnaire.

a physical activity questionnaire.

a neuropsychological test battery for cognitive function , visual verbal learning, colour scale performance (Stroop), and verbal fluency . a quality-of-life assessment .

Upon completion, all questionnaires were checked by study staff and participants were asked to provide missing information where necessary.

All collected study information was entered twice into a database (double entry keypunching) and any discrepancies were resolved by re-checking against the original coding sheets.

In all, they completed the clinical examination in 94% (971/1031) of the people interviewed by telephone.

Full details of causes of attrition for eligible participants to interview and clinical examinations, together with comparisons of perinatal characteristics between those who were included in these follow-up data collections and those who could not be are provided below.

Defining exposure to the famineTo define exposure to the famine for all selected participants, they have

used an ecological measure to classify stage of gestation in relation to the available food rations.

Although maternal nutrition in pregnancy cannot be ascertained at the individual level, evidence for the impact of the famine on morbidity and mortality at the population level is abundant. With regard to nutrition in pregnancy, they have shown that many women actually lost weight in pregnancy.

Exposure by date of last menstrual period

They used the date of last menstrual period (LMP) listed on the birth record to define the start of gestation unless it was missing or implausible (12%).

Exposure by date of birth

In contrast to this prospective approach, in most studies of the Dutch famine to date, prenatal exposure to famine has been defined relative to date of birth

It was found that the children of pregnant women exposed to famine were more susceptible to diabetes , obesity, cardiovascular disease, and other health problems.

Moreover, the children of the women who were pregnant during the famine were smaller, as expected. However, surprisingly, when these children grew up and had children those children were thought to also be smaller than average .

The discovery of the cause of coeliac disease may also be partly attributed to the Dutch famine. With wheat in very short supply there was an improvement at a children's ward of Coeliac patients. Stories tell of the first precious supplies of bread being given specifically to the (no longer) sick children, prompting an immediate relapse.

Thus in the 1940s the Dutch paediatrician was able to corroborate his previously researched hypothesis that wheat intake was aggravating Coeliac disease. Later Dicke went on to prove his theory.

Audrey Hepburn spent her childhood in the Netherlands during the famine and despite her later wealth she had lifelong negative medical repercussions. She suffered from anaemia, respiratory illnesses, and edima as a result. Also, her clinical depression later in life has been attributed to malnutrition.

Subsequent academic research on the children who were affected in the second trimester of their mother’s pregnancy found an increased incidence of schizophrenia in these children .Also increased among them were the rates of schizotypal personality and neurological defects.

Strengths and weaknessesExposure

With archived records of the weekly food rations distributed in the affected areas, there is no need to use birth weight as a proxy measure of maternal nutrition in pregnancy.

In this study, they assigned exposure based on the date of mothers’ LMP from the birth record, adjudicated where necessary.

Study population

They have shown that normally the loss to follow-up is low (11% or less) when infants are traced from their famine birth records to their current address in The Netherlands .

Sibling controls

These controls were chosen to reduce the potential for bias related to family-level factors with an effect on health outcomes that is independent of the exposure of interest.

This is important in light of the strong associations between socioeconomic status of the family and fertility during the famine, with stronger declines in fertility among manual vs non-manual occupations.

Intermediary variables over the life courseAlthough extensive recorded information is available from the time of birth

and from the time of examination , there is no source for intermediary data points except for the individual interview, in which we ascertained recalled weight at age 20 and 30 and collected a medical history.

Within The Netherlands health care system, well baby clinic records were collected for all study participants and reports from annual school health examinations were collected through adolescence that included height, weight and selected medical problems.

COHORT STUDY

National Birthday Trust - Report of the Confidential Enquiry into Home Births

This is probably the most comprehensive study of home birth ever undertaken in the UK.

It attempted to follow all women who booked a home birth in the UK in 1994.

Midwives recorded outcomes for 5971 women who were booked for home births at 37 weeks' gestation, and they tried to find a matching woman from their practice who was as similar as possible to the home birth mother, but was booked to deliver in hospital. In some cases an appropriate matching hospital booking could not be found, so the hospital group only contained 4724 women.

The women were matched for age (within 5 yrs), number of previous children, where they lived, and past obstetric history.

Thus, low-risk mothers were compared with other low-risk mothers, and the overall sample in the home birth group could be accurately compared to that in the matching group. The overall group profile was low-risk.

For all outcomes, planned home births were compared with planned hospital births, so the data for planned home births include those births which occurred at home, and transfers to hospital. Separate data for transfers is also provided.

First-time mothers made up 16% of the group, whilst 84% were expecting second or subsequent children. Mothers who had a previous Caesarean made up 1% of the home birth group, and 3% of the hospital group.

Possible Bias

Women planning home births tend to be more educated and more affluent than those in the hospital group, which would make them slightly lower-risk

The home birth group had less incidence of high blood pressure at 37 weeks,

and the birth - which could be because midwife antenatal care was less stressful than hospital antenatal care, but could also be because women who developed high blood pressure before 37 weeks (and transferred their booking to the hospital) would not be included in the home birth group, but would possibly be included in the hospital group .

The Labour/BirthPlanning a home birth halved the chances of mothers in this study having

assisted or caesarean births. The overall rate of these events was very low, because mainly only low-risk women booked for a home birth.

The authors note that 'The hypothesis that social and environmental factors can affect progress of labour and mode of delivery is strongly supported by experimental evidence. A systematic review of randomized controlled trials shows that continuous professional support during labour is associated with a reduced incidence of Caesarean section and instrumental delivery. In the light of this evidence it is easy to accept that some women may labour better in their own homes.

Home births, including transfers, were less likely to involve post-partum haemorrhage. Home birth mothers had fewer episiotomies but more first-degree perineal tears. Second-degree tears occurred at the same rate in both groups. All cervical tears occurred in the hospital group.One set of twins were born at home, with no complications; one was cephalic and the other breech.

Planned home births

Planned hospital births(including transfers)

Spontaneous vaginal delivery 94.70% 90.20%

Assisted (forceps, ventouse) 2.40% 5.40%

Caesarean 2.00% 4.10%

Previous Caesareans, Home Deliveries and Previous Assisted Deliveries

Of the women planning home birth who had given birth before, 9.7% had previous assisted deliveries and 1.4% (53 women) had previous caesareans. The transfer rate amongst the previous assisted delivery group was 15.6%, and among the previous caesarean group it was 28%; so 72% of these women had a home deliveries.

The study does not give data on the proportion of the women with previous caesareans who had another caesarean after transfer, but the overall caesarean rate for women transferred from home to hospital was 11.2% .

Transfer Rates

16% of women booked for a home birth transferred to hospital, 60% of first-time mothers who had planned to deliver at home, did so, and 40% transferred. 90% of multigravida who had planned to deliver at home, did so, and 10% transferred.

Some of these transfers occurred before labour actually started, whilst others occurred in labour. The single largest reason for transfer was slow or no progress, accounting for 37.2% of transfers. Premature rupture of membranes accounted for 24.8% of transfers, and most of these occurred before labour started. Foetal distress accounted for 14.8% of transfers. There was one cord prolapse.

The number of mothers and babies who transferred was 769 this group included two stillbirths and two neonatal deaths.

The transferred home births had the worst outcome rate of all three categories (planned and born at home, planned and born in hospital, planned home but born hospital) for labour interventions and condition of the baby. Clearly, as transfer generally only occurs if there is a problem, this group would be the highest-risk component of the study.

Pain Relief Women who planned a home birth were much less likely to use drugs for

pain relief, than women who planned a hospital birth. The drugs most commonly available at home births in the UK are Entonox , and Pethidine . In some areas these substances are taken routinely to all home births, and in others they are available only on request.

The table shows the forms of pain relief used, as reported by midwives. It's also worth remembering that what one midwife might report as 'relaxation', another might report as 'no pain relief'

Pain ReliefPlanned home

Planned hospitalHome births Transfers from

overall (born at home) home to hospital

Drugs Entonox 52.60% 72.10% 50.10% 65.80%

Pethidine/Demerol 7.50% 30.30% 4.30% 23.70%

Epidural 2.8% (all transfers) 11.30% 0 17.90%

Spinal Block 0.70% 1.30% 0 4.10%

Non-drug methods

Relaxation 49.00% 30.10% 50.30% 43.10%

TENS 22% 15.40% 20.60% 28.80%

Warm water 24.40% 8% 24.50% 24%

Aromatherapy 5.20% 0.90% 5.20% 5.10%

Homeopathy 3.40% 0.30% 3.30% 4%

Acupuncture 0.60% 0 0.50% 0.90%None 17.10% 8.60% 18.80% 7.90%

The BabyBabies planned for home birth were less likely to be in bad condition (low APGAR score) at birth,

even including those transferred to hospital.

At 1 minute, 5.2% of the planned home babies had APGAR scores below 7, compared to 9.3% of the planned hospital babies.

At 5 minutes, 0.7% of both groups had scores below 7.

Babies planned for home birth were less likely to have any of these interventions.

Again, the rate for transfers was slightly higher than the rate for planned hospital births, but the overall planned home birth rate was lower.

The most common birth injury was bruising, which affected 0.6% of the planned home babies and 1.4% of the planned hospital babies.

The overall rate of stillbirths and neonatal deaths was very low for the whole study - 5 stillbirths and neonatal deaths in the 5,971 planned home births and 5 in the 4,724 planned hospital births, compared to the national rate of 8 per 1,000 births. The researchers concluded that the death rate in both groups was too low to allow meaningful comparison between the two groups.

Planned home Planned hospital

Suctioned 11.30% 18.00%

Bag and mask 5.60% 9.10%

Intubation 0.60% 0.80%

Baby feeding

Exclusive breastfeeding rates 48 hours after birth were 80% in the home birth group and 58.1% in the planned hospital group; six weeks later, the figures were 65% and 44.

However, breastfeeding rates for the transferred home births were almost identical to the home deliveries in all categories, including the mother's assessment of whether the first feed went well. The transferred mothers and babies had the most difficult deliveries on average, so this suggests a high level of commitment from these women to breastfeed despite the circumstances.